Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[N:7]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=1)=[O:3].[NH3:20]>O1CCCC1>[NH2:20][C:2]([C@@H:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[NH:7][C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1)=[O:3]
Reactant: N
Reactant: COC(=O)c1cc(C(=O)Cl)c2c(Cl)cc(Cl)cc2n1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](C(N)=O)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorocarbonyl-5,7-dichloro-2-methoxycarbonylquinoline (1.5 g) was dissolved in dry tetrahydrofuran (20 ml) at 0° C. and an ice-cool solution of tetrahydrofuran (150 ml), presaturated with ammonia gas, was added in one portion. After stirring at room temperature for 30 minutes the white solid which precipitated was collected by filtration and dried (1.4 g). A portion of this solid (1 g) was suspended in glacial acetic acid (20 ml) and sodium cyanoborohydride (1.3 g) was added in portions. When the addition was complete the reaction mixture was heated at 50° C. for 2 h, cooled and stirred at room temperature for 14 h. The solution was diluted with dichloromethane (to a volume of 100 ml) and ice cold 50% sodium hydroxide solution added cautiously until a pH of 14 was attained. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane (2×100 ml). The combined organic fractions were washed with brine (1×150 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by chromatrography on silica gel with 2% methanol in dichloromethane as eluent to give, as the less polar isomer, trans-4-aminocarbonyl-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.15 g, m.p. 217°- 229° C. [recrystallised from methanol]); δ (360 MHz, DMSO) 1.83 (1H, m, CHACHBHCCHD), 2.32 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.72 (3H, s, CH3), 3.78 (1H, dd, J=5.8 and 2.0 Hz, CHACHBHCCHD), 4.01 (1H, dd, J=12.2 and 2.1 Hz, CHACHBHCCHD), 6.63 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.66 (1H, br, s, NH), 6.78 (1H, d, J=2.1 Hz, 6-H or 8-H), 7.02 (1H, br, s, NH), 7.51 (1H, br, s, NH); m/e 302 (M+), 198 (100%, M-H, CONH2 and CO2CH 3); Found: C, 47.46; H, 3.95; N, 9.18 C12H12Cl2N2O3 requires C, 47.55; H, 3.99; N, 9.24%; and as the more polar isomer, cis-4-aminocarbonyl-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.14 g, m.p. 203°-204° C.); δ (360 MHz, DMSO), 2.05 (1H, m, CHACHBHCCHD), 2.52 (1H, m, CHACHBHCCHD), 3.54 (3H, s, CH3), 3.71 (1H, dd, J=7.2 and 3.4 Hz, CHACHBHCCHD), 4.11 (1H, dd, J=5.2 and 3.2 Hz, CHACHBHCCHD), 6.61 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.70 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.84 (2H, br, s, CONH2), 7.20 (1H, br, s, NH); m/e (CI+) 303 (M+1); Found: C, 47.38; H, 3.98; N, 9.14. C12H12Cl2N2O3 requires C, 47.55; H, 3.99; N, 9.24%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:33]1([CH3:42])[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>O1CCOCC1.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:36]4[CH:37]=[CH:38][C:33]([CH3:42])=[CH:34][CH:35]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Reactant: Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.179 mmol) in dioxane (20 mL) and water (10 mL) were added K2CO3 (488 mg, 3.537 mmol) and 4-tolyl boronic acid (179 mg, 1.297 mmol) in a sealed tube. The reaction mixture was degassed with N2 for 20 min, then Pd(PPh3)4 (136 mg, 0.118 mmol) was added to the reaction mixture at RT. The reaction mixture temperature was raised to 100° C., stirred for 18 h at 100° C. The reaction mixture was diluted with water (30 mL) extracted with ethyl acetate (3×30 mL) and organic layer was washed with brine, dried the organic layer over anhydrous sodium sulphate and concentrated under reduced pressure to affords the crude product. Crude was purified by column chromatography using 100-200 mesh silica gel compound eluted with 35% ethyl acetate in petroleum ether to afford the title compound as a white solid.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:18]([O:20][C:21](=[O:22])[C:13]=12)=[O:19]>C1COCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:18]([C:14]2[C:13]([C:21]([OH:20])=[O:22])=[N:12][CH:17]=[CH:16][CH:15]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccnc2C(=O)O)cc1
Reaction time: 1 h

Procedure:
