Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH2:50]>C(Cl)Cl>[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH:50][C:13](=[O:15])[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:17])[CH3:16]
Reactant: CC1(C)CCC(C)(C)C1N
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NC1C(C)(C)CCC1(C)C
Reaction time: 48 h

Procedure:
To a stirred solution of N-Cbz-2-aminoisobutyric acid in dry CH2Cl2 containing dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethyl-1-cyclopentyl amine dissolved in CH2Cl2. After stirring for 48 hours, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and is evaporated to yield N-Cbz-2-aminoisobutyric acid 2,2,5,5-tetramethylcyclopentyl amide.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][C:12]=1[C:13]#[N:14].C(N(CC)CC)C>CC#N>[Cl:10][C:11]1[N:18]=[C:17]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[C:16]([F:20])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 82 °C
Yield: 72 %

Procedure:
A solution of 5-cyclopropyl-1H-pyrazol-3-amine (1.9 g, 16.0 mmol) in CH3CN (20 ml) was added dropwise to a solution of 2,6-dichloro-5-fluoronicotinonitrile (3.0 g, 16.0 mmol) and triethylamine (2.1 g, 20.0 mmol) in CH3CN (80 ml) at 25° C. The resulting solution was heated to 82° C. for 18 hrs, and then cooled to 25° C. The resulted precipitate was collected by filtration and washed with CH3CN (100 ml) to give the title compound (3.2 g, 73%). MS: Calcd.: 277. Found: [M+H]+ 278.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH3:12].[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(CC)CC)C>ClCCl>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[CH3:12])[CH2:17][CH2:16]1)[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1CBr
Reactant: CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2C)CC1

Procedure:
A solution of 1 g (3.78 mmol) 1-bromomethyl-2-methyl-4-nitro-benzene, 0.539 ml (4.16 mmol) 1-ethylpiperazine and 0.63 ml (4.54 mmol) triethylamine in 15 ml dichloromethane is stirred at room temperature for 0.5 h. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, 100% EtOAc=>EtOAc:MeOH=7:3) to afford the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Reaction time: 8 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate (10 g, 0.03 mol), ethyl acetate (800 mL) and platinum on carbon catalyst were combined in a Parr bottle and then the mixture was hydrogenated overnight. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum to provide 9.1 g of 1,1-dimethylethyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a yellow syrup. Analysis: Calculated for C15H21N5O2+0.1 CH3CO2C2H5: %C, 59.25; %H, 7.04; %N, 22.43; Found: %C, 58.96; %H, 6.87; %N, 22.46.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[C:23]([NH:28]C(=O)OC(C)(C)C)[CH:22]=3)=[O:18])=[C:11]([F:36])[C:10]=1[O:37][C:38]1[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:28][C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[C:19]([C:17]([NH:16][CH2:15][C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([O:37][C:38]4[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=4)[C:11]=3[F:36])=[O:18])[NH:20]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(N)cc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of 1,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-6-yl)carbamate (0.046 g, 0.081 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by column chromatography (dichloromethane/methanol) to give the title compound (0.037 g, 74%) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H), 9.35 (br. s., 2H), 9.04 (s, 1H), 7.80 (s, 1H), 7.63 (d, 1H), 7.44-7.54 (m, 3H), 7.38 (t, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 6.88 (d, 1H), 4.55 (d, 2H). MS: m/z 548 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[C:11](Br)(Br)([Br:13])[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[C:11]([Br:13])[Br:12]
Reactant: O=Cc1c(Cl)cccc1I
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1cccc(I)c1C=C(Br)Br

Procedure:
Chloro-2-(2,2-dibromo-vinyl)-3-iodo-benzene was prepared from 2-chloro-6-iodo-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; MS (EI): 425.8 (5%), 423.8 (20%), 421.7 (46%) and 419.7 (18%) (M+), 344.9 (30%), 342.8 (100%) and 340.8 (90%) ([M-Br]+), 263.9 (5%) and 261.9 (25%) ([M-2Br]+), 218.0 (9%), 216.0 (50%) and 214.0 (35%) ([M-Br])+).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[N:19]=3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[O:22][N:21]=[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[N:19]=3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1nc(Cc3ccc(Cl)cc3)no1)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 72 h

