Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([Br:12])[CH:9]=[CH:10][CH:11]=1.[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20](Cl)=[O:21])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>>[Br:12][C:8]1[CH:9]=[CH:10][C:11]([C:20]([CH:19]2[CH2:18][CH2:17][N:16]([C:13](=[O:15])[CH3:14])[CH2:24][CH2:23]2)=[O:21])=[C:6]([F:5])[CH:7]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Yield: 19 %

Procedure:
To a stirred suspension of 21.1 g of aluminum chloride and 63 ml of 3-fluorobromobenzene was added, portionwise, 16.0 g of 1-acetylisonipecotoyl chloride. The reaction mixture was stirred under reflux for 4 hrs. Most of the supernatant 3-fluorobromobenzene was decanted and ice water was added. The aqueous mixture was extracted with dichloromethane and the extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to give an oil. The oil was triturated with ether and a solid separated out. Recrystallization of the solid from cyclohexane gave 4.9 g (19%) of product. Recrystallization from cyclohexane yielded the analytical sample, mp 111°-113° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.C[O:34][B:35](OC)[O:36]C>C1COCC1>[C:27]1([C:13]([C:10]2[CH:11]=[CH:12][C:7]([B:35]([OH:36])[OH:34])=[CH:8][CH:9]=2)=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Into a 250 mL two-necked round-bottom flask under nitrogen was slowly added n-butyllithium (1.6 M in hexane, 7.5 mL, 12 mmol) and a THF solution (80 mL) of 1-(4-bromophenyl)-1,2,2-triphenylethene (3) (4.11 g, 10 mmol) at −78° C. After stirring for 3 h, 2.4 mL of trimethylborate (20 mmol) was added into the reaction mixture. The mixture was warmed to room temperature and the reaction was terminated by adding hydrochloric acid (2 M, 10 mL) after 12 h. The mixture was then poured into water and extracted with dichloromethane. The organic layer was washed with water and dried over magnesium sulfate. After filtration and solvent evaporation, the residue was purified by silica-gel column chromatography using n-hexane/ethyl acetate as eluent. White solid of 4-(1,2,2-Triphenylvinyl)phenylboronic acid (4) was obtained in 70% yield (2.6 g). 1H NMR (300 MHz, CDCl3), δ (TMS, ppm): 7.88 (d, 2H, J=8.1 Hz), 7.13-7.00 (m, 17H), 4.49 (s, 1H). 13C NMR (75 MHz, CDCl3), δ (TMS, ppm): 148.9, 144.2, 144.1, 144.09, 142.4, 141.4, 135.6, 133.5, 132.0, 131.6, 128.4, 128.3, 127.4, 127.2. HRMS (TOF): m/e 376.2030 (M+, calcd 376.1635).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C@H:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:49][C@@H:50]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[CH:61][CH:60]=1)[C:51]([NH:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>CN(C=O)C.C(OCC)C>[CH2:66]([O:65][C:62]1[CH:63]=[CH:64][C:59]([CH2:58][CH:50]([NH:49][C:5](=[O:7])[CH:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH:2]([CH3:1])[CH3:14])[C:51](=[O:52])[NH:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[CH:60][CH:61]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCOCC1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
(S)-4-Methyl-2-morpholin-4-yl-pentanoic acid (0.161 g, 0.800 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added in succession N,N-diisopropyl-ethylamine (0.420 mL, 2.41 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.303 g, 0.799 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes, solid (S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (0.290 g, 0.800 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 45 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether. The resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo, trituration with ether and drying under vacuum provided 0.27 g (62%) of the pure titled compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][C@H:52]1[CH2:57][NH:56][CH2:55][CH2:54][N:53]1C(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:56]6[CH2:55][CH2:54][NH:53][C@@H:52]([CH3:51])[CH2:57]6)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (30 mg, 0.044 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (89 mg, 0.44 mmol, 10 eq) and acetic acid (2.54 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. Methanol (2 mL) then hydrochloric acid (5 μL) were added for the deprotection of 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylphenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. The vial containing the reaction mixture was closed and stirred in a Glas-Col evaporator for overnight at 60° C. The reaction mixture was then concentrated and purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 20.16 mg (53.8%) of the title compound. LC-MS m/z 761 (M+H)+, 1.31 min (ret time).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=O.[C:8]([C:11]1[C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][N:14]([C:16]2([CH2:20][C:21]#[N:22])[CH2:19][NH2+:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].FC(F)(F)S(OCC(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[C:21]([CH2:20][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13]2)[CH2:17][N:18]([CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:19]1)#[N:22]
