Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:24].Cl.[CH2:27](O)[CH2:28][CH2:29]C>>[CH2:2]([O:3][C:4]([C:5]1[N:6]=[C:14]([OH:15])[C:13]2[C:8]([C:7]=1[OH:24])=[CH:9][CH:10]=[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:12]=2)=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)cc3)cc2C1=O
Reactant: CCCCO
Agent: Cl
Agent: [Na]
Product: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc(F)cc3)ccc2c1O
Temperature: 70 °C

Procedure:
Sodium (7.2 g, 310 mmol) was dissolved in n-butanol (300 ml) with stirring at 70° C. Afterwards, the temperature was raised to 95-100° C. and a solution of [5-(4-Fluoro-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester (49.4 g, 150 mmol) in hot n-butanol (300 ml) was added with vigorous stirring. The mixture was stirred for another 90 min at 95-100° C. and was then allowed to cool to 60° C. with stirring before 2 N HCl (160 ml) was added. The mixture was stirred vigorously for 30 min and was then allowed to cool to ambient temperature. Subsequently, the mixture was submitted to vacuum filtration. The filter cake was washed thoroughly with water and dried in vacuo at 70° C. to give a pale yellow solid. Purification by flash column chromatography on silica gel using CH2Cl2 EtOAc=98 2 as the eluent gave the title compound (14.4 g, first fraction); 1H NMR (CDCl3) δ=8.40 (br s, 1H), 8.14 (d, 1H), 7.80 (d, 1H), 7.42 to 7.48 (m, 1H), 7.04 to 7.14 (m, 4H), 4.39 (t, 2H), 1.70 to 1.85 (m, 2H), 1.37 to 1.55 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]Br)=[C:6](CCC)[C:5]=1O)(=[O:3])[CH3:2].[Br:19][C:20]1[CH:30]=[CH:29][C:23]([O:24]CCCBr)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH2:2][CH2:2][CH2:1][C:4]3[CH:14]=[CH:13][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[CH:29][CH:30]=1
Reactant: BrCCCOc1ccc(Br)cc1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Product: OC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(Br)cc2)cc1

Procedure:
Following the procedure of Step 2 of Example 1, but substituting 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide for the bromide from Step 2, the title compound was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23]4[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=4)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31]CN=C=NCCCN(C)C.Cl.C(O)=O>CN(C1C=CN=CC=1)C.ClCCl>[NH:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:22]3[C:16]4[O:15][C:14]([NH:13][C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:18][C:17]=4[CH:19]=[CH:20][CH:21]=3)=[CH:24][C:25]=2[N:30]=[CH:31]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)c(N)c4)c3o2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=CO
Product: COc1cc(Nc2nc3cccc(-c4ccc5[nH]cnc5c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.16 g (0.228 mmol) 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine, 0.068 g (0.346 mmol) EDC-HCl, 0.043 g (0.345 mmol) DMAP, 0.012 g (0.27 mmol) formic acid), and 7 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc:MeOH=9:1) to afford ca. the title compound. 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine is prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene-1,2-diamine as described in Example 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>CCO>[C:10]1([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2ccco2)cc1
Temperature: 140 °C