Procedure:
A solution of 8-chloro-1-(3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.18 g, 0.34 mmol) in DMF (5 ml) was degassed by sequential evacuation of the flask and admission of nitrogen (×3) and morpholine (0.5 ml, 5.8 mmol), and Pd(PPh3)4 (80 mg, 0.068 mmol) added. The solution was stirred for 72 h then concentrated and the residues loaded onto an aminopropyl SPE (10 g) with MeOH. Elution with MeOH followed by 5% AcOH/MeOH provided the title compound as a pale yellow solid, which was washed with ether to yield a white solid (0.053 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 45 %

Procedure:
The titled compound (34 mg) was prepared in 45% yield from trans-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 1-bromomethyl-4-trifluoromethyl-benzene according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.77 (d, 2 H, J=8.0 Hz), 7.65 (d, 2 H, J=8.0 Hz), 7.57 (m, 3 H), 7.45 (d, 2 H, J=12.0 Hz), 7.35 (s, 1 H), 6.80 (s, 1H), 4.44 (AB2,2 H,ΔV=16,Jab=84 Hz), 4.01 (m, 1 H), 1.39 (m, 8 H); MS m/e 475.04 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH2:12].[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=O.C(N(CC)CC)C.[Na]>CO>[ClH:1].[CH3:2][O:3][C:4](=[O:14])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:13])[CH2:11][NH:12][CH:16]1[CH2:15][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1
Reactant: O=C1Cc2ccccc2C1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CN
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 37 %

Procedure:
Glycyl-L-proline methylester hydrochloride (16.0 g, 72.1 m mole) was dissolved in methanol (150 ml), and Indan-2-on (4.75 g, 36.0 m mole) and triethylamine (1.8 g, 18.0 m mole) were added thereto. Sodium syanoborohydride (2.27 g, 36.0 m mole) was gradually added thereto while cooling with ice and stirring. The mixture was stirred for 1 hour while cooling with ice and next for 5 hours at room temperature. A little insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. To the residue, water (100 ml) and ethyl ether (100 ml) were added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring to dissolve it. The ethyl ether layer was removed, and the remaining water layer was washed with ethyl ether (100 ml). The desired product was extracted from the water layer with chloroform (100 ml×3 times). The thus obtained chloroform as extracted was concentrated under reduced pressure. To thus produced tar-like residue ethyl ether and 5% sodium bicarbonate (200 ml) were added and the mixture was stirred to dissolve the solid matter. The aqueous layer was removed and the ethyl ether layer was washed with aqueous solution saturated with sodium chloride. To the ethyl ether layer water (150 ml) was added, and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring and ethyl ether was removed. The water layer was washed with ethyl ether (100 ml) and to the water layer chloroform (200 ml) was added. The solution was adjusted to pH 8.0 with sodium bicarbonate while stirring. The aqueous layer was removed, and chloroform layer was dried with anhydrous sodium sulfate, and the sodium sulfate was sepa rated by filtration. Separately, anhydrous hydrogen chloride gas was brown into the chloroform, and thus obtained hydrogen chloride chloroform solution was added to the above mentioned chloroform layer. After checking the solution acidic enough, the chloroform was removed off under reduced pressure, to yield N-(2-indanyl) glycyl-L-proline methylester hydrochloride (4.50 g, 13.3 m mole, yield: 37%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]O>S(=O)(=O)(O)O>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:2]=1[OH:1]
Reactant: CC(C)c1cccc(C(=O)O)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)C)c1O
Temperature: 45 °C

