Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[N:15]=[C:16]2[N:20]([C:21]=1[S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:18][S:17]2.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:22]([C:21]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[Cl:13])(=[O:23])=[O:24])[CH:5]=1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: BrCCc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1c(Cl)nc2sccn12)n1cc(CCBr)c2ccccc21
Reaction time: 16 h
Yield: 58 %

Procedure:
A mixture of 3-(2-bromoethyl)indole (1.0 g, 4.46 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.96 g, 1.1 eq.) in THF is treated with potassium t-butoxide (0.48 g, 1.1 equiv.) at room temperature, stirred for 16 h, quenched with saturated NaHCO3 and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title product as a brown oil, 1.2 g (58% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].CCN=C=NCCCN(C)C.CN1CCOCC1.Cl.[CH3:33][O:34][NH:35][CH3:36]>Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:35]([O:34][CH3:33])[CH3:36])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
To a solution of CH2Cl2 (1L) was added 3-fluoro-4-nitrobenzoic acid (100 g, 540 mmol) and EDCI (155.3 g, 810 mmol) followed by NMM (178 mL, 1.62 mol) and N-methoxymethanamine hydrochloride (79.0 g, 810 mmol). The solution was allowed to stir under N2 at rt for 17 h. The reaction mixture was then diluted with 1N HCl (1 L), transferred to separatory funnel, and separated. The organic phase was washed with 1N NaOH (2×500 mL) and water (250 ML). All aqueous layers were back extracted with EtOAc (2×500 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. to afford 102.3 g of the above compound as a yellow solid (448 mmol, yield 83%). 1H-NMR (DMSO-d6) δ 8.22 to 8.18 (t, J=8.0 Hz, 1H), 7.79 to 7.76 (d, J=11.5 Hz, 1H), 7.60 to 7.58 (d, J=8.3 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H); MS [M+H]+=229. 1; LCMS RT=2.27 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH3:19]
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and beta-alanine ethyl ester hydrochloride according to the procedure of Example 154 as a yellowish solid; 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.1 Hz, 3 H), 2.56 (t, J=6.1 Hz, 4 H), 2.64 (t, J=5.7 Hz, 2 H), 3.55–3.65 (m, 6 H), 4.15(q, J=7.1 Hz, 2 H), 6.82 (t, J=5.7 Hz, 1 H), 6.95(d, J=8.9 Hz, 2 H), 7.70(d, J=8.9 Hz, 2 H); MS (ES) m/z: 319.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:32]=[C:33]([C:38]([N+:41]([O-:43])=[O:42])=[CH:39][N:40]=1)[C:34]([O:36][CH3:37])=[O:35].Cl>CN(C)C=O.O>[F:1][C:2]([F:22])([F:23])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[CH:32]=[C:33]([C:38]([N+:41]([O-:43])=[O:42])=[CH:39][N:40]=2)[C:34]([O:36][CH3:37])=[O:35])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)c([N+](=O)[O-])cn1
Yield: 72.7 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenol (1.68 g, 4.86 mmol) in N,N-dimethylformamide (30 mL), potassium carbonate (1.34 g) and methyl 2-chloro-5-nitroisonicotinate (1.58 g) were added, and the resultant mixture was stirred in an oil bath with the oil temperature at 80° C. After completion of the reaction, the reaction solution was neutralized by adding 2 mol/L of hydrochloric acid, added with water, and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using thin-layer silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.86 g, yield 73%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](O)=[O:8].[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([NH2:41])[CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([NH:41][C:7]([C:6]2[C:5]3[CH:10]=[CH:11][C:12]([O:14][C:15]4[C:24]5[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)=[CH:22][CH:23]=5)[N:18]=[CH:17][CH:16]=4)=[CH:13][C:4]=3[O:3][C:2]=2[CH3:1])=[O:8])[CH:35]=1
Reactant: Cc1oc2cc(Oc3ccnc4cc(OCCN5CCCC5)ccc34)ccc2c1C(=O)O
Reactant: Cc1cc(C)nc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NC(=O)c2c(C)oc3cc(Oc4ccnc5cc(OCCN6CCCC6)ccc45)ccc23)c1
Reaction time: 48 h

