Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[F:11][C:12]([F:24])([F:23])[C:13](=O)[CH2:14][C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=O>C(O)(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:13]([C:12]([F:24])([F:11])[F:23])=[N:10]1
Reactant: NNc1ccccc1Cl
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 80 °C

Procedure:
Into a 500 mL flask was weighed 25.0 g (139.6 mmol) of 2-chlorophenylhydrazine hydrochloride, 27.4 g (153 mmol) of 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione, and 200 mL of acetic acid. The resulting solution was heated at 80° C. for 18 h then was cooled and was washed into a separatory funnel with 1.0 M NaOH and ethyl acetate. The ethyl acetate was separated, washed with 1.0 M NaOH, brine, dried (Na2SO4), and was concentrated in vacuo. The residue was filtered through a short column of silica gel affording 1-(2-chlorophenyl)-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole as a brown oil, yield: 37.31 g (85%); MS (ES): 313 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([NH:21][NH2:22])=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:23](O)=[O:24]>>[CH:23]([NH:22][NH:21][C:19](=[O:20])[CH2:18][CH2:17][S:16][C:7]1[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=1)=[O:24]
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=CO
Product: CC(C)(C)c1cc(SCCC(=O)NNC=O)cc(C(C)(C)C)c1O
Yield: 89 %

Procedure:
A solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (0.70 g, 2.16 mmol) in 96% formic acid (5.6 mL) is stirred overnight. The reaction mixture is concentrated in vacuo, diluted with ethyl acetate and washed once with a saturated solution of sodium bicarbonate, twice with water, and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives an oil which is crystallized from ethyl acetate/hexane to afford 0.68 g (89%) of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid 2-formylhydrazide, mp 158.0°-159.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:17])[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:4]=1[NH:18][C:19]([NH2:21])=[S:20].BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:18]=[C:19]([NH2:21])[S:20][C:5]=2[C:6]([N:9]([CH3:17])[CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C)CC2CCOCC2)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(N(C)CC2CCOCC2)c2sc(N)nc12
Yield: 98.2 %

Procedure:
1.5 g (0.53 mmol) {2-methoxy-5-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-phenyl}-thiourea were dissolved in 15 ml chloroform and at room temperature 0.025 ml (0.5 mmol) Br2 were added slowly. After 24 hrs of reflux the mixture was concentrated in vactio and the residue suspended in water. Sodium bicarbonate solution was added until the pH was 10, and the crystals were collected by filtration. These were subjected to column chromatography (1/1 hexane/ethyl acetate) to afford 0.16 g (10%) of 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-ylmethyl)-benzothiazole-2,7-diamine as brown solid. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: CC1C(C)=CC=CC=1OCCCC=O.CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=C(C=CC=3)CNC(=O)OC(C)(C)C)C=CC=2)CCC1)=O.[CH3:54][C:55]1[C:97]([CH3:98])=[CH:96][CH:95]=[CH:94][C:56]=1[O:57][CH2:58][CH2:59][CH2:60][C:61]([N:63]1[C:72]2[C:67](=[C:68]([C:73]3[CH:74]=[N:75][N:76]([CH2:78][C:79]4[CH:80]=[C:81]([CH:91]=[CH:92][CH:93]=4)[CH2:82][NH:83]C(=O)OC(C)(C)C)[CH:77]=3)[CH:69]=[CH:70][CH:71]=2)[CH2:66][CH2:65][CH2:64]1)=[O:62]>>[NH2:83][CH2:82][C:81]1[CH:80]=[C:79]([CH:93]=[CH:92][CH:91]=1)[CH2:78][N:76]1[CH:77]=[C:73]([C:68]2[CH:69]=[CH:70][CH:71]=[C:72]3[C:67]=2[CH2:66][CH2:65][CH2:64][N:63]3[C:61](=[O:62])[CH2:60][CH2:59][CH2:58][O:57][C:56]2[CH:94]=[CH:95][CH:96]=[C:97]([CH3:98])[C:55]=2[CH3:54])[CH:74]=[N:75]1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(CNC(=O)OC(C)(C)C)c5)c4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C
Agent: Cc1cccc(OCCCC=O)c1C
