Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10](=[O:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=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)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(Cl)Cl.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(=O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(C(O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reaction time: 1 h

Procedure:
To a solution of the product from Step G (8.89 g, 18.4 mmol) in methanol (200 mL)/methylene chloride (50 mL) at 0° C. was added sodium borohydride (695 mg, 18.4 mmol). After stirring for 1 hour, the reaction was quenched by the addition of sat. aq. NH4Cl until H2 evolution ceased. The solvents were removed in vacuo and the residue was partitioned between methylene chloride (200 mL) and water (200 mL). The layers were separated and the aqueous layer was washed with methylene chloride (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [CH:1]([CH2:3][C:4](O)=[O:5])=[CH2:2].OC1C2N=NNC=2C=CC=1.Cl.[NH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1>ClCCl>[C:4]([NH:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1)(=[O:5])[CH2:3][CH:1]=[CH2:2]
Reactant: C=CCC(=O)O
Reactant: COC(=O)c1ccc2occ(CCN)c2c1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: C=CCC(=O)NCCc1coc2ccc(C(=O)OC)cc12
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Vinylacetic acid (1 mmol), 1-ethyl-3-(3-dimethylaminopropyl-3-ethyl)carbodiimide hydro-chloride (E.D.C.) (1.1 mmol) and hydroxybenzotriazole (HOBT) (1.1 mmol) are dissolved in dichloromethane (30 ml) in a flask cooled to −20° C. After 30 minutes, the compound obtained in Step A of Example 63 (1 mmol), dissolved in dichloromethane (20 ml), is added dropwise. The reaction mixture is stirred for 30 minutes at −20° C. and then overnight at ambient temperature. The dichloromethane is evaporated off and the residue is purified by chromatography on a silica gel column.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.[Br:38][CH2:39][CH2:40][CH2:41]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:38][CH2:39][CH2:40][CH2:41][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[C:14]([F:13])=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:37])=[CH:16]4)=[CH:25][N:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
DEAD (0.47 ml, 2.95 mmol) was added dropwise to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.5 g, 1.47 mmol), (prepared as described in Example 4), 3-bromopropan-1-ol (0.2 ml, 2.21 mmol) and triphenylphosphine (0.78 g, 2.95 mmol) in DMF (10 ml). The mixture was stirred for 1 hour at ambient temperature and the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1). The fractions containing the expected product were combined and evaporated to give 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (0.6 g, 88%) (purity 80%; contaminated by some triphenylphosphine oxide).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:13].N1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>ClCCl>[Br:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12](=[O:13])[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:32]
Reactant: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1NC(=O)CBr
Reaction time: 3 h

Procedure:
To a solution of (2-Amino-5-trifluoromethyl-phenyl)-(5-chloro-2-methoxy-phenyl)-methanone (IV) (14.13 g, 42.9 mmol, 1 eq) in Dichloromethane (120 mL) at 0° C. was added pyridine (4.65 mL, 57.5 mmol, 1.34 eq), then Bromoacetyl bromide (4.98 mL, 57.2 mmol, 1.33 eq). After 3 h, the reaction was quenched with Sodium bicarbonate (aq) and extracted three times into Dichloromethane. The combined organic layers were dried over Magnesium sulfate, filtered and concentrated in vacuo. The product was used without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:17]=3[NH:16][C:15]2=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:25][C:24]1[C:17]2[NH:16][C:15](=[O:26])[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:20][CH2:19][C:18]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2c(F)cccc2CCN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2c(F)cccc2CCN1C1CCNCC1

Procedure:
13.7 g (38.8 mmol) 3-(1-benzyl-piperidin-4-yl)-9-fluoro-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 100 mL MeOH were shaken with 2.00 g palladium on charcoal (Pd/C 10%) under a hydrogen atmosphere (3 bar) at RT. The catalyst was filtered off and the solvent was evaporated down. The residue was purified by flash chromatography. The fractions containing the product were combined and evaporated down. The residue was stirred with DIPE/EtOAc, suction filtered and dried.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:23]12[NH:30][CH:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]([NH:31][C:32]1[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[CH:35]3)[CH2:24]2>ClCCl>[CH2:1]([N:30]1[CH:27]2[CH2:28][CH2:29][CH:23]1[CH2:24][CH:25]([NH:31][C:32]1[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=1)[NH:37][N:36]=[CH:35]3)[CH2:26]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC(C1)N2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2C3CCC2CC(Nc2ccc4[nH]ncc4c2)C3)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 52 %