Procedure:
Furan-2-boronic acid (22) (3.6 g, 32.14 mmol) was coupled to bromobenzene (21) (4.2 g, 26.79 mmol) using Method E, except that Cs2CO3 (17.47 g, 53.58 mmol), Pd(PPha)4 (6.20 g, 0.54 mmol), toluene (25 mL) and EtOH (25 mL) were used and the reaction heated in a CEM Discover microwave at 140° C. (200 W, 200 psi). The crude product was purified by dry-flash chromatography eluting with EtOAc in heptane to yield the title compound. Yield: 2.94 g, 62%; LC tr 1.50 min; HPLC Purity: 84%
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33](Cl)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:33](=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC(C)CC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CC(C)C)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, isovaleryl chloride (24 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 20×50 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (22.4 mg, 68% of theory).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].C([Sn]([N:26]=[N+:27]=[N-:28])(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CCOCC>[NH:26]1[C:1]([CH2:3][C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])=[N:2][N:28]=[N:27]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCC(=O)Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1nnn[nH]1)Nc1ccccc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of 2-cyano-acetanilide (0.801 g, 5.0 mmol) and tri-n-butyltin azide (2.05 mL, 7.5 mmol) in anhydrous toluene (10 mL) was heated at reflux for 48 hrs. The mixture was allowed to cool to room temperature and treated with 2.0 N HCl in Et2O (5.0 mL). The resulting precipate was collected by suction, washed with hexane and dried in vacuo to give 2-(1H-tetrazol-5-yl)acetanilide (0.917 g, 90%) as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[CH2:13][C:12](=[O:16])[C:11]([CH3:18])([CH3:17])[O:10]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([Pb+3])=[C:35]([CH2:40][CH3:41])[CH:34]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([CH:13]2[C:14](=[O:15])[C:9]([CH3:19])([CH3:8])[O:10][C:11]([CH3:18])([CH3:17])[C:12]2=[O:16])=[C:35]([CH2:40][CH3:41])[CH:34]=1
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Dimethylaminopyridine (3.13 g, 25.7 mmol) and toluene (10 ml) are added to a solution of 2,2,6,6-tetramethylpyran-3,5-dione (0.87 g, 5.13 mmol) in chloroform (40 ml) and the reaction mixture is heated to 80° C. 4-Bromo-2-ethylphenyllead triacetate (3.50 g, 6.16 mmol) is added portionwise over 5 minutes, and once the addition is complete the reaction mixture is stirred at 80° C. for a further 4 hours. The mixture is cooled to room temperature, 2M aqueous hydrochloric acid (40 ml) is added, and the mixture is stirred vigorously for 20 minutes, then filtered through a small plug of diatomaceous earth, washing with dichloromethane (40 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (2×40 ml). The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]=[CH:21][N:20]=1)=[O:18].[C:40](Cl)(=[O:43])[CH2:41][CH3:42]>>[C:29]([O:28][C:26]([N:25]([C:23]1[CH:22]=[CH:21][N:20]=[C:19]([C:17]([C:3]2[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]3[C:10]([C:2]=2[NH:1][C:40](=[O:43])[CH2:41][CH3:42])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=3)=[O:18])[CH:24]=1)[C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCOC(=O)n1c(C(=O)c2cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccn2)c(N)c2ccc(Cl)cc21
Reactant: CCC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccn2)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according ot the procedure described in step 1 of Example 2 (Method A) employing 3-amino-2-[4-[N,N-bis(tert-butoxycarbonyl)amino]pyridine-2-carbonyl]-6-chloro-1-(ethoxycarbonyl)indole (step 2) and propionyl chloride. 1H-NMR (CDCl3) δ: 9.52 (1 H, br s), 8.61 (1 H, d, J=5.1 Hz), 8.21 (1 H, d, J=1.8 Hz), 8.05 (1 H, d, J=8.7 Hz), 7.95 (1 H, d, J=2.1 Hz), 7.28-7.23 (2 H, m), 3.93 (2 H, q, J=7.1 Hz), 2.51 (2 H, q, J=7.4 Hz), 1.50 (18 H, s), 1.26 (3 H, t, J=7.4 Hz), 1.02 (3 H, t, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[CH3:18][Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:16])[OH:17]
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cc(-c2cccc(Cl)c2)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (.55 g, 2.2 mmol) in anhydrous THF under nitrogen was added a solution of methyl magnesium bromide (3.0 M in diethyl ether, 1 mL, 3 mmol) at 0° C. The mixture was slowly warmed to room temperature and kept stirring under nitrogen for 18 hours. The mixture was treated with 10 mL of saturated ammonium chloride aqueous solution and ethyl acetate (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO4). After removal of the solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford the title compound as an off-white solid: 186-188° C. (HCl salt). Anal. Calc. For C15H17Cl2NO: C, 60.42, H, 5.75, N, 4.7. Found: C, 60.51, H, 5.62, N, 4.56.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=CC2C=CC=CC=2)=[CH:5][N:4]=[C:3]1[N+:15]([O-:17])=[O:16].C[OH:19]>O=[Os](=O)(=O)=O.O>[CH3:1][N:2]1[C:6]([CH:7]=[O:19])=[CH:5][N:4]=[C:3]1[N+:15]([O-:17])=[O:16]
Reactant: CO
Reactant: Cn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cn1c(C=O)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 60 %

