Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][C@@H:33]([C:35](O)=[O:36])[CH2:32][NH:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:33]3[CH2:32][NH:31][C:30](=[O:29])[NH:34]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NC[C@H](C(=O)O)N1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@H]3CNC(=O)N3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.277 mmol) prepared in the previous step in chloroform (1 ml) were sequentially added (R)-2-oxoimidazolidine-4-carboxylic acid (40 mg) and WSC.HCl (64 mg) at room temperature, and the mixture was stirred for 3 hours. This reaction mixture was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration and was dried under reduced pressure to give the titled compound (56 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([C:15](C(C)(C)C)([C:19]([OH:21])=[O:20])[C:16]([OH:18])=O)(C)(C)C>C(O)(C)(C)C.N1CCCCC1>[C:3]([O:21][C:19]([C:15]1[C:16](=[O:18])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:20])([CH3:6])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C(C(=O)O)(C(=O)O)C(C)(C)C
Reactant: O=Cc1ccc(O)cc1O
Solvent: CC(C)(C)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)c1cc2ccc(O)cc2oc1=O
Yield: 53.4 %

Procedure:
2,4-dihydroxylbenzaldehyde (0.27 g, 2 mmol) and di-tert-buty malonic acid (0.43 g, 2 mmol) are dissolved in tert-butanol (5 mL), and three drops of piperidine are added. The mixture is refluxed for 16 hours to obtain a suspension. After being placed for cooling, insoluble material is removed by filtrating. The mother liquor is concentrated, and the ethyl acetate is added with stirring. The supernatant is separated, concentrated, and chromatographed over silica gel column with petroleum/ethyl acetate (3:4) as eluent to obtain 0.14 g of 7-hydroxyl-3-coumarin carboxylic acid tert-butyl ester, yield: 22.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1.Br[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:33]=[CH:32]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[N:35]=[C:34]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:33]=[CH:32]4)=[CH:18][CH:17]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc2cc(-c3ccc(SCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 70 °C
Yield: 23.1 %

Procedure:
A mixture of crude [4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]boronic acid (76 mg, 0.18 mmol), ethyl 6-bromo-2-quinolinecarboxylate (42 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.0006 mmol) in 1,2-dimethoxyethane (0.8 mL), and 2 M sodium carbonate (0.65 mL) was heated in a 70° C. oil bath for 1.5 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with magnesium sulfate filtered and concentrated. The residue was purified by silica gel chromatography (hexane to 2:5 ethyl acetate:hexanes gradient elution) to give 20 mg (22% as 0.4 ethyl acetate) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]-2-quinolinecarboxylate. 1H NMR (400 MHz, CDCl3): δ 8.38-8.32 (m, 2H), 8.21 (d, J=9 Hz, 1H), 7.98 (s, 1H), 7.96 (d, J=2 Hz, 1H), 7.59 (d, J=8 Hz, 2H), 7.43-7.32 (m, 5H), 4.57 (q, J=7 Hz, 2H), 3.82 (s, 2H), 3.07 (septet, J=7 Hz, 1H), 1.50 (t, J=7 Hz, 3H), 1.27 (d, J=7 Hz, 6H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:70])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:26]([O:64][CH3:65])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:62][CH3:63])[C@@H:36]([CH3:61])[C:37]([NH:39][C@@H:40]([CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1)[C:41]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:3])=[O:2].O[N:72]1[C:76](=[O:77])[CH2:75][CH2:74][C:73]1=[O:78].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C1C=CN=CC=1)C>[O:78]=[C:73]1[CH2:74][CH2:75][C:76](=[O:77])[N:72]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:70])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:66]([CH3:69])[CH2:67][CH3:68])[C@H:26]([O:64][CH3:65])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:62][CH3:63])[C@@H:36]([CH3:61])[C:37]([NH:39][C@@H:40]([CH2:51][C:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[NH:54][CH:53]=1)[C:41]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: O=C1CCC(=O)N1O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17 mg (18 μmol) of N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 98) were dissolved in 2.8 ml of dichloromethane and admixed with 20 mg (174 mmol) of 1-hydroxypyrrolidine-2,5-dione and then with 10 mg (52 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.21 mg (0.17 μmol) of DMAP. After stirring at RT for 4 h, the reaction mixture was concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 8.2 mg (43% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH:36]=[CH:37][CH:38]=[N:39]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:30]([OH:29])[CH2:32][O:33][C:34]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:35]=3[CH:36]=[CH:37][CH:38]=[N:39]4)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Solvent: CC(C)O
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 70 °C
Yield: 51 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (150.7 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (79.8 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→100% acetone in hexanes) affording the desired product (118.2 mg) as a white solid. ESMS: MH+ 580.4 (base).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:19])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH:16]([CH3:18])[CH3:17])=[CH:7]2)[CH:2]=[CH2:3].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][CH2:3][C:2]1[O:19][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH:1]=1)[NH:10][C:9](=[O:15])[C:8]([CH:16]([CH3:17])[CH3:18])=[CH:7]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCc1cc(C)c2[nH]c(=O)c(C(C)C)cc2c1O
Solvent: ClC(Cl)Cl
Product: Cc1cc2cc(CBr)oc2c2cc(C(C)C)c(=O)[nH]c12
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 109.3 %