Procedure:
To a solution of 2-hydroxy-3-isopropylbenzoic acid (4.5 g, 25 mmol) in MeOH (75 mL) is added 10 drops of sulfuric acid and the mixture is heated in an oil bath at 45° C. for 18 h. Extra sulfuric acid (10 drops) is added and the mixture is heated again at 60° C. for 18 h. Solvent is evaporated under reduced pressure and the residue is dissolved in EtOAc. The organic phase is then washed with saturated NaHCO3 (4×), water (1×) and brine and is dried with Na2SO4 and MgSO4, and concentrated. The residue is purified by flash column chromatography to give the title compound as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Br:25]Br.O[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([F:38])[CH:31]=1>C(Cl)Cl>[Br:25][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([F:38])[CH:31]=1
Reactant: COc1ccc(CCO)cc1F
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1F
Yield: 59.8 %

Procedure:
A mixture of resin bound triphenyl phosphine (polystyrene 2% cross linking, loading =3 mmol/g, 3 g, 9 mmol) and imidazole (0.48 g, 7.1 mmol) in DCM (30 mL) cooled on an ice bath was drop wise added Br2 (1.13 g, 7.1 mmol), whereupon a solution of 4-(2-hydroxy-ethyl) -2-fluoro-1-methoxy-benzene (1.0 g, 5.88 mmol) in DCM (5 mL) was added. The cooling bath was removed and the reaction mixture was stirred for 16 hs before the resin was filtered off. The resin was washed with DCM and the filtrate was concentrated in vacuo. The residue was purified using column chromatography (SiO2, heptane-EtAOc 95:5) to give 0.82 g of 4-(2-bromo-ethyl)-2-fluoro-1-methoxy-benzene
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([C:21](N(C)OC)=[O:22])[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][Mg]Br.O1CCCC1.O>O1CCCC1>[C:21]([C:14]1[CH:13]=[C:12]2[C:17]([NH:18][C:19](=[O:20])[C:10]3[N:11]2[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:8][CH:9]=3)=[CH:16][CH:15]=1)(=[O:22])[CH3:27]
Reactant: CON(C)C(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Reaction time: 3.7 h

Procedure:
To a suspension of 354 mg of 1-cyclohexyl-N,O-dimethyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-hydroxamic acid as synthesized in above Example 142 in 10 mL of tetrahydrofuran, 1.33 mL of 3M methylmagnesium bromide/tetrahydrofuran solution was added, followed by 3.7 hours' stirring under nitrogen atmosphere and addition of 30 mL of water. The organic layer extracted with ethyl acetate-tetrahydrofuran mixed solvent was washed with water, dried over magnesium sulfate and the solvent therein was distilled off. The crude product was heat-suspended in 10 mL of methanol and purified, to provide 106 mg of the title compound.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[C:10]2[N:11]([CH:21]=[C:22]([CH3:24])[N:23]=2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>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.[Cu]I.CN(C=O)C>[CH2:19]([O:18][C:16]([N:15]1[C:14]2[CH:13]=[CH:12][N:11]3[CH:21]=[C:22]([CH3:24])[N:23]=[C:10]3[C:9]=2[CH:32]=[C:31]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH3:20]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)Nc1ccn2cc(C)nc2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(-c2ccccc2)cc2c1ccn1cc(C)nc21
Reaction time: 0.08 h
Yield: 10.8 %