Iodine (catalytic amount) was added to a THF (30 ml) suspension of magnesium (2.4 g) in a nitrogen atmosphere at room temperature with stirring, and then a THF (20 ml) solution of 4-bromotoluene (17.1 g) was dropwise added thereto and stirred for 1 hour. The resulting mixture was added to a THF (50 ml) solution of 2,3-pyridinedicarboxylic acid anhydride (12.7 g) at 0-5° C. with stirring, and this was stirred for additional 30 minutes as it was and then for 1 hour at room temperature. The solvent was removed from the reaction mixture by distillation, and water (30 ml) was added to the residue, which was then adjusted the pH to 1.0 with hydrochloric acid. The mixture was extracted with dichloromethane, washed with water and dried. Then, the solvent was removed by distillation. Dichloromethane (about 10 ml) was added to the residue, and then isopropyl ether (about 70 ml) was added thereto. This was stirred for 16 hours at room temperature, and 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid was obtained as colorless crystals (5.0 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A RBF equipped with a reflux condenser was charged with 2-bromo-5-methoxy benzoic acid (430 g, 1.8614 mol), 4-bromo phenol (322 g, 1.8614 mol, 1 eq), potassium carbonate (514.5 g, 3.7 228 mol, 2.0 eq) and CuOTf-toluene complex (24.08 g, 0.04653 mol, 0.025 eq). Ethyl acetate (9.0 ml 0.09679 mol, 0.052) and toluene (1.3 L) was carefully added portion wise. After stirring at RT for 10 min, the mixture was heated to 50° C. and stirred for 30 min. The mixture was then heated to 110° C. for 20 hrs. The reaction was monitored by TLC. After 20 hrs, TLC showed total consumption of starting materials. The reaction mixture was cooled to RT, diluted with water and acidified by 2N HCl. The reaction mixture was extracted with ethyl acetate (3.0×2 liter) followed by filteration of the extract through celite bed and washing with ethyl acetate (1.0 liter). Combined extracts were dried over sodium sulfate and concentrated to yield a crude mass of 590 g. (Dark brown solid). This mass was used directly in step 2.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].C[O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19](Cl)[N:18]=1.O>O1CCOCC1.[Cu](I)I>[Cl:23][C:21]1[CH:20]=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:18]=[C:17]([C:16]([OH:25])=[O:15])[CH:22]=1
Reactant: COC(=O)c1cc(Cl)cc(Cl)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 125 °C
Reaction time: 10 h

Procedure:
3-(trifluoromethyl) phenol (3.15 g, 0.0019 mol) was dissolved in 50 ml of dried dioxane. Sodium hydride (0.8 g (ca. 60% in mineral oil), 0.0019×1.05 mol) was added to the obtained solution at room temperature. After completion of the foaming, a solution obtained by dissolving 4,6-dichloro picolinic acid methyl ester (4.0 g, 0.0019 mol) in 5 ml of dried dioxane, was dropped into the above solution. Successively, copper iodide (3.7 g, 0.0019×1.0 mol) was added to the obtained solution. The resultant mixture was heated and stirred at a temperature of 120 to 130° C. for 10 hours. Thereafter, the obtained reaction solution was cooled, mixed with 10 ml of water, and then filtered through a glass filter provided with High-flow Super Cell. The obtained filtrate was extracted with 100 ml of ethyl acetate two times, thereby separating an organic phase therefrom. The obtained organic phase was dried with sodium anhydride. After the dried organic phase was subjected to distillation to remove the solvent therefrom, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>COCCOC>[CH2:18]([O:17][C:15]([C:14]1[N:1]=[C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][N:3]2[CH:13]=1)=[O:16])[CH3:19]
Reactant: Nc1cnc(C(F)(F)F)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(C(F)(F)F)ncc2n1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-5-(trifluoromethyl)pyrazine (500 mg, 3.07 mmol) in 1,2-dimethoxyethane (10 mL) was added dropwise ethyl bromopyruvate (0.5 mL, 4.0 mmol). The reaction mixture was warmed to 60° C. for 72 hours. The reaction mixture was then cooled to room temperature, and water was added (10 mL) to precipitate a solid. The suspension was stirred for 10 minutes, filtered, and the isolated solid was washed with water to afford the desired ester which was used in the next step without further drying. 1H NMR (CDCl3) δ 9.22 (s, 1H), 8.59 (s, 1H), 8.39 (s, 1H), 4.50 (q, 2H), 1.47 (t, 3H).