Procedure:
A solution of 121-G (43 mg), 4,6-dimethylpyridin-2-amine (25 mg), HATU (132 mg) and Et3N (47 mg) in DMF (2 ml) was heated to 70° C. for 4 hours. A small amount of product was seen by TLC. The reaction was allowed to stay for another 48 hours at room temperature. The reaction mixture was purified by HPLC (20-60% CH3CN/H2O, 0.1% AcOH over 30 min.) to give N-(4,6-dimethylpyridin-2-yl)-2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide 121.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][CH:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][CH:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(N)cc1C(NC(C)=O)CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(NC(=O)[C@H](C)NC(=O)OCc3ccccc3)cc1C(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
A solution of N-benzyloxycarbonyl-(L)-alanine (63 mg, 0.28 mmol) in dichloromethane (4 ml) at −20° C. was treated with N-[3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (100 mg, 0.28 mmol), (V. Fernholz Justus Liebigs Ann., 1950, 568, 63–72), and 1,3-dicylcohexylcarbodiimide (134 mg, 0.31 mmol) and the solution stirred for 16 hours at ambient temperature. Solvent was evaporated under reduced pressure and the residue chromatographed on silica gel, eluting with ethyl acetate to give a white solid which was triturated with diethyl ether. The title compound (85 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:12])([CH3:13])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:8][CH2:7]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)C(C)(C)CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 79.4 %

Procedure:
2,2-Dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (156 mg, 0.78 mmol) from above was mixed with 2-chloro-5-nitropyridine (124 mg, 0.78 mol) in tetrahydrofuran (2 mL) containing triethylamine (0.24 mL). The mixture was heated in a microwave at 140° C. for 30 minutes. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was triturated with ether to give 2,2-dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid methyl ester (199 mg) as a crystalline material. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH:8]=1)(=O)=O.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].[F-].[Cs+]>O1CCOCC1>[C:13]([CH:10]1[CH2:11][CH2:12][C:7]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=2)=[CH:8][CH2:9]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=CCC(C(C)(C)C)CC2)cc1
Reaction time: 16 h

Procedure:
A mixture of Example 5A (286 mg, 1.0 mmol), (4-methoxycarbonylphenyl)-boronic acid (216 mg, 1.2 mmol), Pd(dppf)Cl2CH2Cl2 (37 mg, 0.05 mmol), and cesium fluoride (454 mg, 3.0 mmol) in dioxane (5 mL) was heated to 90° C., stirred for 16 hours, filtered through a pad of silica gel (10 g) with diethyl ether (5 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][N:18]([CH2:26][CH2:27][OH:28])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[N:3]=1.CCN(CC)CC.[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([O:49][CH3:50])=[O:48])#[CH:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.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>[C:21]([O:20][C:19]([N:18]([CH2:17][C:16]1[CH:29]=[CH:30][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:39]#[C:38][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)[CH2:26][CH2:27][OH:28])=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN(CCO)C(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate (A71) (0.518 g, 1.15 mmol), Et3N (0.75 mL), methyl 2-(2-ethynylphenyl)acetate (K1) (0.242 g, 1.39 mmol), PdCl2(PPh3)2 (0.041 g, 0.058 mmol), CuI (0.022 g, 0.116 mmol) and PPh3 (0.030 g, 0.12 mmol) in DMF (4.5 mL) was heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated in vacuo and the residue purified using silica gel column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 20-50% EtOAc in cyclohexane) to give the title compound A72 as an orange foam (0.589 g, 86%); 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.48-7.28 (m, 6H), 4.49 (brs, 2H), 3.97 (s, 2H), 3.72 (m, 5H), 3.47 (brs, 2H), 3.01 (brs, 1H), 1.51 (s, 9H). LCMS-B: rt 8.350 min; m/z 585 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]1[C@H:9]([NH:10][C:11](=[O:38])/[C:12](=[N:26]\[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:13]2[N:14]=[C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:16][CH:17]=2)[C:8](=[O:39])[NH:7]1.C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:22]([O:21][C:19]([NH:18][C:15]1[S:16][CH:17]=[C:13](/[C:12](=[N:26]/[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:11](=[O:38])[NH:10][C@H:9]2[C@@H:6]([CH2:5][N:4]3[CH2:3][CH2:2][NH:1][C:45]3=[O:46])[NH:7][C:8]2=[O:39])[N:14]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCNC2=O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of tert-Butyl 2-(((Z)-(2-(((2R,3S)-2-(((2-aminoethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (100 mg, 0.151 mmol) in chloroform (756 μl) was added CDI (98 mg, 0.604 mmol) followed by TEA (105 μl, 0.756 mmol). After stirring at rt for 1 h it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (73 mg, 81%) as a white solid. It was used as crude in step 4. LCMS: Rt=0.70 min, m/z=596.2 (M+1) Method 2m_acidic.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]([CH3:20])([CH3:19])[CH3:18])/[C:5]1=[O:21])(=O)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:17]([C:16]1[O:15][CH:14]=[N:13][C:12]=1/[CH:11]=[C:6]1/[C:5](=[O:21])[NH:4]/[C:9](=[CH:27]\[C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)/[C:8](=[O:10])[NH:7]/1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(=O)N1CC(=O)N/C(=C\c2ncoc2C(C)(C)C)C1=O
Reactant: COc1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=c2\[nH]c(=O)/c(=C/c3ncoc3C(C)(C)C)[nH]c2=O)c1

