Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([CH2:20][OH:21])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>ClCCl>[C:1]([NH:8][C@H:9]([CH2:20][OH:21])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: N[C@H](CO)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reaction time: 3 h

Procedure:
Acetic anhydride (4 grams) was added to the solution of (R)-2-amino-N-benzyl-3-hydroxypropanamide compound of formula-10 (6 grams) in dichloromethane (60 ml) at 10-15° C. The reaction mixture was stirred for 3 hours and reaction mixture quenched with water. Both the organic and aqueous layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution followed by water. The organic layer was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:31]>C(O)CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:2])[NH:31][C:6](=[O:7])[C:5]3=[CH:10][C:11]=2[NH:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21

Procedure:
Analogously to Example 1, 290 mg (0.7 mmol) of 4,5-bis(4-fluoroanilino)phthalic acid dimethyl ester in 22 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of orange crystals, m.p.>220° C., FAB-MS: 366 [M+ +H].
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:10]([O:12][C:13](=[O:19])[C:14](OCC)=[O:15])[CH3:11].O>C1C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:10]([O:12][C:13](=[O:19])[C:14]([C:7]1[S:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:9][CH:8]=1)=[O:15])[CH3:11]
Reactant: CCCCc1cccs1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCCc1ccc(C(=O)C(=O)OCC)s1
Temperature: 5 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a 0° C. solution containing 2-butyl-thiophene (5 g, 35.6 mmol) dissolved in benzene (90 mL) and diethyloxalate (5.1 g, 35.6 mmol) was added (dropwise) a solution containing TiCl4 (6.7 g, 35.6 mmol) dissolved in benzene (10 mL). The reaction was let stir at 5° C. for 1 h then poured into water (300 mL) and extracted with ether. The organic layer was separated, washed with brine, then dried over MgSO4, filtered and stripped. The residue was purified by flash chromatography on silica gel in hexane/ethyl acetate 20:1. A yellow oil (4 g, 46% yield) was recovered. MS m/e 241 (M)+; 1HNMR (400 MHz, DMSO-d6 300 MHz) δ 0.9 (t, 3H), 1.4 (m, 5H), 1.6 (m, 2H), 2.9 (t, 2H), 4.4 (t, 2H), 7.1 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.[Cl-].[NH4+]>O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(F)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1B(O)O
Reaction time: 1 h
Yield: 382.5 %

Procedure:
A cold solution (−78° C.) of 2-bromo-4-fluoro-anisole (20 g, 10 mmol, 1 equiv) in anhydrous tetrahydrofuran (200 mL) was treated dropwise, over 20 min, with 2.5M n-butyllithium solution in hexanes (44 mL, 110 mmol, 1.1 equiv). The reaction was stirred for 1 hour, then trimethyl borate (16.75 mL, 150 mmol, 1.5 equiv) was added in one portion. After stirring overnight at room temperature, the reaction was poured into saturated ammonium chloride (200 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was triturated with methyl tert-butyl ether (100 mL) to give (5-fluoro-2-methoxyphenyl)boronic acid (1) (6.5 g, 39% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][C:28]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)=[O:29]
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2ccccc2c1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Yield: 75.7 %