Procedure:
6-Allyl-5-hydroxy-3-isopropyl-8-methylcarbostyril (1.50 g, 5.34 mmol) was dissolved in chloroform (100 ml). N-bromosuccinimide (1.10 g, 6.18 mmol) was added to the solution, and the mixture was stirred at 75° C. for 90 minutes. The reaction mixture was extracted from chloroform-water, and the organic phase was washed with saturated aqueous NaCl solution, dried, and condensed under reduced pressure. The residue was recrystallized from chloroform -ethyl acetate-ether to obtain 1.95 g of the title compound as pale yellow needles (99.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[O:15][CH2:16][C:17]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=3[N:19]=1)[CH2:10][CH2:9][CH2:8]2.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[O:15][CH2:16][C:17]3[CH:23]=[C:22]([NH:24][C:28]([CH:25]4[CH2:27][CH2:26]4)=[O:29])[CH:21]=[CH:20][C:18]=3[N:19]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CCC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)C4CC4)cc3CO1)CCC2
Yield: 97.1 %

Procedure:
Prepared from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 22) (162 mg, 0.50 mmol, HPLC 1.090 min) and cyclopropanecarbonyl chloride (53 ul, 0.55 mmol) according to the procedure described for Example 17. Obtained the title compound as an off-white solid (190 mg, 90%, HPLC 1.479 min 93%), MS (ISP) m/e=392.2 [(M+H)+].
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([OH:27])[CH3:26].[O-]CC.[Na+]>O>[CH2:1]([N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[O:27][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc2cnc3cccnc3c2n1Cc1ccccc1
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1nc2cnc3cccnc3c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
To 1-benzyl-2-methanesulfonyl-1H-imidazo[4,5-c][1,5]naphthyridine (6.8 g, 20.1 mmol) was added ethanol (200 mL) and the suspension was stirred at room temperature. To this suspension was added sodium ethoxide (2.0 g) and the reaction was heated at reflux for 1 hour. After 1 hour additional sodium ethoxide was added, and the reaction was heated at reflux for 2 hours and then cooled to ambient. To this reaction was added water (500 mL), and the suspension was stirred for 30 minutes. The gray precipitate was isolated by filtration and washed with water and ether. The solid was dried under reduced pressure to afford 1-benzyl-2-ethoxy-1H-imidazo[4,5-c][1,5]naphthyridine (4.5 g) as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[F:21])=[O:4].[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[F:21])=[O:4])=[CH2:23]
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Reactant: C=COCCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 78.1 %

Procedure:
To a solution of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.050 g, 0.17 mmol) in THF (1.5 mL) under N2 was added O-(2-vinyloxy-ethyl)-hydroxylamine (0.044 g, 0.43 mmol). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.86 mL, 0.86 mmol, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 40 minutes, the reaction mixture was quenched by the addition of NaHCO3 and partitioned between EtOAc and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.048 g (77%) pure desired product as an off-white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.C(OCC)(=O)C>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>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:13]=1[NH:12][C:4]1[C:5]([CH3:11])=[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=1)[NH:9][CH:8]=[CH:7]2)[C:19]#[N:20]
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Reactant: OB(O)c1cc2ccccc2o1
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: CCOC(C)=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3ccccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 60 °C
Yield: 15 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (122 mg, 0.3 mmol) in DMF (4 mL) was added 2-benzofuranboronic acid (162 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) under nitrogen atmosphere and the reaction mixture was heated at 60° C. overnight. After the solution was cooled to room temperature, ethyl acetate was added, and the organic phase was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give 5-(1-benzofuran-2-yl)-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile (18 mg, 15%). HPLC retention time: 13.4 min.(g); MS: 399.3 (M+H); and HRMS: 399.1009.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:17])[N:7]([C@@H:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:41])[CH2:24][CH:25]([NH2:40])[CH:26]([OH:39])[CH2:27][O:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[C:31]([F:37])[C:30]=1[F:38])([CH3:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:18]([O:22][C:23](=[O:41])[CH2:24][C@H:25]([NH:40][C:12](=[O:14])[CH:11]([N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:6]1=[O:17])[CH2:15][CH3:16])[C@H:26]([OH:39])[CH2:27][O:28][C:29]1[C:30]([F:38])=[C:31]([F:37])[CH:32]=[C:33]([F:36])[C:34]=1[F:35])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC[C@@H](C(=O)O)n1cccc(NC(C)=O)c1=O
Reactant: CC(C)(C)OC(=O)CC(N)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCC(C(=O)N[C@@H](CC(=O)OC(C)(C)C)[C@H](O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A stirred mixture of (S)-2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyric acid (100 mg, 0.42 mmol), 3-amino-5-(2,3,5,6-tetrafluorophenoxy)-4-hydroxy-pentanoic acid tert-butyl ester (163 mg, 0.462 mmol), HOBt (62 mg, 0.462 mmol), DMAP (56 mg, 0.462 mmol) and THF (5 mL) was cooled to 0° C. then EDC (89 mg, 0.462 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (50-50% ethyl acetate/hexane) to afford the title compound as a white foam (221 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 0.88-0.93 (3H, m), 1.37-1.38 (9H, 2 s), 1.86-1.96 (1H, m), 2.15-2.25 (4H, m), 2.55-2.71 (2H, m), 3.70-4.64 (5H, m), 5.30-5.39 (1H, m), 6.30-6.35 (1H, m), 6.75-6.86 (1H, m), 7.17-7.31 (2H, m), 8.31-8.47 (2H, m).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH3:9]/[C:10](=C\C)/[C:11](O)=[O:12]>>[O:5]1[C:4]2[CH:3]=[CH:1][CH:8]=[CH:7][C:6]=2[C:11](=[O:12])[CH:10]=[CH:9]1
Reactant: Oc1cccc(O)c1
Reactant: C/C=C(\C)C(=O)O
Product: O=c1ccoc2ccccc12