Procedure:
To a solution of 4 (50 mg, 0.17 mmol) in DMF (4 mL) was added 3-methoxybenzaldehyde (31.4 μL, 0.26 mmol) and the solution was repeatedly evacuated in a short time to remove oxygen and flushed with Ar, followed by the addition of Cs2CO3 (111.9 mg, 0.34 mmol) and the evacuation-flushing process was repeated again. The resultant mixture was heated for 3 h at 85□. After the solvent was removed by evaporation, the residue was AcOEt, washed with water for two times and saturated NaCl for three times, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in 70% MeCN aq and applied to reverse-phase HPLC column (μBondasphere 5C18 100 A, 19×150 mm) and eluted using a linear gradient from 30 to 100% CH3CN in 0.1% TFA aq over 30 min at a flow rate of 12 mL/min, and the desired fraction was collected and concentrated by evaporation to give a 35.3 mg (55.9%) of yellow colored KPU-201. mp 114-116° C.; 1H NMR (300 MHz, CDCl3) δ 11.40 (br s, 1H), 8.14 (br s, 1H), 7.88 (s, 1H), 6.96-7.00 (m, 2H), 6.92 (s, 1H), 6.88 (s, 1H), 6.88-6.92 (m, 1H), 3.83 (s, 3H), 1.44 (s, 9H); HRMS (EI) m/z 367.1538 (M+) (calcd for C20H21N3O4: 367.1532).
Reaction SMILES: [Br-].[Cl:2][C:3]1[C:4]([C:29]([O:31][CH3:32])=[O:30])=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.C1CN2C(=NCCC2)C1>C(#N)C>[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:6][C:5]2[C:4]([C:29]([O:31][CH3:32])=[O:30])=[C:3]([Cl:2])[CH:28]=[CH:27][CH:26]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)c1c(Cl)cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: COC(=O)c1c(Cl)cccc1C=Cc1ccc(Br)cc1

Procedure:
To a mixture of. 44.6 g (84.9 mmol) of 3-chloro-2-methoxycarbonylbenzyltriphenylphosphonium bromide and 16.7 g (90.4 mmol) of 4-bromobenzaldehyde was added 150 ml of acetonitrile, and then, 14.8 g (119 mmol) of 1,5-diazabicyclo[4,3,0]-5-nonene was added dropwise to the mixture. Thereafter, the mixture was refluxed for 3 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=1)=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc2c1=O
Reactant: O=C(CBr)Nc1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O

