Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.O=S(Cl)Cl.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O.C1COCC1>[O:7]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:5]1[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: Nc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3ccccc3o2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round-bottom flask with 3-hydroxy-4-methylbenzoic acid (2.5 g, 16.4 mmol), was added dropwise SOCl2 (15 mL). The reaction was refluxed for 30 min and cooled to rt. The excess of SOCl2 was removed in vacuo and the oily acid chloride was dissolved in THF (15 mL). This resulting solution was added dropwise to a mixture of 2-aminophenol (1.8 g, 16.4 mmol), triethylamine (1.7 g, 16.4 mmol) and THF (30 mL) at 0° C. The resulting reaction mixture was then brought to rt for 30 min and the resulting precipitate was removed by filtration. The filtrate was concentrated and dried under vacuum. The resulting dark brown solid residue was dissolved in toluene (20 mL) and p-toluenesulfonic acid (15.6 g, 82 mmol) was added. The reaction was refluxed overnight, cooled at rt and EtOAc (500 mL) was added. The EtOAc solution was washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized in EtOAc to afford 5-(1,3-benzoxazol-2-yl)-2-methylphenol as a light yellow solid. MS (ESI) 226 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-])=O)=[CH:19][S:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.[SH-].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[N:16]=[C:17]3[N:21]([CH:22]=2)[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])=[CH:19][S:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cn3c(-c4ccccc4[N+](=O)[O-])csc3n2)CC1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn3c(-c4ccccc4N)csc3n2)CC1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
4-[3-(2-Nitro-phenyl)-imidazo[2,1-b]thiazol-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (320 mg, 0.73 mmol) was mixed with 20 mL of MeOH and 5 mL of water containing sodium hydrosulfide hydrate (244 mg, 6 eq). The reaction mixture was stirred under reflux for 4 hours. It was then cooled to room temperature and concentrated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 280 mg of 4-[3-(2-amino-phenyl)-imidazo[2,1-b]thiazol-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (92% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:31]1[C:32]2[C:39]([I:40])=[CH:38][N:37]([C@@H:41]3[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:43]([CH2:53][OH:54])[CH2:42]3)[C:33]=2[N:34]=[CH:35][N:36]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].O>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:31]1[C:32]2[C:39]([I:40])=[CH:38][N:37]([C@@H:41]3[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[C@H:43]([CH:53]=[O:54])[CH2:42]3)[C:33]=2[N:34]=[CH:35][N:36]=1)=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (51 mg) was added to a solution of (2S,4S)-tert-butyl 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (66 mg) obtained in Step 4 in methylene chloride (2 ml), and the resulting mixture was stirred at room temperature for 1 hour. Dess-Martin periodinane (100 mg) was further added to the mixture, and stirred at room temperature for 1 hour. Dess-Martin periodinane (70 mg) was additionally added thereto, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and a 10% sodium thiosulfate aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, amorphous substance (68 mg). Physical properties: m/z [M+H]+ 658.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[S:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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>[S:14]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:15]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cccc(N2CCNCC2)c1
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: O
Solvent: Cc1ccccc1
Product: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixed solution of 1-(3-bromophenyl)-piperazine (300 mg, 1.24 mmol), 3-thienylboronic acid (239 mg, 1.87 mmol), tetrakis(triphenylphosphine)palladium (173 mg, 0.149 mmol), 2N aqueous solution of sodium carbonate (4.98 ml, 9.95 mmol), and toluene (12 ml) was stirred at 95° C. for 15 hours under a nitrogen atmosphere. After cooling to room temperature, water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give the titled compound 254 mg (83.5%) as an oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:25]1([CH2:31][CH2:32][CH2:33][C:34]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[S:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=4)=[N:17][CH:16]=3)=[CH:23][CH:22]=2)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OC(=O)CCCc4ccccc4)cc3)s2)cc1
Reaction time: 8 h
Yield: 26.9 %

Procedure:
0.675 g of 4-{2-(4-hexylphenyl)thiazole-5-yl}phenol, 0.328 g of 4-phenylbutanoic acid, 0.41 g of DCC (1,3-dicyclohexylcarbodiimide) and 40 mg of 4-(N-pyrrolidino)pyridine were dissolved in 40 ml of dichloromethane, followed by stirring overnight. After the reaction, the reaction mixture was subjected to filtration to remove an insoluble matter, followed by distilling-off of the solvent and purification by silica gel column chromatography to obtain 0.260 g of an objective product (Yield: 26.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:30])OC(C)(C)C)[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1.[C:35](O)(C(F)(F)F)=O.C(Cl)Cl.CCN(CC)CC.C(C1NC=CN=1)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH3:35])[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(C)CCOc2ccc(I)cc21
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(C)CCOc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a CH2Cl2 (5 ml) solution of tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-chromen-4-yl)amino]propylcarbamate (Diastereomer B). (0.47 g, 0.79 mmol), at r.t., was added 25 ml of 20% TFA/CH2Cl2. The mixture was stirred at r.t for 30 min. The solvent was removed in vacuo and the residue dissolved in CH2Cl2 (75 ml) and washed with aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield a white foam. The residue was dissolved in CH2Cl2 (5 ml) and chilled to 0° C. followed by the addition of Et3N (0.24 ml, 1.7 mmol) and acetyl imidazole (0.10 g, 0.90 mmol). The mixture was then warmed to r.t. and stirred overnight. The reaction mixture was diluted with CH2Cl2 (25 ml) and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield a white foam (0.35 g, 84%) after flash chromatograph 5% MeOH/CHCl3 (Biotage 40 S). Rf=0.29. HRMS (ESI+) calcd for C22H25N2O3IF2+1H calcd m/z 531.0958; found 531.0958 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=1.Cl.[CH3:33][NH:34][CH3:35].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:33][N:34]([CH3:35])[C:29]([C:27]1[O:28][C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[CH:25][CH:26]=1)=[O:31]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)C(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Yield: 76.2 %

Procedure:
A solution of 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (0.42 g, 1.00 mmol), dimethylamine hydrochloride (0.17 g, 2.04 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g, 1.35 mmol), 1-hydroxybenzotriazole hydrate (0.21 g, 1.54 mmol) and 4-methylmorpholine (0.30 mL, 2.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, the residue was taken up into ethyl acetate (75 mL) and washed sequentially with 1 M hydrochloric acid (2×50 mL), water (50 mL) and brine (50 mL). The organic phase was further diluted with dichloromethane until all the material was in solution, then was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (29:1) afforded N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide (0.34 g, 77%) as a colorless solid: mp 224-226° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ7.32 (dd, J=7.5, 7.5 Hz, 1H), 7.22-7.14 (m, 2H), 7.05 (dd, J=7.8, 7.5 Hz, 1H), 6.96 (m, 1H), 6.62 (m, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 5.06 (d, J=16.4 Hz, 1H), 4.97 (d, J=16.4 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.22-4.14 (m, 2H), 4.14-4.06 (m, 2H), 3.05 (br s, 3H), 2.94 (br s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 158.9, 154.6, 150.8, 147.2, 144.2, 141.8, 137.8, 131.6, 128.8, 123.6, 123.3, 121.2, 116.5, 111.0, 109.9, 109.4, 98.8, 79.3, 64.2, 63.6, 57.2, 37.7, 36.7, 35.8; MS (ES+) m/z 446.9 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26]3[O:31][C:30](=[O:32])[C:29]4[CH:33]=[CH:34][CH:35]=[C:36]([CH3:37])[C:28]=4[N:27]=3)=[CH:24][C:23]([C:38]([F:41])([F:40])[F:39])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>O1CCCC1>[CH:9]1([CH2:12][NH:13][C:30]([C:29]2[C:28]([NH:27][C:26]([C:25]3[N:21]([C:16]4[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:22]=[C:23]([C:38]([F:40])([F:39])[F:41])[CH:24]=3)=[O:31])=[C:36]([CH3:37])[CH:35]=[CH:34][CH:33]=2)=[O:32])[CH2:11][CH2:10]1
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NCC1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NCC2CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
1.49 g of triethylamine was gradually dropwise added to a mixed solution comprising 0.8 g of cyclopropylmethylamine hydrochloride and 40 ml of tetrahydrofuran under cooling with ice, followed by stirring at room temperature for 30 minutes. Then, a mixed solution comprising 1 g of 2-[1-(3-chloro-2-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one and 10 ml of tetrahydrofuran was gradually dropwise added. After completion of the dropwise addition, the mixed solution was reacted for 4 hours under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and to the residue, ethyl acetate and water were added for extraction. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 0.54 g of the desired product having a melting point of 199.4° C.