Procedure:
Alternatively, the resorcinol can be reacted with methyl crotonic acid according to the method of Fahrenholtz [J. Am. Chem. Soc. 89 5934 (1967)] to give the benzopyran-4-one which in turn is reacted with a Grignard or other organometallic compound to give the desired benzopyran.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([O:11]CC)=[O:10])[CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[O:1]=[C:2]([CH3:14])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1
Reactant: CCOC(=O)c1cc(CC(C)=O)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: CC(=O)Cc1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36.4 %

Procedure:
Ethyl 5-(2-oxopropyl)isoxazole-3-carboxylate (0.65 g, 3.30 mmol) was dissolved in ethanol (10 ml). A solution of cesium carbonate (1.611 g, 4.94 mmol) in water (5 ml) was added to the reaction mixture and it was stirred for 7 h at RT. The reaction mixture was concentrated, diluted with water and pH was adjusted to 2 with citric acid. The aqueous phase was extracted with ethyl acetate, dried with Na2SO4 and evaporated to dryness afforded 0.203 g (36%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ, 2.21 (s, 3H), 4.20 (s, 2H), 6.67 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:28])[S:26][C:19]=23)=[CH:38][CH:39]=1)=[O:11]
Reactant: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCC(=O)O)sc34)cc2)c1
Temperature: 60 °C

Procedure:
To a stirred solution of ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate (110 mg, 0.20 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 60° C. for 3 hours, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid as white solid. Yield: 100 mg, 96%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:14]([C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)#[N:15]>>[C:14]([C:16]1[CH:33]=[CH:32][C:19]2[NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:28])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)#[N:15]
Reactant: N#Cc1ccc2[nH]c(-c3ccc(C(=O)[O-])cc3)nc2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: N#Cc1ccc2[nH]c(-c3ccc(C(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc2c1

Procedure:
Compound 450 was prepared from 4-morpholinoaniline and 4-(5-cyano-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C25H21N5O2: 424.18; found: 423.95.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([C:21]3[CH:33]=[CH:32][C:24]4[O:25]C(C)(C)[O:27][C:28](=[O:29])[C:23]=4[CH:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([C:21]3[CH:33]=[CH:32][C:24]([OH:25])=[C:23]([CH:22]=3)[C:28]([OH:29])=[O:27])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc(O)c(C(=O)O)c1
Yield: 88.9 %

Procedure:
A solution of N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-hexyl-2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carboxamide (108 mg, 0.20 mmol) and lithium hydroxide (120 mg, 2.9 mmol) in THF (1 mL) and water (1 mL) was heated at 70° C. overnight. The solvents were removed under reduced pressure. The residue was taken up in EtOAc and washed with an aqueous solution of HCl (1N) and brine, dried over MgSO4 and the solvent was removed under reduced pressure to give 91 mg (91%) of hte title compound. HPLC, Rt: 5.72 min (purity: 98.9%).
Reaction SMILES: C([O:3][C:4](=[O:30])/[CH:5]=[C:6](\[CH3:29])/[CH:7]=[CH:8]/[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)C.[OH-].[K+].C(Cl)Cl.Cl>CO>[CH3:29]/[C:6](/[CH:7]=[CH:8]/[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)=[CH:5]\[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(/C=C/C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1)=C\C(=O)O
Temperature: 25 °C

Procedure:
The mixed (15:2) ester product from Example 1 is combined with 5 ml of 2N aqueous potassium hydroxide in 10 ml of methyl alcohol and stirred at reflux temperature for 3 hours. The reaction mixture is cooled to room temperature, poured into a mixture of ice and methylene chloride, and acidified to pH 3 with 3N hydrochloric acid. The organic layers are combined, dried over sodium sulfate and evaporated to give a light yellow solid. The solid is recrystallized form absolute ethyl alcohol to give 0.5 g of the desired compound as colorless crystals.