Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].[N:22](OCCC(C)C)=[O:23]>C1COCC1.CCOC(C)=O>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=[N:22][OH:23])[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:19])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)CCON=O
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=NO)C(=O)c2ccccc2)ccc1=O
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (513 mg) was added to a suspension of NaH (60% dispersion in mineral oil) (84 mg) in THF (5 ml) and the mixture was stirred at 45-50° C. for 30 minutes. After addition of isoamyl nitrite (0.27 ml), the mixture was stirred at the same temperature for 8 hours. The mixture was dissolved in EtOAc, washed with 1N HCl and brine and dried over MgSO4. The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime as a solid (185 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:13][C:12]2[CH:14]=[C:15]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])[CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH2:8]1.[Al].C(OCC)C.C(O)C>COCCOC.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:13][C:12]2[CH:14]=[C:15]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])[CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(c2)CN(c2ccccn2)CCO3)S1
Agent: [Al]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc3c(c2)CN(c2ccccn2)CCO3)S1
Temperature: -2.5 °C
Reaction time: 0 h

Procedure:
5-(4-Pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine -2,4-dione [compound of Example 3] (0.54 g, 1.5 mmol) was taken in 1,2-dimethoxyethane (45 mL) and heated to dissolve. The reaction mixture was then cooled to −5 to 0° C. and to this solution kept under nitrogen, were added pieces of aluminum foil (10×10×0.02 mm, 0.306 g, 11.3 mmol) which had been freshly dipped for 10 seconds sequentially in each of diethyl ether, ethanol, 2% aqueous mercuric chloride solution, ethanol and again diethyl ether. To the reaction mixture, water was added (0.45 mL), and stirred for 3.5 hours at −5 to 0° C. under N2 atmosphere. To this solution, celite (2.4 g) was added, stirred at room temperature for 5 min, filtered through a celite bed and washed with DMF (3×60 mL). The filtrate was concentrated to give crude material (0.820 g) which was purified by silica chromatography using 1% CH2Cl2 in MeOH, to give 5-(4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yl-methyl)-thiazolidine-2,4-dione.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1.CN(C)C=[O:20]>C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([OH:20])[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1
Reactant: CN1CCC(c2ccc(Br)cn2)C1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCC(O)(c2ccc(Br)cn2)C1=O
Reaction time: 1.5 h

Procedure:
Sodium hydride (55% in mineral oil, 0.13 g) was added to a solution of 3-(5-bromo-pyridin-2-yl)-1-methyl-pyrrolidin-2-one (0.69 g) in N,N-dimethylformamide (10 mL) at room temperature. The resulting mixture was stirred in the presence of air for 1.5 h and then diluted with ethyl acetate. The precipitate formed thereafter was separated by filtration, washed with ether, and dried. The title compound was obtained as a colorless solid. Yield: 0.71 g (93% of theory); LC (method 1): tR=1.38 min; Mass spectrum (ESI+): m/z=271/273 (Br) [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15](Cl)=[O:16])=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:16])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: COc1ccc(C=CC(=O)N2CCCCC2)cc1

Procedure:
In a conical flask, 1.96 g of the paramethoxycinnamoyl chloride are dissolved in 20 ml of benzene. 2 ml of piperidine are added. After evaporation to dryness in vacuo, the residue is taken up in N hydrochloric acid and extracted with chloroform. The chloroform solution is washed successively with a 10% aqueous solution of KHCO3 and with water. It is then collected, dried over magnesium sulfate and evaporated. The product obtained is precipitated in cyclohexane and filtered off. After recrystallization from a 95° ethanol/water mixture (1/3:2/3), 2.15 g of white crystals are isolated (yield=78%).
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[C:7]([CH3:10])[C:6]([Cl:11])=[C:5](Cl)[C:3]=1[NH2:4].C1(O)C=CC=CC=1.[H][H].Cl>[Pd].O.C1(C)C=CC=CC=1.[Ta]>[Cl:9][C:8]1[CH:2]=[C:3]([CH:5]=[C:6]([Cl:11])[C:7]=1[CH3:10])[NH2:4]
Reactant: Cc1c(Cl)c(Cl)c(N)c(Cl)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Ta]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1c(Cl)cc(N)cc1Cl
Yield: 98 %