Reaction SMILES: [ClH:1].C(=N)(OCC)C.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1C(=O)N[C:25]([CH3:29])=[N:24]1>C(Cl)Cl.Cl.C(=N)(OCC)C>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][N:24]=[C:25]([Cl:1])[CH3:29]
Reactant: Cl
Reactant: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Agent: CCOC(C)=N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)=NNc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A stirred solution of 13.6 grams (0.1100 mole) of ethyl acetimidate hydrochloride and 13.2 grams (0.1300 mole) of triethylamine in 100 grams of methylene chloride was cooled to about 0° C. for five minutes, and 17.7 grams (0.1000 mole) of 2,4-dichlorophenylhydrazine (1) was added. Upon completion of addition the reaction mixture stirred at 0° C. for about one hour, then it was allowed to warm to ambient temperature where it stirred for about two hours. GC analysis of the reaction mixture indicated the presence of a small amount of unreacted (1). An additional 0.6 gram of ethyl acetimidate hydrochloride was added (total 14.2 gram-0.1150 mole), and the reaction mixture was stirred for an additional one hour. After this time the reaction mixture was washed with about 20 mL of water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a semi-solid residue. The residue was triturated with 20 mL of hexane, and the resultant solid was collected by filtration. The solid was washed with 50 mL of hexane and dried, yielding 20.4 grams (93.4% yield) of 2-(2,4-dichlorophenyl)hydrazidethaneimidic acid (A).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][C:41](=[O:58])[C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][C:43]=1[F:57].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41](=[O:58])[C:42]1[CH:47]=[CH:46][C:45]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:44][C:43]=1[F:57]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 74.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 122, 0.57 g, 1 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 1.2 g, 4.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.1 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (400 mg, 72%) as a white solid: LC/MS m/e calcd for C28H24F2N2O5S [M+H]+ 539.57, observed 539.0.
Reaction SMILES: C([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[C:7](C(OC)=O)([CH3:12])[CH2:6]1)(OC)=O.[BrH:17]>CO>[BrH:17].[CH3:12][CH:7]1[C:8](=[O:11])[CH2:9][CH2:10][NH:5][CH2:6]1
Reactant: COC(=O)N1CCC(=O)C(C)(C(=O)OC)C1
Agent: Br
Solvent: CO
Product: CC1CNCCC1=O
Temperature: 25 °C

Procedure:
A solution of 1,3-dicarbomethoxy-3-methyl-4-piperidone (51.45 g, 225 mmol) in hydrobromic acid (48%, 250 mL) is heated under reflux for 4 h and then cooled to room temperature. The resultant solution is concentrated in vacuo to give an orange colored solid. The solid is suspended in methanol (50 mL) and concentrated in vacuo again to give 3-methyl-4-piperidone hydrobromide salt: 42.9 g; 98%; mp 203-°205° C.