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(CN)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 14543-(aminomethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that tert-butyl 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzylcarbamate was replaced with tert-butyl 3-((4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)methyl)benzylcarbamate. LCMS, [M+H]+=509.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2O.[OH-].[NH4+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:29])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[Cl:29]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1cnc2cc(F)c(Br)cc2c1O)C1CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(c1cnc2cc(F)c(Br)cc2c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
(6-Bromo-7-fluoro-4-hydroxyquinolin-3-yl)(cyclopropyl)methanone (3.35 g, 10.8 mmol) was suspended in phosphoryl chloride (10 mL) at 0° C. The reaction was warmed to room temperature and stirred overnight. After this time 2M ammonium hydroxide was added dropwise until a solid formed. Ethyl acetate was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (1.5 g, 42%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 8.63 (d, J=7.2 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 2.70-2.45 (m, 1H), 1.55-1.35 (m, 2H), 1.35-1.05 (m, 2H).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19]C)=[O:18].[OH-].[Na+]>C(O)C>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][C:9]2[S:1][C:2]([C:17]([OH:19])=[O:18])=[CH:3][C:4]=2[CH2:5]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1

Procedure:
A solution of 5-tert-butyl 2-methyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1 eq) obtained in step VII and NaOH (1.5 eq). was refluxed in ethanol for 2 h Reaction mixture was concentrated under reduced pressure and neutralized to get 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:22][C:21]([CH:23]([NH:25]S(C(C)(C)C)=O)[CH3:24])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl.O>[NH2:25][CH:23]([C:21]1[S:22][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C@@H:8]([OH:7])[C@H:9]([NH:5][C:3](=[O:4])[CH:2]([F:34])[F:1])[CH2:10][F:11])=[CH:17][CH:16]=2)=[CH:19][N:20]=1)[CH3:24]
Reactant: CC(NS(=O)C(C)(C)C)c1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)s1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(N)c1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
To a solution of N-(1-(5-(4-((4S,5R)-3-(2,2-difluoroacetyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-5-yl)phenyl)thiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (315 mg, 0.6 mmol) in CH2Cl2 (25 mL) at 0° C. is added trifluoroacetic acid (5 mL) and 5 drops water. The reaction is allowed to warm to room temperature and stir for 1 hour. Toluene (20 mL) is added and contents are concentrated under vacuum. Toluene addition/concentration is repeated and contents are placed under high vacuum for 5 minutes. Methanol (25 mL) is added to the reaction flask and the solution is cooled in an ice bath. HCl in methanol (4 mL of 1.25 mL solution) is added and the reaction is allowed to warm to room temperature while stirring. After 2 hours, the reaction is concentrated under vacuum to −3 mL of solvent left and purified directly using reverse phase chromatography, eluting from 95:5 water/acetonitrile/0.1% trifluoroacetic acid to 95:5 acetonitrile/water/0.1% trifluoroacetic acid. The purified fractions are concentrated under vacuum to remove acetonitrile. The aqueous phase is diluted with saturated NaHCO3 (100 mL) and extracted with ethylacetate (2×100 mL). The combined organic phase is dried (Na2SO4) and concentrated under vacuum to afford the title compound (93 mg): 1H NMR (400 MHz, DMSO-d6) δ: 1.39 (d, 3H), 2.38 (m, 2H), 4.18-4.33 (m, 2.5H), 4.40-4.44 (m, 0.5H), 4.52-4.56 (m, 0.5H), 4.64-4.67 (m, 0.5H), 4.85 (t, 1H), 5.88 (d, 1H), 6.19 (t, 1H), 7.38 (d, 2H), 7.58 (d, 2H), 8.03 (s, 1H), 8.80 (d, 1H); m/z (Cl) 374 