Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:16]([OH:36])[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][N:23]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[C:20]2=[N:21][CH:22]=1)[CH2:13][CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:13][CH2:14][CH3:15])[C:16]([C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][N:23]([Si:26]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:34])[CH3:35])[CH:27]([CH3:28])[CH3:29])[C:20]2=[N:21][CH:22]=1)=[O:36])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC1(C(O)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCC1(C(=O)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CCCN1C(=O)OC(C)(C)C
Yield: 78.5 %

Procedure:
To a stirred solution of 2-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.528 g, 1.03 mmol) in DCM (15 mL) at ambient temperature under nitrogen was added DMP (0.652 g, 1.54 mmol) in a single portion. After 90 minutes the reaction mixture was diluted with DCM, washed with 1 N NaOH and brine, then dried (MgSO4), filtered and concentrated in vacuo to a brown oil. Purification by chromatography (silica, 5 to 10% EtOAc in hexanes) gave 2-propyl-2-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.415 g, 0.809 mmol, 79%) as a yellow gum.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:33]S(C)(=O)=O)=[N:27][C:28]([S:31][CH3:32])=[N:29][CH:30]=1.[NH4+].[Cl-]>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:33][C:26]3[C:25]([Br:24])=[CH:30][N:29]=[C:28]([S:31][CH3:32])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CSc1ncc(Br)c(CS(C)(=O)=O)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (12.00 g, 38.3 mmol) in THF (200 mL) was cooled to 0° C. NaH (0.919 g, 38.3 mmol) was added. The mixture was stirred at 0° C. for 30 min. The title compound from Step A (10.0 g, 31.9 mmol) in THF (30 mL) was added. The mixture was stirred at 0° C. and then room temperature for 4 h. Saturated NH4Cl (10 mL) was added. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 65i, eluting with EtOAc/hexane (20/80) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.57 (s, 1H), 7.94 (s, 1H), 7.82 (s, 2H), 5.86 (d, J=8.5 Hz, 1H), 4.97 (d, J=18.0 Hz, 1H), 4.46 (m, 1H), 4.28 (d, J=17.5 Hz, 1H), 2.60 (s, 3H), 0.83 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:32]([CH:28]4[CH2:31][CH2:30][CH2:29]4)=[O:33])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)C1CCC1
Product: C[C@H](NC(=O)C1CCC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and cyclobutanecarbonyl chloride (18 mg, 150 μmol). Yield 18 mg (82%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][N:29]=3)(=[O:27])=[O:26])[N:14]([CH3:37])[N:13]=2)=[N:6][CH:7]=1.C([O-])=O.[Na+].[C]=O>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.CN(C)C=O>[CH:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:37])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][CH:2]=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:26])=[O:27])=[N:29][CH:30]=1)([CH3:36])[CH3:35]
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C[O-]
Agent: [C]=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(OCCOc3ncccn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropylpyridine-2-sulfonamide (Example 41) (393 mg), powdered sodium formate (68 mg) and dichlorobis(triphenylphosphine)palladium (II) (9.4 mg) were placed in a Wheaton® vial (2.5 ml) volume containing a stirring vane. Dimethylformamide (2.0 ml) which had been saturated with carbon monoxide gas at room temperature, was added to the vial so as to produce a yellow solution. The sealed vial was magnetically stirred at 100° C. (oil bath temperature) for 3 hours before being left to cool to room temperature. A TLC check showed the presence of a significant amount of starting material. Addition of dichlorobis(triphenylphosphine)palladium (II) (9.4 mg) and resaturation of the dimethylformamide with carbon monoxide was followed by heating of the vial's contents for a further hour. On cooling to room temperature, the solution was degassed by bubbling nitrogen gas through it. The mixture was treated with ethyl acetate and filtered through a bed of Celite™ (5 g), followed by washing the Celite with ethyl acetate so as to take the solution volume to 100 ml. Washing of this phase with water (3×100 ml) and brine (100 ml), was followed by drying (Na2SO4), filtering and concentration in vacuo. This afforded the title compound as white crystals (157 mg).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:40])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]([C:37](=[O:39])[CH3:38])[O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:24][CH2:23]2)[CH:17]([CH:41]([OH:43])[CH3:42])[C:16]3=[O:44])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:49].O>[Pd].O1CCOCC1>[Na+:49].[C:37]([N:28]([CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:40])[CH:18]3[N:15]([C:16](=[O:44])[CH:17]3[CH:41]([OH:43])[CH3:42])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)N(CC1CC(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)C(C(C)O)C3C2C)CO1)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N(CC1CC(SC2=C(C(=O)[O-])N3C(=O)C(C(C)O)C3C2C)CO1)OCc1ccccc1