Procedure:
To a solution of 0.8 g. of 1-methyl-2-nitro-5-styrylimidazole in 300 ml. of methanol, a solution of 1.6 g. of NaIO4 in 40 ml. of water, and 0.02 g. of OsO4 are added. The mixture is stirred at room temperature for 10 hours, then an additional 0.01 g. of OsO4 is added and stirring is carried on for 8 hours. The reaction mixture is filtered and evaporated to dryness under vacuum at room temperature. The residue is extracted with ethyl acetate. After concentration of the resulting solution, 0.325 g. of the product are obtained. Yield 60%.
Reaction SMILES: [N:1]12[CH2:9][C@@H:5]([CH2:6][CH2:7][CH2:8]1)[C@@H:4]([O:10]C(=O)C)[CH2:3][CH2:2]2>[OH-].[Na+]>[N:1]12[CH2:9][C@@H:5]([CH2:6][CH2:7][CH2:8]1)[C@@H:4]([OH:10])[CH2:3][CH2:2]2
Reactant: CC(=O)O[C@H]1CCN2CCC[C@@H]1C2
Agent: [Na+]
Agent: [OH-]
Product: O[C@H]1CCN2CCC[C@@H]1C2
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
(4S,5R)-acetic acid 1-aza-bicyclo[3.3.1]non-4-yl ester (5.45 g, 29.7 mmol) is dissolved in 10% aq. NaOH soln. and stirred for 1 h at 50° C. After cooling to rt, the mixture is extracted with THF/brine. The organic layer is dried over Na2SO4, filtered and the filtrate is evaporated to give 3.83 g (91%) of (4S,5R)-1-aza-bicyclo[3.3.1]nonan-4-ol, which is dissolved in 50 ml THF and cooled to 0° C. NHMDS (35 ml of 1 M THF soln.) is added dropwise, the reaction mixture is stirred at rt for 0.5 h and then added to a precooled soln. (−15° C.) of 5-bromo-2-chloro-pyrimidine (5.89 g, 30.5 mmol) in THF. The mixture is stirred for 15 h at rt, then diluted with THF and extracted with 1M aq. NaOH soln. and brine. The aq. layers are 2× reextracted with THF, the combined organic layers are dried over Na2SO4, filtered and the filtrate is evaporated. The resulting crude product (10.15 g) is recrystallized from CH3CN/MeOH to give 5.21 g (65%) of (4S,5R)-4-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[3.3.1]nonane.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.CC[N:18]([CH:22]([CH3:24])C)[CH:19]([CH3:21])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1>CN(C=O)C>[Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([N:18]1[CH2:19][CH2:21][CH2:24][CH2:22]1)=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(c1cc(-c2ccccc2)sc1Cl)N1CCCC1
Temperature: 25 °C
Yield: 252.4 %

Procedure:
2-Chloro-5-phenyl-thiophene-3-carboxylic acid (28 mg, 0.11 mmol) was dissolved in DMF (1 mL). DIPEA (0.22 mmol), HATU (0.11 mmol) and pyrrolidine (0.11 mmol) were added and the reaction mixture stirred at room temperature. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic solution was separated and dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by preparative HPLC, eluting with 50%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (81 mg). LCMS m/z 292.10 [M+H]+ R.T.=11.27 mins (Analytical Method 1)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1.[CH3:32][C:33]1([CH3:41])[CH2:38][CH2:37][C:36](=[O:39])[O:35][C:34]1=[O:40].C(N(CC)CC)C>CS(C)=O>[CH3:32][C:33]([CH3:41])([CH2:38][CH2:37][C:36](=[O:39])[N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:23])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1)[C:34]([OH:40])=[O:35]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: O=C(Nc1ccc(OC2CCCNC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(CCC(=O)N1CCCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1)C(=O)O
Yield: 56.4 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl]-amide (44.1 mg, 0.102 mmol), 3,3-dimethyl-dihydro-pyran-2,6-dione (17.5 mg, 0.122 mmol) and triethylamine (28.5 uL, 0.204 mmol) in 1 mL DMSO were treated as above. The crude product was purified by flash chromatography to yield 2,2-dimethyl-5-oxo-5-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidin-1-yl)-pentanoic acid as a white solid (33 mg, 56%). ES-MS calcd for C29H30F3N3O6 (m/e) 573.57, obsd 574 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[NH:23][NH2:24]>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:24][NH:23][C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol) in 120 mL of anhydrous CH2Cl2 was treated with triethylamine (6.7 mL, 48.2 mmol) and tert-butyl carbazate (3.20 g, 24.2 mmol). After stirring under nitrogen for 2.5 hour (h), an additional portion of tert-butyl carbazate (3.2 g, 24.2 mmol) was added. After stirring overnight, the deep red solution was washed with H2O (2×) and brine. The organic portion was dried over Na2SO4 and concentrated to give a red foam. The material was passed through a SiO2 column eluting with 2.5% methanol/CH2Cl2. The resulting red powder was treated with 5:1 hexanes/CH2Cl2 and filtered. The solid was washed several times with hexanes and was dried under vacuum to give tert-butyl N′-(3-nitroquinolin-4-yl)hydrazinecarboxylate (4.97 g) as an orange powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH2:15](OC=O)[CH3:16].C(OC(=O)C)(=O)C>>[CH2:15]([NH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: COc1ccc2c(c1)OCCC2CN
Reactant: CCOC=O
Solvent: CC(=O)OC(C)=O
Product: CCNCC1CCOc2cc(OC)ccc21