Reaction SMILES: CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH2:26])[CH2:20]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>CCOC(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH:26][C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:20]2
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
(R)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (12.56 mmol, 5.58 g) was dissolved in EtOAc (30 mL)/water (30 mL) and potassium carbonate (37.7 mmol, 5.21 g) added. The mixture was cooled in an ice bath and benzyl chloroformate (13.81 mmol, 1.964 mL, 2.356 g) added dropwise. Stirring was continued overnight during which time the reaction came to room temperature. The crude reaction mixture was diluted with water and ethylacetate and the phases mixed and separated. The aqueous layer was further extracted with EtOAc (×2). Combined organics were dried and concentrated before crystallisation of the product from ethylacetate/heptane mixture to give (R)-benzyl 5-bromo-2,3-dihydro-1H-inden-2-ylcarbamate as colourless needles (3.89 g, 89%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H) 3.26 (m, 2H) 4.53 (bm, 1H) 4.93 (bm, 1H) 5.10 (bs, 2H) 7.07 (m, 1H) 7.26-7.37 (m, 7H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH2:75][F:76])([CH2:73][F:74])[O:71][B:70]([OH:77])[C:69]=2[CH:78]=1>CN(C=O)C>[F:76][CH2:75][C:72]1([CH2:73][F:74])[O:71][B:70]([OH:77])[C:69]2[CH:78]=[C:65]([CH2:64][NH:63][C:19](=[O:21])[C:18]3[CH:22]=[CH:23][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:25]([F:27])([F:26])[F:28])[O:14][N:13]=4)=[CH:16][C:17]=3[CH3:24])[CH:66]=[CH:67][C:68]1=2
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(CF)CF
Reaction time: 0.17 h
Yield: 33 %

Procedure:
A solution of 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (100 mg, 0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5 mL) was stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (116 mg, 0.44 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by prep-TLC to provide the product (48 mg, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (s, 1H), 7.82 (s, 2H), 7.59-7.57 (m, 2H), 7.49-7.44 (m, 3H), 7.33-7.31 (m, 2H), 4.61-4.31 (m, 8H), 2.36 (s, 3H) ppm; HPLC purity: 97.63% at 220 nm and 97.48% at 254 nm.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[N:34]1([CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reactant: O=C(O)CCCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCCN3CCCCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C

Procedure:
A mixture of 2.4 g. (6.06 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 1.35 g. (6.06 mm.) of δ-piperidinovaleric acid hydrochloride and 1.30 g. (6.30 mm.) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride are stirred at room temperature for 5 hours. The reaction mixture is cooled overnight in the refrigerator and the by-product of dicyclohexylurea removed by suction filtration. The mother liquor is evaporated and the residue dissolved in a mixture of methylene chloride/cyclohexane and allowed to stand in the cold for 2 hours. Gravity filtration separates the small amount of solid which appears, and the solvents are removed using a rotary evaporator. Crystallization from methylene chloride/diethyl ether yields the desired product.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:14][CH2:15][C:16](=[O:23])[CH2:17][C:18](OCC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[K].[C:25]([C:29]1[CH:34]=[CH:33][C:32](CI)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:27])[CH3:26]>C(OCC)C.O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([CH2:18][CH2:17][C:16](=[O:23])[CH2:15][CH2:14][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)CCC1CCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC(=O)CCC2CCCCCC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
454 mg (4.06 mmol) of potassium-t-butoxide were added to 10 ml of a tetrahydrofuran solution containing 1.00 g (4.16 mmol) of ethyl 5-cycloheptyl-3-oxovalerate (prepared as described in Preparation 5). The mixture was then stirred for 10 minutes to prepare the corresponding potassium salt. 1.11 g (3.47 mmol) of 2-t-butyl-5-iodomethyl-1-nitrobenzene (prepared as described in Preparation 51) were added to the mixture in an ice bath, and the mixture was stirred for 2 hours at the temperature of the ice bath. The reaction solution was diluted with diethyl ether and washed with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 10 ml of ethanol. 1.73 ml of a 2N aqueous solution of sodium hydroxide were added, and the mixture was heated for 4 hours under reflux. The reaction mixture was then cooled in an ice bath, sufficient concentrated aqueous hydrochloric acid was added to adjust its pH to a value of 5.0, and the mixture was heated for a further 2 hours under reflux. At the end of this time, the reaction solution was diluted with diethyl ether and washed with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 70 g of silica gel. Elution with a 2:1 by volume mixture of methylene chloride and hexane afforded 850 mg (yield 68%) of the title compound as an oily substance.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]4[N:25]=[C:21]([CH3:20])[S:22][CH:23]=4)[CH:27]=3)[C:5](=[O:7])[CH:4]([CH3:9])[CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 424.03 g/mol.