Yield: 26.5 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.272 g of product from Example 74, 0.0402 g of sodium bicarbonate, 2 ml of water, 11.3 ml of dioxane, and 0.110 g of 10% palladium/carbon to give 0.059 g of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[C:16]([O:21]C)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13])([CH3:4])([CH3:3])[CH3:2].Br>CC(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[C:16](=[O:21])[NH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:13])[F:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1ccc(OC(F)F)c(C(C)(C)C)c1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2ccc[nH]c2=O)ccc1OC(F)F
Temperature: 70 °C
Yield: 49.8 %

Procedure:
step 3—A mixture of 22 (82 mg, 0.267 mmol), 48% HBr (90 □L, 0.784 mmol) and HOAc (4 mL) in a sealed tube was heated overnight at 70° C. The reaction mixture was carefully poured into a cold sat'd. aq. NaHCO3 solution, and then extracted with EtOAc. The organic layer was washed with brine dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative TLC plate developed with 66% EtOAc in hexanes to afford 39 mg (50% yield) of 1-6 as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][OH:6])[CH3:2].[H-].[Na+].Br.[Br:11][C:12]1[CH:13]=[C:14]([CH2:19]Br)[C:15]([NH2:18])=[N:16][CH:17]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:6][CH2:19][C:14]1[C:15]([NH2:18])=[N:16][CH:17]=[C:12]([Br:11])[CH:13]=1)[CH3:2]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CO
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hydroxy acetic acid ethyl ester (294 mg, 2.8 mmol) is dissolved in 5.0 mL of DMF and 60% sodium hydride (113 mg, 2.8 mmol) is added at 0° C. The mixture is stirred for 15 min and 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (392 mg, 1.1 mmol) is added. The mixture is warmed up to room temperature for 2.5 hr. Then water (15 mL) is added along with EtOAc (30 mL). The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×20 mL). The organic layers are combined and concentrated to give (2-amino-5-bromo-pyridin-3-ylmethoxy)-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Fe].O>[NH2:19][C:18]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(N)c1SCc1ccccc1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
69.8 g of iron powder are added in portions to a mixture of 68.0 g (0.22 mol) of methyl 2-benzylmercapto-3-nitrobenzoate, 215 ml of glacial acetic acid and 480 ml of water. The reaction solution is then stirred at 50°-60° C. for 3 h. The solid is separated off by filtration and then the mother liquor is washed with water and salt and subsequently dried over MgSO4. After concentration of the solution under reduced pressure, 47.1 g of a yellow oil (77%) are obtained; 1H NMR (CDCl3, 80 MHz): δ=3.8 (s, 3H, OCH3), 3.9 (s, 2H, SCH2Ph), 5.9 (s, 2H, NH2), 6.6-7.3 (m, 8H, Harom.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:12]
Reactant: O=C1CCc2c(Br)cc(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCc2c(Br)cc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
According to Scheme 2, step 1: To a solution of 4-Bromo-6-fluoro-indan-1-one (10.0 g, 43.7 mmol) in ethanol (183 ml) at 0° C. NaBH4 (3.67 g, 97.0 mmol) was added in portions and then the mixture was stirred at room temperature for 18 h. After evaporation of solvents in vacuo, water was added to the residue, the solution was extracted 3 times with ethyl acetate, then 2N aqueous HCl was added and the combined organic layers were washed with saturated aq. NaHCO3 and water. After drying over Na2SO4 and filtration, solvents were evaporated in vacuo to give 10.0 g of 4-Bromo-6-fluoro-indan-1-ol (4a) which was used immediately in the next step without purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:16])[C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[C:4]([C:17](=[O:19])[NH2:18])[CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:71]([CH:73]([CH2:81][CH2:82][CH2:83][CH3:84])[CH2:74][O:75][C:76](=[O:80])[CH2:77][CH2:78][SH:79])[CH3:72]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:71]([CH:73]([CH2:81][CH2:82][CH2:83][CH3:84])[CH2:74][O:75][C:76](=[O:80])[CH2:77][CH2:78][S:79][C:2]1[S:6][C:5]([NH:7][C:8](=[O:16])[C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[C:4]([C:17](=[O:19])[NH2:18])[CH:3]=1)[CH3:72]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sc(Br)cc1C(N)=O