Procedure:
The product from Example 2 was reacted as described in Example 3 replacing ethylformate with acetic anhydride, giving the desired product, (M+H)+ 222. 1H NMR(CDCl3): 1.15 (t,3H); 2.05 (m,2H); 2.6-2.0 (m,4H); 3.75 (s,3H); 4.2 (m,1H), 6.3-7.1 (m,3H).
Reaction SMILES: [N:1]1([C:10]2[C@:11]3([CH2:28][CH2:27][C@H:26]4[C@@H:16]([CH2:17][CH2:18][C:19]5[C@:24]4([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=5)[C@@H:13]3[CH2:14][CH:15]=2)[CH3:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li][CH3:31]>C1COCC1>[CH3:31][C:21]1([OH:29])[CH2:22][CH2:23][C@@:24]2([CH3:25])[C:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:26]2[CH2:27][CH2:28][C@@:11]2([CH3:12])[C@H:13]3[CH2:14][CH:15]=[C:10]2[N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:20]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC1(O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(n5cnc6ccccc65)=CC[C@@H]34)[C@@]2(C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of ketone (32) (0.1 g, 0.26 mmol) in dry THF (3 mL) was added MeLi (1.6 M solution in ether, 0.41 mL, 0.60 mmol) at −60° C., and the resulting mixture was stirred at 0° C. for 1 h then room temperature for 3 h. The reaction was quenched with saturated aqueous NH4Cl and was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by short FCC [petroleum ether, EtOAc, TEA (60:40:0.5)] to afford product 40 (0.05 g, 48%); mp 95-97° C.; IR (Neat) 3329, 2827, 2853, 1489, 1453, 1376, 1292, 1226, 1133, 918, 741 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.00 (s, 3H, 18-CH3), 1.07 (s, 3H, 19-CH3), 1.27 (s, 3H, C3-CH3), 5.25 (t, J=1.6 Hz, 1H, 6-H), 5.96 (t, 1H, J=1.52 Hz, 16-H), 7.29 (m, 2H, aromatic-Hs), 7.49 (m, 1H, aromatic-H), 7.82 (dd, J=7.0, 2.6 Hz, 1H, aromatic-H), and 7.95 (s, 1H, 2′-H); 13C NMR (500 MHz, CDCl3) δ 145.3, 127.6, 124.4, 123.6, 122.7, 120.4, 111.4, 70.1, 55.7, 54.8, 37.8, 35.6, 35.3, 34.7, 32.5, 30.4, 28.5, 21.1, 18.8, 16.3. HRMS calcd 425.2563 (C27H34ON2.Na+). found 425.2570.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24]Cl)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:26][C:27]1[C:32]([CH2:33][CH2:34][CH3:35])=[C:31]([SH:36])[CH:30]=[CH:29][C:28]=1[C:37](=[O:39])[CH3:38].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][S:36][C:31]2[CH:30]=[CH:29][C:28]([C:37](=[O:39])[CH3:38])=[C:27]([OH:26])[C:32]=2[CH2:33][CH2:34][CH3:35])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCl)ccc(C(C)=O)c1OCCCC(=O)OCC
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(SCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 19 h
Yield: 82.8 %

Procedure:
A mixture of ethyl 4-[6-acetyl-3-(2-chloroethoxy)-2-propylphenoxy]butyrate (0.60 g), (2-hydroxy-4-mercapto-3-propylphenyl)ethanone (0.51 g), potassium iodide (0.1 g) and potassium carbonate (0.65 g) in acetone (40 ml) was heated and refluxed with stirring for 19 hours. After cooled, inorganic materials were separated by filtration and the filtrate was concentrated. The resultant residue was separated and purified through silica gel column chromatography (eluting with benzene:ethyl acetate=15:1, then 9:1) to give the title compound (0.73 g, 82.8%) as brown oil.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[C-:13]#[N:14].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]([OH:8])[C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(OC(F)F)c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)c1cccc(OC(F)F)c1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To 3-difluoromethoxybenzaldehyde (1.77 g, 10 mmol) in ethyl acetate (25 mL) was added a solution of KCN (2.0 g) and NaHSO3 (3.2 g) dissolved in H2O (25 mL). It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 131A (1.85 g, 92% yield) as an oil.
Reaction SMILES: Cl[C:2]1([CH2:7][Cl:8])[O:5][C:4](=[O:6])[CH2:3]1.[CH3:9][OH:10]>C(=O)(O)[O-].[Na+]>[CH3:9][O:10][C:4](=[O:6])[CH2:3][C:2]([CH2:7][Cl:8])=[O:5]
Reactant: CO
Reactant: O=C1CC(Cl)(CCl)O1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CC(=O)CCl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7.8 Parts of 4-chloro-4-chloromethyloxetan-2-one are dissolved in 200 parts of methanol containing 4.2 parts of anhydrous sodium bicarbonate. After stirring for 20 hours at room temperature, the solids are filtered off, the filtrate is evaporated and the residue distilled to give methyl-γ-chloroacetoacetate, b.p. 48°-50° C./0.8 mb.