Procedure:
By operating as described in Example 6(a), 7 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine are reacted with 6.15 g of 2-naphthylacetyl chloride in the presence of 4.15 g of triethylamine in methylene chloride to give 9 g of 1-(2-naphthylacetyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; m.p. 125°-130° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41]([O:43]C)=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:41]([OH:43])=[O:42])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)OC)n3)cc12
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of methyl 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinate (540 mg, 0.87 mmol), LiOH.H2O (110 mg, 2.62 mmol) in 1,4-dioxane/H2O (15 mL/5 mL) under N2 was stirred at 100° C. for 1 h. After being filtrated and acidified with HCl to pH=5, the mixture was extracted with EtOAc, the organic phases were dried and concentrated to afford 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (520 mg, yield: 98%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.56 (d, J=4.8 Hz, 1H), 7.94˜8.07 (m, 3H), 7.73˜7.85 (m, 3H), 7.50 (d, J=7.2 Hz, 2H), 7.42 (t, J=7.6 Hz, 4H), 7.35 (br s, 1H), 5.30 (s, 2H), 3.20 (s, 3H), 2.94 (s, 3H), 2.82 (d, J=4.4 Hz, 3H). MS (M+H)+: 604.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CC(N(C)C)=O.O>[CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution (10 mL) of 4-(cyclohexyl{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methoxy)benzoic acid (0.43 g) synthesized above in dimethylacetamide were added ethyl 3-(methylamino)propanoate (0.14 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.23 g) at room temperature, and the mixture was stirred at 60° C. for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was purified by silica gel chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a methyl ester form of the title compound (0.44 g). This was dissolved in ethanol (2 mL), 1N sodium hydroxide (1.5 mL) was added and the mixture was stirred at room temperature for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue to give the title compound (0.40 g, 78%) as an amorphous form.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[NH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CS(C)=O>[N:26]1([C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCCNCC1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, crude) in DMSO (6 mL) was added DIEA (543 mg, 4.20 mmol) and azepane (208 mg, 2.10 mmol). The solution was stirred overnight at 90° C. Then the reaction was quenched by the addition of water (50 mL), extracted with ethyl acetate (5×20 mL) and the organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford methyl 3-(azepan-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (165 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[NH:15]1[CH2:19][C@H:18]([OH:20])[C@@H:17]([OH:21])[CH2:16]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:15]3[CH2:19][C@H:18]([OH:20])[C@@H:17]([OH:21])[CH2:16]3)=[O:13])[S:10][C:3]=12
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1C[C@H](O)[C@@H](O)C1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3S,4S)-pyrrolidine-3,4-diol by a procedure analogous to Example 1B. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1
Reactant: CCO
Product: CCOC(=O)C1CC(=O)N(c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (unknown amount) was dissolved in 20 ml ethanol and cooled to 0° C. HCl gas was bubbled into the solution until the solution became red in color. The reaction was allowed to warm to room temperature and stir overnight. The solvent was removed to yield ethyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (M+1=251.93).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[S:11]([C:15]1[CH:16]=[C:17]([NH:21][C:22]([C:24]2[C:25](ON3C4=NC=CC=C4N=N3)=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:23])[CH:18]=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:25]2[C:24]([C:22]([NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:16]=3)=[O:23])=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(F)ccc1O
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2cc3ccccc3nc2On2nnc3cccnc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2cc1C(=O)Nc1cccc(S(N)(=O)=O)c1
Temperature: 90 °C
Yield: 34 %

Procedure:
4-Fluoro-2-methoxy-phenol (6.17 μL, 0.05 mmol), N-(3-sulfamoylphenyl)-2-(triazolo[4,5-b]pyridin-3-yloxy)quinoline-3-carboxamide (25 mg, 0.05 mmol) and K2CO3 (22.46 mg, 0.16 mmol) were combined in DMF (0.5 mL) and heated at 90° C. for 1 h. The reaction was diluted with DMF (0.5 mL), filtered, and purified by reverse phase HPLC (30-99% CH3CN/5 mM aqueous HCl) to provide 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (61) (7.95 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.73 (s, 1H), 8.40-8.35 (m, 1H), 8.07 (dd, J=7.8, 1.6 Hz, 1H), 7.88 (td, J=4.4, 2.1 Hz, 1H), 7.72 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.64-7.52 (m, 4H), 7.42 (s, 2H), 7.38 (dd, J=8.9, 6.0 Hz, 1H), 7.12 (dd, J=10.8, 2.9 Hz, 1H), 6.87 (td, J=8.5, 2.9 Hz, 1H), 3.70 (s, 3H), 8.76-8.68 (m, 1H) ppm. ESI-MS m/z calc. 467.09, found 468.3 (M+1)+; Retention time: 1.78 minutes (3 minutes run).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1.P([O-])([O-])([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: -45 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
1,1,3,3-Tetramethylguanidine (0.5 mL, 4.0 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 1.00 g, 1.9 mmol) in tetrahydrofuran (8 mL) at −45° C. The solution was stirred at −45° C. for 5 min and then quinoline-3-carboxaldehyde (300 mg, 1.9 mmol) was added. After the reaction was allowed to proceed at −40° C. for 30 min, the mixture was warmed to room temperature and was stirred for another 2 h. Ethyl acetate and pH 6 phosphate buffer (200 mL each) were added and the resulting solid was filtered to furnish (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (500 mg, 47% yield). The layers in the filtrate were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (MgSO4), filtered through a bed of silica gel and the filtrate was evaporated to give an additional quantity of (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (520 mg, 49% yield) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: C=Cc1ncc(C(=O)OCC)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc(CC)o1
Yield: 98.9 %