Procedure:
To a mixture of Et3N (10 mL), DMF (75 μL), carbamate 19 (215 mg, 0.72 mmol), PdCl2(PPh3)2 (10 mg, 2 mol %) and phenylacetylene (89 mg, 0.87 mmol) stirred 5 min beforehand, CuI (5 mg, 4 mol %) was added and stirring was continued for another 2 min before flushing with Ar. After stirring for 2 days at 60° C., the mixture was concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with CH2Cl2 (3×30 mL). The organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography using cyclohexane/EtOAc (4/1, v/v) as eluent to afford compound 20 as an oil (24.8 mg, yield: 11%); 1H NMR (400 MHz, CDCl3) δ 1.06 (t, 3H, J=7.1 Hz), 2.48 (s, 3H), 4.25 (q, 2H, J=7.1 Hz), 7.09 (s, 1H), 7.32 (s, 1H), 7.40 (m, 5H), 7.69 (d, 1H, J=7.3 Hz), 7.87 (d, 1H, J=7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 13.5, 14.2, 63.6, 103.0, 108.1, 109.5, 115.8, 121.5, 127.8, 127.9, 129.0, 132.3, 133.7, 139.7, 140.4, 141.7, 151.3. Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 72.03; H, 5.42; N, 13.25. Further elution afforded starting material 19 (124 mg, 58%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.Cl.O>C(O)(=O)C>[C:4]([C:6]1[O:7][C:8]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2o1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1cc2oc(C(=O)O)cc(=O)c2cc1Oc1ccccc1
Yield: 92.1 %

Procedure:
3.5 g of 2-ethoxycarbonyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was suspended in 30 ml of acetic acid. Thereto was added 20 ml of concentrated hydrochloric acid. The mixture was refluxed for 1 hour. To the reaction mixture was added 100 ml of water. The resulting crystal was collected by filtration and then recrystallized from ethanol to obtain 3.0 g (yield: 91%) of 2-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of >250° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Cl:11][C:12]1[N:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:13]=1[C:14]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[N:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:13]=1[C:14]([C:16](=[CH:22][NH:4][C:3]1[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[F:10])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)nc1Cl
Reactant: Nc1c(F)cc(F)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1c(F)cc(F)cc1F)C(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 5 ml of a toluene solution containing 1.39 ml of 2,4,6-trifluoroaniline was added dropwise to 10 ml of a toluene solution containing 6.40 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-ethoxyacrylate and stirred overnight at room temperature. The solvent was distilled off then to the residue, ethanol was added. The resulting crystals were collected by filtration and washed with diethyl ether, to give ethyl 2,6-dichloro-5-fluoronicotinoyl-3-(2,4,6-trifluorophenyl)aminoacrylate. To 9 ml of a N,N-dimethylformamide solution containing 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl-3-(2,4,6-trifluorophenylamino)acrylate was added 0.63 g of potassium carbonate. The solution was stirred for 90 minutes at room temperature. The reaction solution was poured into ice water, the precipitated solid was collected by filtration and washed with ethanol and diethyl ether, to give 1.38 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 2-(aminomethyl)-1N-Boc-pyrrolidine (20.9 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 25 mL/min, 220 nM, product retention=32.9 min) to provide (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol, 65.6% yield): LCMS=614.3 [M+H]+. The (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol) was added to TFA (1 mL, 12.98 mmol) and stirred for 30 min. The reaction mixture was concentrated to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyrrolidin-2-ylmethyl)acetamide, TFA (24 mg, 0.037 mmol, 80% yield): LCMS=514.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=7.92 Hz), 7.54-7.79 (7 H, m), 5.21 (1 H, s), 3.66-3.81 (1 H, m), 3.48-3.62 (2 H, m), 3.16-3.30 (2 H, m), 1.91-2.18 (3 H, m), 1.70-1.82 (1 H, m); HPLC peak RT=8.3 min (Condition A).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.FC(F)(F)C(O[C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36])=O.N1C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Yield: 90 %

Procedure:
4-(2-Fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and pentafluorophenyl trifluoroacetate were reacted in the presence of pyridine in THF as for example 4, step A. The crude residue was purified by flash chromatography on silica gel (60% EtOAc/Hexane) to give 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (90%). 1H NMR [400 MHz, (CD3)2SO] δ 9.02 (s, 1H), 8.60 (s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.20 (dd, J=11.6, 1.1 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 5.24 (d, J=1.6 Hz, 1H), 3.48 (s, 3H), 2.34 (s, 3H).