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=C(C)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C[CH2:26][O:27][C:28]([CH3:30])=[O:29]>S(=O)(=O)(O)O>[CH3:26][O:27][C:28](=[O:29])[C:30]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 2-chloro-4-methyl-5-nitropyridine (Aldrich Chemical Co.) (5.0 g, 29.0 mmol) in concentrated sulfuric acid (60 mL) with stirring at 0° C., was added a solution of sodium dichromate dihydrate (14.3 g, 1.65 eq) in concentrated sulfuric acid (100 mL) at a rate which kept the internal temperature less than 10° C. After addition was complete, the reaction mixture was stirred from 0° C. to room temperature over 6 hours. By TLC, the reaction was not complete, so additional sodium dichromate dihydrate (8.4 g, 1 eq) was added directly to the solution at 0° C. The resulting solution was stirred from 0° C. to room temperature overnight. The reaction was complete by TLC the next morning, and it was poured into a mixture of ice (1 L) and EtOAc (900 mL). The resulting mixture was stirred for about 10 minutes and then the layers were separated. The organic layer was washed with brine (2×600 mL), and the EtOAc layer was dried over magnesium sulfate and filtered. With stirring at room temperature, trimethylsilyl diazomethathane (2.0M in hexanes, 15 mL) was added to the EtOAc filtrate. The resulting mixture was stirred at room temperature for 30 min. By TLC, there was no acid remaining, and then MeOH (150 mL) was added and the solution stirred for 30 minutes. The solution was concentrated and then EtOAc (700 mL) was added to the residue which was dried over magnesium sulfate, filtered, concentrated and pumped to give the title compound (1A) as an off-white powder (5.79 g, M+=216, M.P.=60.5–64.1° C.).
Reaction SMILES: FC1C=CC=C(F)C=1O.C([O-])([O-])=O.[K+].[K+].BrCC([O-])=O.C([O:23][C:24](=[O:35])[CH2:25][O:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[F:34])C.[OH-].[Na+]>CC(C)=O.C(O)C.O>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[O:26][CH2:25][C:24]([OH:35])=[O:23]
Reactant: CCOC(=O)COc1c(F)cccc1F
Agent: O=C([O-])CBr
Agent: O=C([O-])[O-]
Agent: Oc1c(F)cccc1F
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(O)COc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
2,6-Difluoro-phenol (10.0 g, 92.47 mmol) was dissolved in 15.0 mL of acetone, K2CO3 (7.40 g, 92.47 mmol) and α-bromoacetate (15.44 g, 10.25 mL, 231.18 mmol) were added and the reaction was allowed to reflux overnight. The mixture was filtered through a plug of cotton and the solvent removed in vacuo to give 18.93 g as a colorless oil, 98% yield. 1H NMR (400 MHz, CDCl3): σ 1.26 (t, J=m Hz, 3H), 2.29 (s, 3H), 4.24 (q, J=Hz, 2H), 4.61 (s, 2H), 6.64 (d, J=Hz, 1H), 6.83 (t, J=Hz, 1H), 7.16 (q, J=Hz, 2H) 13C NMR (CDCl3): 169.37, 156.36, 131.13, 127.51, 126.91, 121.63, 111.43, 65.90, 61.41, 16.39, and 14.34. (2,6-Difluoro-phenoxy)-acetic acid ethyl ester (1.66 g) was dissolved in ethanol (10.0 mL), NaOH (2 eqv's) and 5 drops of H2O was added and the reaction stirred at room temperature overnight. The product was filtered and dried to give a white solid, 1.11 g, 64% yield. 1H NMR (400 MHz, d-DMSO): σ 4.84 (s, 2H), 7.31 (m, 1H), 7.46 (m, 1H), 7.93 (m, 1H), 13.19 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[Br:11]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:11][C:8]1[CH:9]=[CH:10][C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[CH:7]=1
Reactant: Clc1nsc2ccccc12
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Clc1nsc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