Procedure:
61.5 parts of 2,3,5,6-tetrachloro-4-methylaniline, 180 parts of phenol and 15 parts of a 1% strength palladium/charcoal catalyst are reacted with hydrogen under a maximum pressure of 50 bar at 180° C. in a tantalum autoclave, in the presence of a small amount of hydrochloric acid, in the course of 5 hours, while stirring. After the pressurized vessel has been cooled and the pressure released, the mixture is diluted with 300 parts of water and 200 parts of toluene, rendered alkaline, heated to 90°, and separated from the catalyst. The catalyst is boiled up with toluene, and the combined toluene solutions are distilled. 44 parts of 3,5-dichloro-4-methylaniline, bp. 146°-155°/18 mbar, 98% strength, are obtained; yield: 98% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2cccc(Cl)c2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-3-{1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester, which was subsequently saponified to yield rac-3-{1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid as brown solid.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[NH:21][C:20](=[O:25])[C:19]3[NH:26][CH:27]=[CH:28][C:18]=3[C:17]=2[CH:16]=1)=O.[CH2:29]([C:31]([O-:33])=[O:32])[CH3:30].C(N(CC)CC)C>C(O)C>[O:25]=[C:20]1[C:19]2[NH:26][CH:27]=[CH:28][C:18]=2[C:17]2[CH:16]=[C:15]([C:13]3[N:10]=[C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:9][CH:12]=3)[CH:24]=[CH:23][C:22]=2[NH:21]1.[CH2:29]([C:31]([O-:33])=[O:32])[CH3:30]
Reactant: NC(=S)Nc1ccccc1
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(-c3csc(Nc4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
34 mg (1.5 mmol) of N-phenylthiourea is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90° C. for 48 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added, then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol/triethylamine 8/2/1). After drying, 11 mg (17%) of 4-oxo-8-(2-phenylamino-thiazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16](=[O:29])[CH:17]=[C:18]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=2)[CH2:19]1)[CH3:14].C(N(CC)CC)C>[Cu](I)I.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.ClCCl>[CH2:13]([O:15][C:16](=[O:29])[CH:17]=[C:18]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:12])[F:1])=[CH:5][CH:6]=3)[CH:23]=2)[CH2:19]1)[CH3:14]
Reactant: CCOC(=O)C=C1CC(c2cccc(Br)c2)C1
Reactant: C#Cc1ccc(OC(F)F)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Yield: 54.8 %

Procedure:
In a CEM snap top microwave vial were combined 1-Difluoromethoxy-4-ethynyl-benzene (1.48 g, 8.80 mmol), [3-(3-Bromo-phenyl)-cyclobutylidene]-acetic acid ethyl ester (2.00 g, 6.78 mmol), Copper iodide (232 mg, 0.131 mmol), Tetrakis(triphenylphosphine)palladium (470 mg, 1155.56 g/mol, 0.046 mmol), and triethylamine (20 g, 198 mmol). The capped vial was placed in a CEM Explorer microwave instrument and irradiated for 30 minutes at 80° C. The crude reaction mixture and dichloromethane washings were poured directly onto silica gel. Purification by column chromatography (isocratic; 5% EtOAc in hexanes) afforded an oil 1.42 g (55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.2 Hz, 3H) 2.94-3.03 (m, 1H) 3.06-3.16 (m, 1H) 3.19-3.28 (m, 1H) 3.49-3.60 (m, 1H) 3.62-3.72 (m, 1H) 4.08 (q, J=7.2 Hz, 2H) 5.68-5.78 (m, 1H) 7.06-7.32 (m, 3H) 7.39 (dd, J=8.8, 3.7 Hz, 3H) 7.46-7.52 (m, 1H) 7.62 (d, J=8.8 Hz, 2H); MS (ES) m/z 383.1 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH:19]1[O:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[OH:21][CH:19]([CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9])[CH2:20][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CCNCC1
Reactant: COc1ccccc1OCC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CN1CCC(=O)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 20 g of the hydrate of 4-piperidone-hydrochloride, 46.8 g of 1-(2-methoxyphenyloxy)-2,3-epoxy-propane, 18 g of potassium carbonate and 250 ml of isopropanol is stirred for 6 hours at a reaction temperature of 60° C. After cooling, the suspension is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of 6N hydrochloric acid and washed with four 75 ml portions of ethyl acetate. The aqueous acid solution is adjusted with a 2N sodium carbonate solution to a pH of 10 and extracted with three 75 ml portions of ethyl acetate. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. The red residue is dissolved in methanol and the solution is boiled for 30 minutes with the addition of activated charcoal. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of ethyl acetate and petroleum ether to give 1-[2-hydroxy-(2-methoxyphenyloxy)-propyl]-piperidin-4-one with a melting point of 77°-78° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][OH:34])[CH:14]([N:16]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]3=[O:32])[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:36]>[Ag]=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][O:34][CH3:36])[CH:14]([N:16]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C:17]3=[O:32])[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC2CC(N3CCC(NC(=O)OCc4ccccc4)C3=O)C(CO)C2C1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COCC1C2CN(C(=O)OC(C)(C)C)CC2CC1N1CCC(NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
A solution of 5-(3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-4-hydroxymethyloctahydrocyclopenta[c]-pyrrole-2-carboxylic acid tert-butyl ester in a small amount of DMF and a large excess of iodomethane is treated with silver oxide and stirred at room temperature until the reaction is complete. Upon completion of the reaction, the reaction mixture is filtered through celite and concentrated under vacuum yielding a residue. The residue is purified by flash column chromatography providing the title product.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:22]([NH:24][N:25]1[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[NH:27][C:26]1=[O:33])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C(OC([C@H]([C@@H](CC(C)C)C(NN)=O)CCCC1C=CC=CC=1)=O)(C)(C)C.N(C(C)(C)C(OCC)=O)=C=O>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:22]([NH:24][N:25]1[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[NH:27][C:26]1=[O:33])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC(C)(C)C1=O)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Agent: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCOC(=O)C(C)(C)N=C=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC(C)(C)C1=O)[C@H](CCCc1ccccc1)C(=O)NO