Reaction SMILES: O.C([O-])([O-])=O.[K+].[K+].[CH3:8][N:9]([CH2:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH2:17][N:18](C(=O)C(F)(F)F)[CH2:19][CH2:20][C:14]=2[CH:13]=1)[CH3:10]>CO>[CH3:8][N:9]([CH3:10])[CH2:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=2[CH:13]=1
Reactant: CN(C)Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
50 mL water and 8.5 g (61.51 mmol) K2CO3 were added to a solution of 4.5 g (14.98 mmol) 1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoroethanone in 50 mL MeOH and the reaction mixture was stirred for 72 h at RT. The reaction solution was evaporated down i.vac., the residue was combined with DCM, filtered to remove insoluble ingredients and evaporated down i.vac. The desired product was obtained in the form of a light-brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][CH2:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CCCI
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 38.2 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (20 mg, 0.077 mmol), potassium carbonate (107 mg, 0.77 mmol) and propyl iodide (0.023 mL, 0.23 mmol) in N,N-dimethylformamide (1 mL) were heated in a sealed vial at 150° C. for 5 minutes. After cooling the reaction was diluted with dichloromethane, washed with water (3 times) and saturated brine, filtered and concentrated. Silica gel chromatography using a mixture of hexanes, ethyl acetate, and dichloromethane (3.5:0.5:4) followed by trituration with diethyl ether and hexanes afforded 9 mg (40%) of 3-(2-pyridyl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ-8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H) 7.39 (s, 1H), 4.06 (t, 2H), 1.88 (m, 2H), 1.08 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[CH:29]=2)=[CH:22][N:21]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[CH:29]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCn1ccc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cc1=O

Procedure:
2-[4-(Dimethylaminomethyl)pyrid-2-ylmethylthio]ethylamine (0.90 g) and 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.12 g) were refluxed in ethanol (15 ml) for 72 hours. As the reaction had not gone to completion, the ethanol was replaced by pyridine (15 ml) and the mixture was refluxed for a further 6 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10](O)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=C=O)=[CH:19][CH:18]=1>C(N(CC)CC)C.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH:10]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[O:5][CH:6]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Br)co1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NC(Nc1ccc(Cl)cc1)C(Cl)(Cl)Cl)c1cc(Br)co1

Procedure:
was prepared in accordance with reported methods: see Ulrich, H. et al J Org. Chem., 33, 1968, 2887. A solution of 4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)furan-2-carboxamide (preparation as for 6 above) (0.566 g, 1.67 mmol), 1-chloro-4-isocyanato-benzene (0.264 g, 1.68 mmol) and triethylamine (2 drops) in benzene (4 mL) was heated at 95° C. for 1.5 h. The mixture was evaporated under reduced pressure. The residue was solvated with chloroform and concentrated onto silica gel. Chromatographic purification on an auto-column with 30% dichloromethane in hexanes gave 4-bromo-N-(2,2,2-trichloro-1-(4-chlorophenylamino)ethyl)furan-2-carboxamide (Compound 33) as a white solid; 422 mg (57%).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.NC1N=CC(C(CC(OC)=O)C(C(OC)=O)(C(OC)=O)C(OC)=O)=CC=1.[OH-].[Na+].Cl>CO>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1
Reactant: COC(=O)CC(c1ccc(NC(=O)OC(C)(C)C)nc1)C(C(=O)OC)C(=O)OC
Agent: COC(=O)CC(c1ccc(N)nc1)C(C(=O)OC)(C(=O)OC)C(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CC(=O)OC)c1ccc(N)nc1