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1cc(C(N)=O)c(NC(=O)C(C)(C)OC(C)=O)s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Intermediate 11 (1.4 g, 4 mmol) is dissolved in toluene (16 mL) and DIEA (1.4 mL, 8 mmol). Next, Pd2dba3 (110 mg, 0.12 mmol), Xantphos (139 mg, 0.24 mmol) and 3-Mercaptopropionic acid 2-ethylhexylester (1.14 mL, 5 mmol) are added, and the resulting solution is flushed with N2. Reaction mixture is stirred at 110° C. overnight. After evaporation, the crude is purified using column chromatography. The resulting product is obtained as an oil, which crystallised overnight. Obtained product is used as such.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.[CH:10]1[C:11]2[C:26](=[O:27])[C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]([CH:31]3[CH2:33][CH2:32]3)[C:12]=2[CH:13]=[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:15]=1[F:16].O>CC(C)=O>[CH:10]1[C:11]2[C:26](=[O:27])[C:25]([C:28]([OH:30])=[O:29])=[CH:24][N:23]([CH:31]3[CH2:32][CH2:33]3)[C:12]=2[CH:13]=[C:14]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[C:15]=1[F:16].[O:1]=[C:2]1[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CC[C@H](C(=O)O)O1
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@H](C(=O)[O-])O1
Reaction time: 0.5 h

Procedure:
0.781 G (0.006 mole) of (R)-5-oxotetrahydrofuran-2-carboxylic acid and 1.99 g (0.006 mole) of Ciprofloxacin were added to 10 mL of distilled water. The resulting mixture was stirred for 30 minutes to dissolve it completely. After adding 20 mL of anhydrous acetone, the resulting solution was further stirred for 30 minutes under ice-cooling and allowed to stand to precipitate solids. The precipitated solids were filtered under reduced pressure through a filter paper (Whatman Filter Paper No. 1), washed three times with each 30 mL of anhydrous acetone, and dried under vacuum to give 2.33 g of the titled compound as white solids. M.P. 211-212° C. (decomposition) [α]D25 =+4.72 (H2O)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15](OCCC)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].O.[NH2:24][NH2:25].O>C(O)C.O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15]([NH:24][NH2:25])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1ccc(-c2ccc(OCCC)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of propyl 4-(4′-propoxyphenyl)benzoate (20.00 g) in a mixture of ethanol (100 ml) and tetrahydrofuran (40 ml) was added hydrazine monohydrate (32.5 ml). The mixture was refluxed for 2 hours, during this period additional hydrazine monohydrate (32.5 ml) was added into the mixture. After cooling to room temperature, the reaction mixture was poured into water (1800 ml) and then the mixture was stirred for 30 minutes at room temperature. The resulting precipitate was filtered, washed with water, and dried to give the objective compound, 4-(4′-propoxyphenyl)-benzoyl hydrazine (17.63 g), as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]2[C:34]([O:36][C:37](=O)[C:27]=2[CH:26]=1)=[O:35]>>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:34](=[O:35])[C:28]5[C:27](=[CH:26][CH:25]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=5)[C:37]4=[O:36])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(C(F)(F)F)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-trifluoromethylbenzoxazole (113 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (120 mg, 59%). 1H NMR (DMSO) δ 8.41(m, 2H), 8.30(s, 1H), 8.23(s, 1H), 8.12(d, 1H), 8.07(d, 1H), 7.97(d, 1H), 7.77(d, 1H), 7.49(dd, 1H), 7.04(d, 1H), 3.34(m, 2H) 1.75(m, 2H), 1.06(t, 3H). MS 507.7 m/z (M−H)−.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]#[CH:16].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.[Cl-].[Na+]>CCCCCC.C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]#[C:16][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21]
Reactant: O=C(Cl)C1CC1