Procedure:
The 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-4-methyl-N-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)valeramide used as the starting material was prepared in a manner analogous to that described in Example 7, part (ii) and Example 1, parts (vii) and (viii), starting from 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide and ethyl 2-isocyanato-2-methylpropionate.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH2:7][CH2:8][C:9]#[N:10])[CH:5]=1
Reactant: Cc1sccc1CCC#N
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc(Br)cc1CCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of 3-(2-methylthiophen-3-yl)-propionitrile 60 (320 mg, 2.1 mmol) in acetic acid (5 mL) was treated with bromine (0.12 mL, 2.3 mmol) and the mixture stirred at rt for 1 hour. Water was added and the mixture was extracted with EtOAc (2×20 mL). The combined organics were washed with water and dried over MgSO4. Removal of the solvent followed with silica gel column chromatography (eluent: DCM/hexane, 1/1) gave 61 as a colorless liquid (330 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC(C(F)(F)F)=O.[NH2:24][C@@H:25]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([C@@:28]1([CH3:31])[CH2:30][O:29]1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:24][C@@H:25]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26]([C@@:28]2([CH3:31])[CH2:30][O:29]2)=[O:27])=[O:12])[CH2:16][CH2:15]1
Reactant: C[C@]1(C(=O)[C@@H](N)Cc2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid (1.02 g, 4.44 mmol) was added (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one TFA salt (1.34 g, 4.44 mmol), HATU (2.02 g, 5.33 mmol), and DMF (10 mL). The mixture was cooled to 0° C. and DIEA (3.09 mL, 17.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-70% ethyl acetate/heptane) provided tert-butyl ((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (1.33 g, 72%) as a colorless solid. MS (EI) for C23H32N2O5, found 417.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[O:6])[CH2:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[N:19]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: Cc1cccc(Cl)n1
Product: O=C(Cc1cccc(Cl)n1)c1ccccc1Br
Yield: 77 %