Procedure:
To a solution of ethyl 2-vinyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (100 mg, 0.094 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is collected and concentrated to give ethyl 2-ethyloxazole-5-carboxylate (470 mg). HPLC retention time=1.09 minutes (condition A); MS (m+1)=170.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.6 Hz, 3 H) 1.36 (t, J=7.2 Hz, 3 H) 2.87 (q, J=7.7 Hz, 2 H) 4.35 (q, J=7.2 Hz, 2 H) 7.71 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][N:21]([CH2:32][CH2:33]O)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:33][CH2:32][N:21]([CH2:20][CH2:19][OH:18])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCN(CCO)S(=O)(=O)c3ccc(C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.0 g, 21.7 mmol), N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide (16.89 g, 65.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.530 g, 4.34 mmol) in CH2Cl2 (250 mL) and DMF (3 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 4.99 g, 26.05 mmol). The reaction mixture was stirred overnight at room temperature, and then partitioned between CH2Cl2 and HCl (1N). The aqueous layer was washed with CH2Cl2 and the combined organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAC/hexane (1:1) to give the title compound as a thick oil (7.15 g, 15.16 mmol, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.6 Hz, 2H), 7.66 (m, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=2.5, 8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 3.88 (q, J=7.2 Hz, 1H), 3.38 (m, 2H), 3.09 (t, J=5.1 Hz, 2H), 2.44 (s, 3H) 2.18 (t, J=6.0 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 472 (MH+), 489 (M+18+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC=CC=1>CN(C)C=O>[CH3:20][NH:21][C:22]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:14]=[C:15]([NH2:19])[N:16]=[CH:17][N:18]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:23]
Reactant: CNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3cc(N)ncn3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
Sodium hydride (199 mg, 4.97 mmol) was suspended in N,N-dimethylformamide (10 ml) under nitrogen atmosphere, 6-(1H-indol-5-yloxy)pyrimidin-4-ylamine (1.07 g, 4.73 mmol) synthesized in Production example 2-2 was gradually added while the reaction mixture was stirred at room temperature. After 30 minutes, the reaction mixture was cooled with an ice water bath, then phenyl N-methylcarbamate (751 mg, 4.97 mmol) synthesized in Production example 2-1 was added. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; ethyl acetate) to yield the title compound (847 mg, 2.99 mmol, 63%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CCCC(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a solution of 4-(1-(tert-butoxycarbonyl)-4-(methoxy-carbonyl)piperidin-4-yl)butanoic acid (23.4 g, 0.071 mol) from Step D in 3:1 dichloromethane/methanol (480 mL) at 0° C. was added a solution of trimethylsilyldiazomethane (53 mL, 0.11 mol, 2.0M in hexane). The reaction mixture was stirred for 15 min and then concentrated to afford 25.5 g. The residue was purified by flash chromatography eluting with 20–30% ethyl acetate in hexanes to give the title compound (20.1 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(F)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.05 g, 0.086 mmol) and (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.022 g, 0.103 mmol) in DMF (1 ml) was added sodium hydride (5.13 mg, 0.128 mmol) and the resulting yellow mixture was stirred at rt. After 5 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The oil was purified by flash chromatography (Biotage; 0%-10% MeOH/DCM; 10 CV) to give (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (20 mg, 0.031 mmol, 36.6% yield) was obtained as an amber oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J=9.0, 2.9 Hz, 1H), 6.89 (dd, J=8.1, 3.2 Hz, 1H), 6.84-6.75 (m, 1H), 6.60 (s, 1H), 6.10-5.95 (m, 1H), 5.89-5.75 (m, 1H), 5.52-5.38 (m, 1H), 5.23-4.99 (m, 4H), 4.80 (s, 2H), 4.66 (s, 2H), 4.45-4.28 (m, 1H), 4.06-3.93 (m, 2H), 2.71-2.54 (m, 3H), 2.47 (d, J=5.9 Hz, 1H), 2.40-2.30 (m, 1H), 2.08-1.56 (m, 4H), 1.49-1.01 (m, 15H). LCMS (M+H) calcd for C35H48FN4O6: 639.35. found: 639.2.