Procedure:
Benzaldehyde (37 μl, 0.364 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol) were added to a suspension of the N-(8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (73 mg, 0.301 mmol) obtained in Example 525 in dichloromethane (1 ml), and the resulting mixture was stirred at room temperature for 25 hours. The reaction was terminated by the addition of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was washed with cold methanol and collected by filtration to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-indazol-5-amine (52 mg, 52%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:14])(=[O:3])[CH3:2].[H-].[Na+].Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][CH:13]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[O:14][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[O:8]
Reactant: COC(=O)C(C)Br
Reactant: COC(=O)c1cccc(C(C)=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(C)=O)c1OC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
5.3 g of methyl 3-acetylsalicylate are dissolved in 50 ml of dimethylformamide and the solution is added dropwise to a suspension of 1.26 g of 62.5% sodium hydride in 15 ml of dimethylformamide, and the mixture is stirred for 20 minutes. 5.40 g of methyl 2-bromo-propionate are added dropwise to the mixture and the mixture is heated at 60°-80° C. for 7 hours. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1) to give 5.10 g of methyl 2-(2-methoxycarbonyl-6-acetylphenoxy)propionate as colorless oil.
Reaction SMILES: I[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.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.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[CH2:19]([NH:26][C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2c1ccnc2I
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2c1ccnc2NCc1ccccc1
Temperature: 120 °C
Yield: 76.4 %

Procedure:
A mixture of tert-butyl 5-iodo-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (5 g, 13.8 mmol), benzylamine (1.776 g, 16.6 mmol), bis(dibenzylideneacetone)palladium (397 mg, 0.79 mmol), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (858 mg, 1.38 mmol), and sodium tert-butoxide (2.65 g, 27.6 mmol) in dioxane (50 mL) was heated to 120° C. for 16 h under nitrogen. The mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc v/v 1:1) to give tert-butyl 5-(benzylamino)-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (3.6 g, 76% yield) as a yellow solid. ESI MS: m/z 342 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]([CH3:11])=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26](S(C)(=O)=O)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]([CH3:11])=[CH:5][C:4]=3[C:3]=2[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[N:25]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1cc2c(C(=O)OCc3ccccc3)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3[nH]c(C)cc3c2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A mixture comprising 2.2 g of benzyl 5-hydroxy-2-methylindol-4-carboxylate, 1.7 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.3 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at a temperature of from 70° to 80° C. for two hours. The mixture was returned to room temperature, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from isopropyl ether to obtain 2.8 g (yield: 85%) of the desired product. mp: 135°-139° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([OH:15])[CH:14]=1)[CH:10]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>C(O)(=O)C>[S:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:10]1[C:9]1[CH:12]=[C:13]([OH:15])[CH:14]=[C:7]([OH:6])[CH:8]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cc(O)cc(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1cc(O)cc(-c2nc3ccccc3s2)c1
Yield: 48.8 %

Procedure:
An acetic acid (0.8 mL) and sodium acetate (196.6 mg, 2.40 mmol) were added to a suspension including 3,5-dihydroxybenzaldehyde (91.6 mg, 0.66 mmol) and 2-aminothiophenol (0.095 mL, 0.80 mmol, purity: 90%), and then, the reaction mixture was refluxed for 2 hours. The resultant precipitate was filtered, and the filtered product was washed with water and methylene chloride to obtain a gray solid Compound 21 (78.3 mg, 48.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (1.016 g, 3.35 mmol) in anhydrous DCM under N2 atmosphere was added 1 M TiCl4 (in DCM, 6.7 mL, 6.7 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (1.374 g, 7.37 mmol) dropwise. The resulting mixture was stirred for another 24 h after the addition. The reaction mixture was poured into ice-water (100 g), stirred for a while and filtered through a pad of Celite. The filtrate was extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-2-phenylchroman-4-ylidene)cyanamide as light brown solid (899 mg), which was used in the next step without further purification. MS ESI+ve m/z 327 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(Oc3ccc([N+](=O)[O-])cc3)c2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A mixture of 1.00 g (3.94 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate, 0.56 g (3.94 mmol) of 1-fluoro-4-nitrobenzene, 0.16 g (3.94 mmol) of 60% sodium hydride and 30 ml of dimethylformamide was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice water. The mixture was then extracted with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1.25 g of ethyl 4-chloro-1-methyl-7-(4-nitrophenoxy)-2-indolecarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](N)[S:9][C:10]=1[CH3:11])=[O:5])[CH3:2]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N)sc1C
Solvent: C1CCOC1
Product: CCOC(=O)c1ncsc1C
Yield: 68.2 %