3-Chlorobenzo[d]isothiazole (10 g, 59.0 mmol) was added to a solution of bromine (3.2 mL, 62.0 mmol) and silver sulfate (19.6 g, 63.0 mmol) in sulfuric acid (200 mL). The resulting brown mixture was allowed to stir at room temperature for 2 h under nitrogen. The color slowly faded to pale yellow as a white precipitate formed. The precipitate was collected by vacuum filtration and triturated with hexanes to yield 5-bromo-3-chlorobenzo[d]isothiazole as a white solid (3.8 g). 1H NMR (300 MHz, CDCl3): 8.18 (s, 1H), 7.8 (d, 1H), 7.64 ppm (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])=O)(C)(C)C.Cl>FC(F)(F)C(O)=O.ClCCl>[O:12]=[C:11]1[CH2:16][CH2:17][NH:8][CH:9]([CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCNC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 50 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (353 mg, 0.88 mmol) was cooled in an ice bath and then dissolved in a solution of 20% trifluoroacetic acid/dichloromethane (7 ml). The reaction was stirred for 5 minutes in the ice bath then another 3 hours at ambient temperature, after which it was concentrated in vacuo affording a solid residue. To the solid was added 2N hydrochloric acid (9 ml) and the mixture was heated at 50° C. (oil bath) with stirring for 24 h. The cooled reaction mixture was quenched with saturated sodium bicarbonate solution until the pH was basic. The aqueous layer was extracted with chloroform (3×20 ml) and the combined organic extracts dried (K2CO3), filtered, and the solvent evaporated in vacuo to give 205 mg (91%) of 2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1>Br>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[N:15]=2)[CH:17]=1
Reactant: COc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Agent: Br
Product: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 8 h

Procedure:
A 25.0 g portion of N-(4-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine was dissolved in 200 ml of 48% hydrobromic acid and stirred overnight under an argon atmosphere. The mixture was then heated on a steam bath for 7 hours, cooled overnight and evaporated at 60° C. The residue was basified with 200 ml of saturated potassium bicarbonate solution and stirred for 1.5 hours. The solid was collected, washed with water, dried and recrystallized from hot absolute ethanol, giving 19.1 g of the desired product, mp 223°-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:17]=[S:18]1(=[O:35])[CH2:23][CH2:22][N:21]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[C:20]2=[N:19]1.[Cl-].[Ca+2].[Cl-]>CC#N.C(O[Cu]OC(=O)C)(=O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:34][C:31]2[CH:30]=[CH:29][C:28]([C@H:27]3[C:20]4=[N:19][S:18](=[O:35])(=[O:17])[CH2:23][CH2:22][N:21]4[CH2:24][CH2:25][CH2:26]3)=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(Br)cc4)cc3)C2=N1
Yield: 6.5 %

Procedure:
Diacetoxycopper (648 mg) was added to a mixture of pyridine (0.433 mL), (4-bromophenyl)boronic acid (1075 mg), cesium carbonate (581 mg) and 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg) in MeCN (35 mL). The mixture was stirred at room temperature under a dry atmosphere (anhydrous calcium chloride tube) for 19 hr. The insoluble, light-blue precipitates were removed by filtration through Celite-pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (50.6 mg) as colorless crystals.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH2:15][C:16]([OH:18])=[O:17]>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[CH2:15][C:16]([OH:18])=[O:17])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)CC1C=CC=CC1=NO
Solvent: ClCCl
Product: O=C(O)CC1C=CC=CC1=NOC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a mixture of methylene chloride (45 ml) and dichloroacetyl chloride (10 ml) was added portionwise with stirring 2-hydroxyiminophenylacetic acid (synisomer) (5g) in portions over about 15 minutes. The reaction mixture became solid, and was stirred for 1 hour at room temperature after the addition was complete. The reaction was diluted with petroleum (b.p. 40°-60°), filtered, and the solid washed several times with petroleum spirit to remove residual acid chloride. The solid was dried under vacuum, giving 2-dichloroacetoxyiminophenylacetic acid (syn-isomer)(8.0g; 96%), m.p. 115°, νmax. (CHBr3) 3470 and 1750 (--CO2H), 1765 cm. -1 (ester), τ (CDCl3) values include 2.0 - 2.7 (multiplet; aromatic protons), 3.85 (singlet; CHCl2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.CCCCCC.CCOCC.I[C:23]1[CH:46]=[CH:45][C:26]2[NH:27][C:28]([N:30]3[CH2:35][CH2:34][C:33]4([C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:37](=[O:44])[O:36]4)[CH2:32][CH2:31]3)=[N:29][C:25]=2[CH:24]=1>C1COCC1.