Procedure:
In a similar manner as described in Example 1 from ethyl 2-bromobenzoate (50.0 g, 218 mmol) and 6-chloro-2-picoline (24 mL, 218 mmol), 1-(2-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (52.4 9, 77%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 7.53 (d, 1 H), 7.45 (d, 1 H), 7.25 (d, 1 H), 7.05 (d, 1 H), 6.97 (d, 1 H), 6.67 (d, 1H), 6.53 (d, 1H), 5.28 (s, 1H); MS m/z 310 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([CH2:25]O)[CH:10]=2)=[CH:5][CH:4]=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([CH2:25][N:33]3[C:29](=[O:39])[C:30]4[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:32]3=[O:34])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COc2cnc(CO)cc2OCc2ccc(OC)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cnc(CN3C(=O)c4ccccc4C3=O)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of (4,5-bis(4-methoxybenzyloxy)pyridin-2-yl)methanol (Intermediate 63, 1.5 g, 3.93 mmol), phthalimide (0.579 g, 3.93 mmol) and triphenylphosphine (1.028 g, 3.93 mmol) in THF (15 mL) at room temperature was added diisopropyl azodicarboxylate (2.091 mL, 10.62 mmol). The reaction was stirred at room temperature overnight then concentrated onto silica gel. Silica gel chromatography (0%-70% ethyl acetate) afforded the title compound as a light brown solid (1.1 g, 55%).
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=2)=[CH:4][N:3]=1)=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=3.[O-:27][CH2:28][CH3:29].[Na+]>C(O)C>[CH2:25]([S:22]([C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:14]4[CH:13]=[C:12]([CH3:15])[CH:11]=[N:10][C:9]=4[NH:8][C:7]=3[C:2]([O:27][CH2:28][CH3:29])=[N:3][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CC[O-]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(-c2cccc(S(=O)(=O)CC)c2)c2c1[nH]c1ncc(C)cc12
Yield: 78 %

Procedure:
Compound 32 (4 mg, 0.01 mmol) was heated in a solution of sodium ethoxide in ethanol (21 wt. %, 0.5 mL) at 200° C. in the microwave for 30 min. Purification by prep-HPLC gave 3.2 mg (78%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD-d4): δ 8.47 (br s, 1H), 8.18 (s, 1H), 8.03 (d, 1H, J=7.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.81-7.89 (m, 3H), 4.63 (q, 2H, J=7.2 Hz), 3.26 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.56 (t, 3H, J=7.6 Hz), 1.32 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for C21H21N3O3S, 396; found 396.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH:16]1[CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:15][CH:16]1[CH2:18][O:17]1
Reactant: ClCC1CO1
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCC1CO1)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H, 5.0 g, 0.028 mole), 2-chloromethyl-oxirane (4.4 mL, 0.056 mole), and potassium carbonate (11.6 g, 0.084 mole) was stirred in 50 mL of DMF at 70° C. overnight under Argon. The reaction was then diluted with 200 mL of ethyl acetate and washed 3 times with water. The ethyl acetate solution was dried over sodium sulfate and the solvent removed in vacuo to yield the title compound (Intermediate M). MS m/z 236 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(F)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(F)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A suspension of 5-fluoro-isophthalic acid dimethyl ester (1.7 g, 8.0 mmol) in methanol (41 ml) was treated with 1.0 N sodium hydroxide (7.2 ml, 7.2 mmol). The reaction was left stirring overnight at room temperature. After the solution was concentrated, the residue was dissolved in water and transferred to a separatory funnel. The aqueous layer was washed with dichloromethane (3 times) and then acidified with 1.0 N HCl to pH 2. Ethyl acetate was used to extract the precipitate, which was then washed with brine and dried over anhydrous sodium sulphate. After removal of solvent in vacuo, a total of 1.3 g (83%) of 5-fluoro-isophthalic acid monomethyl ester was isolated as a white solid. 1H NMR (DMSO), δ (ppm): 8.31 (t, 1H), 7.96 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=O)C>CO>[O:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(-c2ncco2)cc1
Solvent: CO
Product: Oc1ccc(-c2ncco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 789.7 %

Procedure:
To a solution of 4-(2-oxazolyl)phenyl acetate (44.7 g, 22 mmol) in methanol (500 ml) was added an aqueous solution of potassium carbonate KOH (176 g in 800 mL, 5.8 eq.). The reaction was stirred at ambient temperature for 1 hour under nitrogen. Methanol was removed under reduced pressure and the residue was treated with concentrated hydrochloric acid to give a slurry with a pH of 6. The precipitated solid was isolated by filtration and dried to give 35 g. Recrystallization from methanol gave 4-(2-oxazolyl)phenol (28 g, 79% th.; 63% pract); 1H NMR (DMSO) δ 10.05 (s, 1H), 8.10 (s, 1H), 7.75 (d, 2H), 7.20 (s, 1H), 6.85 (d, 2H) ppm.