Procedure:
A mixture comprising (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid tert-butyl ester (Intermediate L) (226.7 mg, 0.82 mmol), 2-bromo-N-(2,6-dichloro-pyridine-4-yl)-acetamide (Intermediate N) (256.5 mg, 0.902 mmol) and Cs2CO3 (545.1 mg, 1.64 mmol) in DMF (5 ml) is stirred at RT for 3 hours. The resulting mixture is treated with water and the precipitate is filtered under vacuum. The solid is washed with water, iso-hexane and then dried to give the title compound, [M+H]+ 479
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH3:44])[CH2:17][CH2:18][N:19]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1)[C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:15][CH:16]([CH3:44])[CH2:17][CH2:18][N:19]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[CH:40][CH:41]=1)[C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[N:24]=1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Reactant: CC(C)CCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC1c1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 46.2 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.152 g, 0.790 mmol), {4-[((3-methylbutyl){4-[4-(trifluoromethyl)phenyl]-1,3- thiazol-2-yl}amino)methyl]phenyl}methanol (0.312 g, 0.718 mmol) and tributylphosphine (0.291 g, 1.44 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.363 g, 1.44 mmol) was added, and the mixture was stirred at room temperature for 60 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.202 g, yield 42%) as a colorless oil.
Reaction SMILES: CC([S@]([NH:7][C@@H:8]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[F:21][C:20]([F:22])([F:23])[CH2:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH2:7]
Reactant: CC(C)(C)[S@@](=O)N[C@H]1CCCc2c(OCC(F)(F)F)cccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCCc2c(OCC(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of Intermediate 13B (245 mg, 0.701 mmol) in DCM (1 mL) was added 4 N HCl (175 μl, 0.701 mmol) in dioxane. The resulting mixture was stirred at rt for 0.5 h. The solvents were evaporated and DCM (3×) was added and evaporated. The resulting white solid was vacuum dried for 1 h to give Intermediate 13 (140 mg, 0.571 mmol, 81.0% yield) as a HCl salt which was used directly without further purification. LCMS=1.48 min [M+1-17]=229 (Method B).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[NH2:14][C:15]1[CH:20]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:17][C:16]=1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:2]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:17][C:16]=2[NH:26][C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])=[O:3])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl 4-(chlorocarbonyl)benzoate (0.75 g, 3.79 mmol) and anhydrous DCM (0.25 M) was treated with tert-butyl 2-amino-4-thien-2-ylphenylcarbamate (1.0 g, 3.44 mmol). The resulting solution was stirred at ambient temperature for 14 hours. The reaction mixture was quenched with a solution of aqueous NaOH (1M) and partitioned between ethyl acetate and water. The organic layer was washed with water, saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was carried on without further purification.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CC/C=C/CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC/C=C\CCOS(=O)(=O)c1ccc(C)cc1
Yield: 99 %

Procedure:
This compound was synthesized as a colorless oil from (E)-hex-3-en-1-ol (70.0 mg, 0.70 mmol), TsCl (173.5 mg, 0.91 mmol), Et3N (109.2 mg, 1.05 mmol), and DMAP (85.5 mg, 0.70 mmol) in 99% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.78 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 5.58-5.35 (m, 1H), 5.28-5.08 (m, 1H), 3.99 (t, J=7.0 Hz, 2H), 2.44 (s, 3H), 2.42-2.31 (m, 2H), 2.07-1.90 (m, 2H), 0.91 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, δH) 144.94, 135.73, 133.33, 130.03, 128.11, 122.27, 70.06, 27.18, 21.86, 20.82, 14.30. ESI-MS: 255.1 (M+H+), 277.1 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1Cl)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(C#N)cc1Cl
Temperature: 135 °C

Procedure:
A mixture of diethyl 2-(2-chloro-4-cyanobenzyl)malonate (9.0 g, 0.03 mol), sodium chloride (2.12 g, 0.04 mol), and water (0.86 g 0.05 mol) in 30 mL of DMSO was heated to 135° C. and then the temperature was gradually raised to 170° C. over a 3 h period. The mixture was diluted with water and extracted with ether. Evaporation and distillation gave ethyl 3-(2-chloro-4-cyanophenyl)propanoate as an oil: 5.8 g; bp 138°-140° C. (0.1 mm Hg) Anal. calcd for C12H12ClNO2 : C, 60.64; H, 5.09; N, 5.89. Found: C, 60.48; H, 5.08; N, 5.84. ##STR29##