Temperature: 25 °C
Yield: 169 %

Procedure:
To a mixture of trimethyl 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)propane-1,1,3-tricarboxylate (2.5 g, 6.1 mmol) and tetramethyl 2-(6-aminopyridin-3-yl)propane-1,1,1,3-tetracarboxylate (1.8 g, 4.9 mmol) in MeOH (30 mL) was added aqueous NaOH solution (2.44 g NaOH in 5 mL water, 60.9 mmol). The resulting mixture was heated to reflux by oil bath for 1 hour. The reaction mixture was cooled down to room temperature, and concentrated under reduced pressure via rotavap. To the concentrated residue were added water (15 mL) and conc. HCl (3 mL). The resulting mixture was heated to reflux overnight. The reaction mixture was cooled down, and concentrated under reduced pressure via rotavap, and a solid was obtained. The obtained solid residue was triturated with methanol (100 mL) and the precipitates was removed by filtration, and a light color filtrate was obtained. To the filtrate was added conc. HCl (200 μL) and the resulting mixture was heated to reflux via external oil bath for 1 h. The reaction mixture was cooled down, and concentrated. The residue was partitioned between EtOAc/sat. NaHCO3 (50 mL/50 mL). Aqueous layer was extracted with EtOAc (50 mL). The EtOAc extracts were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated. A white solid was obtained as desired dimethyl 3-(6-aminopyridin-3-yl)pentanedioate (2.6 g, 10.31 mmol, 93.9% yield). LCMS (m/z) 253.2 (MH+) 0.38 min; 1H NMR (CDCl3) δ ppm 7.95 (d, J=2.3 Hz, 1H), 7.32 (dd, J=8.2, 2.3 Hz, 1H), 6.46 (d, J=8.6 Hz, 1H), 4.37 (br. s., 2H), 3.61 (s, 6H), 3.55 (quin, J=7.5 Hz, 1H), 2.80-2.66 (m, 2H), 2.65-2.51 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:20]=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23]O.C(OC(=O)C)(=O)C.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1c[nH]c2ccc(C(=O)OCc3ccccc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1c[nH]c2ccc(C(=O)OCc3ccccc3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 3-formyl-1H-indole-5-carboxylic acid benzyl ester (4.3 g) and pyridine (4.8 g) in tetrahydrofuran (60 ml) was added hydroxylamine hydrochloride (1.6 g) at room temperature and this mixture was stirred at 80° C. overnight. Acetic anhydride was added to reaction mixture at the same temperature and this mixture was stirred for 8 hours. After cooling to ambient temperature, 1 mol/L sodium hydroxide solution (20 mL) was added to this mixture and resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and this residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).
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].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]1[CH2:41][NH2:42].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]1[CH2:41][NH:42][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][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:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: NCc1cc2ccccc2[nH]1
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: O=C(NCc1cc2ccccc2[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 43.5 %

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, 20 mg, 0.046 mmol), (1H-indol-2-yl)methanamine (10.17 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (YMC S5 ODS 5u 20×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.3 min) to provide (R/S)-N-((1H-indol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13 mg, 0.02 mmol, 43.7% yield): LCMS=560.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.20 (2 H, m), 7.55-7.75 (9 H, m), 7.27-7.46 (2 H, m), 6.92-7.08 (2 H, m), 6.29 (1 H, s), 5.20 (1 H, s), 4.48-4.64 (2 H, m); HPLC peak RT=10.7 min (Method A).