[Pd].CCOC(C)=O.[Cl-].[Zn+2].[Cl-].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>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:23]1[CH:46]=[CH:45][C:26]2[NH:27][C:28]([N:30]3[CH2:31][CH2:32][C:33]4([C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:37](=[O:44])[O:36]4)[CH2:34][CH2:35]3)=[N:29][C:25]=2[CH:24]=1
Reactant: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21
Reactant: c1cocn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1OC2(CCN(c3nc4cc(-c5ncco5)ccc4[nH]3)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add a solution of oxazole (5.0 mL, 7.24 mmol) in deoxygenated THF (50 mL) at −78° C. to 1.6 M n-butyllithium in hexane (5 mL, 7.96 mmol). After stirring for 30 minutes, add 1M zinc chloride in Et2O (22 mL, 21.7 mmol) and warm the reaction mixture to 0° C. for 2 hours. To the reaction mixture, add first a solution of 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (3.2 g, 7.18 mmol), then the palladium catalyst which is prepared by treating a suspension of (Ph3P)2PdCl2 (0.25 g, 0.36 mmol) in deoxygenated THF (50 mL) with 1.6 M n-butyllithium in hexane (0.45 mL, 0.72 mmol). Reflux the reaction mixture for 20 hours. After cooling to ambient temperature, dilute the mixture with EtOAc (50 mL), and wash with water (50 mL) and saturated aqueous NaCl (50 mL). Dry the organic portion over Na2SO4, filter and concentrate. Purify by flash column chromatography (5% MeOH—CH2Cl2) to obtain 1′-(5-oxazol-2-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[CH3:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O>[CH3:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2C)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1C
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 55.1 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 15.12 mmol) was dissolved in MeOH (60 mL) and cooled to −40° C. 3.8 M NaOH (3.98 mL, 15.12 mmol) was dissolved in water (6 mL) and added to the mixture and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.926 mL, 15.12 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. warm solution of 6 M HCl (76 mL, 453.53 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified in two runs by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.2 g, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.81-1.93 (m, 2H), 2.21-2.42 (m, 2H), 2.44 (s, 3H), 3.03-3.13 (m, 1H), 3.59 (s, 3H), 3.63-3.75 (m, 1H), 4.12-4.20 (m, 1H), 5.02 (dd, 1H), 5.65 (s, 1H), 7.30 (d, 1H), 7.37-7.44 (m, 2H). MS m/z 383 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[C:16]([F:19])([F:18])[F:17])[CH3:2].[H-].[Na+].[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[N:8]([C:23](=[O:25])[CH3:24])[C:7]=1[C:16]([F:17])([F:18])[F:19])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(C)cc12
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of (5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (4.90 g, 17.2 mmol) in DMF (25 mL) is added a suspension of 60% NaH in mineral oil (824 mg, 20.6 mmol). The reaction mixture is stirred for 1 h at room temperature. After cooling to 0° C. acetylchloride (1.84 mL, 25.8 mmol) is added dropwise. The resulting reaction mixture is stirred for 1 h at room temperature, quenched with an aqueous saturated NH4Cl solution and partitioned between water and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, cyclohexane/EtOAc 95:5) affords the title compound as a yellow solid (2.89 g, 8.83 mmol, 51%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.75 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.91 (q, J=2.2 Hz, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 1.24 (t, J=7.1 Hz, 3H). MS (ES+): 345 (M(C16H16F3NO3)+H2O)+.