Procedure:
In a 3-neck round bottom flask mix 2-amino-5-methyl-thiazole-4-carboxylic acid ethyl ester (62.9 g, 338 mmol) and THF (630 mL). Heat to reflux and treat the reaction mixture with isoamyl nitrile (52.6 g, 60.1 mL, 449 mmol) dropwise. Upon completion of the addition, stir the reaction at reflux for 1 h, then concentrate the reaction mixture by rotavap (hi-vac) to give 70 g crude product as a thick orange oil. Purify on silica gel (400 g, 20-45% EtOAc/hexanes) to afford 39.47 g (68%) of the title compound as a yellow solid. LC-ES/MS m/z 172 (M+1), TR=1.5 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:39]#[N:40]>C1COCC1>[C:39]([C:38]1[CH:37]=[C:36]([NH:35][C:15]([C@@:11]2([CH:18]([CH3:19])[CH3:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10]2)=[O:16])[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=1)#[N:40]
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C#N)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (25 mg, 0.091 mmol) and methanesulfonyl chloride (9 μL, 0.12 mmol) in THF (0.9 mL) at 0° C. was added diisopropylethylamine (0.047 mL, 0.27 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-amino-5-(trifluoromethyl)benzonitrile (34 mg, 0.18 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC, which failed to provide the desired product in sufficient purity. To a solution of the crude mixture (14 mg) in 2 mL THF was added aqueous NaOH (3 mL, 1.0 M) and the solution was stirred at 50° C. overnight. The following day, the solution was quenched with 10% HCl, partitioned with ethyl acetate, and the organic layer was separated. The organics were subsequently dried with sodium sulfate, concentrated in vacuo, and purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 10.28 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.04-7.17 (m, 3H), 3.99 (d, J=11.2 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 3.05 (d, J=17.2 Hz, 1H), 2.70 (d, J=17.2 Hz, 1H), 2.38 (septet, J=6.8 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 0.98 (t, J=6.8 Hz, 6H). LC-MS Rt (retention time): 2.81 min; MS: (ES) m/z 444 (M+H+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:16]=[C:15]([Cl:25])[CH:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]2([C:21]([F:24])([F:22])[F:23])[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=3)[CH2:20]2)[CH:16]=[C:15]([Cl:25])[CH:14]=1
Reactant: Cc1ccc(C(Cl)=NO)cc1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1

Procedure:
A solution of 4-methylbenzaldehyde oxime (2 g) and N-chlorosuccinimide (2.17 g) in dimethylformamide (20 mL) was stirred for one hour at 55° C. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over-anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-hydroxy-4-methylbenzene carboximidoyl chloride (2 g). A solution of resultant N-hydroxy-4-methylbenzene carboximidoyl chloride and 1,3-dichloro-5-[1-(trifluoromethyl)-vinyl]benzene (5.3 g) in toluene (50 mL) was heated to reflux for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain [5-(3,5-dichlorophenyl) 3-(4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (5.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[F:24])[CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Compound 4i was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 32 mg (0.12 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one 3d, 6 mg (0.14 mmol) of 60% sodium hydride and 26 mg (0.14 mmol) of 2-fluorobenzyl bromide were combined in 0.5 mL N,N-dimethylformamide and stirred at rt for 2 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. The HPLC fractions containing pure product were lyophilized to give 43 mg of a pale yellow solid 4i as trifluoroacetate salt: LC-MSD, m/z for C24H19FN2O2 [M+H]+=387.5, HPLC retention time: 1.8 min; 1H NMR (400 MHz, CDCl3): δ 2.5 (s, 3H), 2.8 (s, 3H), 5.7 (s, 2H), 7.1-7.2 (m, 3H), 7.3-7.4 (m, 1H), 7.5-7.6 (m, 1H), 7.6-7.7 (m, 1H), 7.7-7.8 (m, 1H), 8.1-8.2 (m, 1H), 8.5-8.6 (m, 1H), 9.05 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:17]([C:16]1[CH:15]=[C:14]([CH:21]=[CH:20][CH:19]=1)[O:13][C:4]1[CH:3]=[C:2]([CH3:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])=[O:18]
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)c1
Yield: 35.4 %

Procedure:
4-Methyl-2-nitrobenzonitrile (0.50 g, 3.1 mmol), 3-hydroxybenzaldehyde (0.38 g, 3.1 mmol) and cesium carbonate (1.00 g, 3.1 mmol) were heated with stirring in dry DMF (5 mL) at 80° C. for 28 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 0.1N sodium hydroxide solution (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-phenoxy)-4-methyl-benzonitrile (0.26 g, 36%) as a brown resin, and was carried forward without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Reactant: Cn1c(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccc(Cl)cc2)n1C
Yield: 53.17 %

Procedure:
3-Benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-07) (290.0 mg, 53.17%) was synthesized as a light yellow solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-07) (500.0 mg, 1.08 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).