Reactant: C#Cc1ccc(SC)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C#CC(=O)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexane (4.4 ml) was added to a stirred solution of [2-chloro-4-(methylsulphenyl)phenyl]acetylene (2.0 g) in THF while maintaining the temperature below -70° C. The mixture was stirred for 5 minutes and cyclopropanecarbonyl chloride (2.4 g) was added. The mixture was warmed to room temperature and poured onto aqueous sodium chloride solution. The aqueous layer was extracted with ether and combined organic layers dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in methanol and heated at reflux for 5 minutes. Toluene was added and the mixture was evaporated to dryness. The residue was purified by chromatography eluted with a mixture of hexane and ether to give 1-[2-chloro-4-(methylsulphenyl)phenyl]-3-cyclopropylprop-1-yn-3-one as yellow oil which crystallized on standing, m.p. 46°-50° C. [2-Chloro-4-(methylsulphenyl)phenyl]acetylene was prepared by the reaction of 1-bromo-2-[2-chloro-4-(methylsulphenyl)phenyl]acetylene with n-butyllithium and wet zinc chloride in THF at -70° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[NH:17][C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=2)[C:7]=1[Br:30].[CH3:32]C([O-])(C)C.[K+].[H-].[Na+]>C1COCC1>[Br:30][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:16]3[N:17]([CH3:32])[C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:2])=[O:31]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OC)ccc3c2)[nH]c2ccccc12
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid methyl ester (0.410 g, 0.853 mmol) in THF (20 mL) at 0° C. was added KOt-Bu (0.105 g, 0.938 mmol) followed by Mel (0.064 mL, 1.02 mmol). The reaction was warmed to rt and let stir for 1 h. It appeared by TLC and MS that all the starting material was gone; however, two polar acids (one N—Me and one N—H) had been generated due to hydrolysis in these basic conditions. After concentration, the residue was taken up in DMF (20 mL). Added NaH (0.075 g, 60% by wt., 1.88 mmol) followed by excess Mel to convert all intermediate to one acid (N—Me). After 1 h, the reaction mixture was concentrated and then diluted with EtOAc (200 mL) and 1 N HCl (20 mL). The organic layer was washed with H2O (20 mL) and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by preparatory plate chromatography (10% MeOH:CHCl3) to afford the product (0.232 g, 57%) as a yellowish-orange foamy solid, mp>73° C. (decomp.); 1H NMR (DMSO-d6) δ 0.73 (t, J=7.0 Hz, 3H), 1.11-1.20 (m, 4H), 1.50-1.58 (m, 2H), 2.66 (t, J=7.3 Hz, 2H), 3.58 (s, 3H), 4.93 (s, 2H), 7.07 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.1 Hz, 1H), 7.42-7.48 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.68 (dd, J=1.7, 8.7 Hz, 1H), 7.99 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 11.95-14.75 (bs, 1H); IR (neat) 3050, 2955, 2925, 2850, 1725, 1670, 1600, 1480, 1470, 1430, 1370, 1325, 1275, 1220, 1190, 1145, 1095, 1015, 980, 925, 895, 830, 800, 765, 735, 700, and 665 cm−1; mass spectrum [(+) ESI], m/z 480/482 (M+H)+;
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([F:15])([F:14])[F:13].P(Cl)(Cl)([Cl:19])=O>[NH4+].[OH-]>[Cl:19][C:3]1[C:2]([CH3:1])=[N:11][C:10]2[C:5]([N:4]=1)=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][CH:9]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cccc(C(F)(F)F)c2nc1O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2cccc(C(F)(F)F)c2nc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-methyl-8-(trifluoromethyl)quinoxalin-2-ol (0.8292 g, 3.634 mmol) and phosphorous oxychloride (6.653 mL, 72.68 mmol) was stirred at 100° C. After 1.5 h, the mixture was cooled to room temperature. The mixture was poured into ice (˜50 mL) with stirring and neutralized with NH4OH (30 mL) and ice with stirring. The resulting precipitate was collected by filtration, rinsed with water (100 mL), and dried to give 3-chloro-2-methyl-5-(trifluoromethyl)-quinoxaline as a pink solid: 1H NMR (400 MHz, DMF) 8 ppm 8.35 (1 H, d, J=8.4 Hz), 8.25 (1 H, d, J=7.4 Hz), 7.94-8.02 (1 H, m), 2.80 (3 H, s); LC-MS (ESI) m/z 247.0 [M+H]+. The pink solid was carried on crude without purification for the next step.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:25][O:26][C:27]([C:29]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30]1)=[O:28]>CO>[CH3:25][O:26][C:27]([C:29]1([CH2:33][NH:34][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:4])[CH2:32][CH2:31][CH2:30]1)=[O:28]
Reactant: COC(=O)C1(CN)CCC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CO
Product: COC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCC1

Procedure:
After a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (129 mg, 0.401 mmol), 1-aminomethyl-cyclobutanecarboxylic acid methyl ester (115 mg, 0.803 mmol in MeOH was microwaved at 150° C. for 500 min; cooled, concentrated, the residue was partitioned between EtOAc and diluted HCl solution, EtOAc phase was washed with water and diluted NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated and column purified to give product (172 mg). LC MS ESI+: 432 (M+1)+.