Reactant: O=C([O-])C(F)(F)F
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)C[NH2+]C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CN(CC(F)(F)F)C1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (23 mg, 0.078 mmol) in dioxane (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (36 mg, 0.15 mmol), followed by K2CO3 (23 mg, 0.078 mmol). The resulting mixture was heated to 110° C. and allowed to stir for 2 hours. The reaction was then cooled to ambient temperature, water was added and the reaction mixture was extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound, Example #19. 1H NMR (600 MHz, CDCl3): δ 8.78 (s, 1H), 7.75 (s, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.26 (t, J=7.9 Hz, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.62 (s, 2H), 3.81 (d, J=8.6 Hz, 2H), 3.74 (d, J=8.6 Hz, 2H), 3.34 (s, 2H), 3.09 (q, J=9.1 Hz, 2H). LRMS (ESI) calc'd for C17H17F3N6O [M+H]+: 379. Found: 379.
Reaction SMILES: [C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C([C:40]2[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=2)C=1>>[C:1](=[O:26])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(Br)cc2)nn1-c1ccccn1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(I)c2)nn1-c1ccccn1
Product: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccccc3)c2)nn1-c1ccccn1
Yield: 89 %

Procedure:
The title compound was prepared in the same manner as in Example C-1, except that an equimolar amount of 3-(3-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (23) prepared in Example B-4 was used in place of Compound 21 prepared in Example B-2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([Cl:21])=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Solvent: c1ccccc1
Product: ClC(=Nc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a slurry of 5-bromo-2-chloro-N-(2,3-dichlorophenyl)pyridine-3-carboxamide (0.75 g, 1.97 mmol) in benzene was added phosphorous pentachloride (0.5 g, 2.365 mmol) and the mixture heated to reflux. After 1.5 hours, the resulting solution was concentrated to provide 0.76 g of N-((5-bromo-2-chloropyridin-3-yl)chloromethylene)-2,3-dichlorobenzenamine as an off white solid. This material was used directly in the next reaction as is.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][C:16](=[O:20])[CH:17]=NO)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>O>[S:6]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]3[C:11]=2[C:17](=[O:2])[C:16](=[O:20])[NH:15]3)[N:8]=[CH:7]1
Reactant: O=C(C=NO)Nc1ccc2ncsc2c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C1Nc2ccc3ncsc3c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate, and 100 mL of water. The mixture was magnetically stirred until all the solids were dissolved. To the resultant aqueous solution was added a solution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1 N aqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred, and chloral (6.0 g, (36 mmol) was added. To the resultant solution was added a solution of hydroxyl amine hydrochloride (7.50 g, 108 mmol) in 30 mL of water. The final mixture was heated with stirring to a gentle boil until all solids disappeared, and heating was continued for an additional 15 min. The flask was removed from the heat, and the solution was poured onto 500 g of ice. The mixture was stirred as the product precipitated from solution. The precipitate was collected by suction filtration, washed thoroughly with water, filtered, and air dried to provide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: 1H NMR (DMSO-d6): 67 12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCI−MS m/z 220 (M−H)−. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 100 ml of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100° C., and 10.0 g (45.2 mmol) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. The solution was heated for ˜1 hour, and the reaction mixture was poured into 750 g of ice and water. The residual reaction mixture in the reaction vessel was washed out with an additional 20 mL of cold water. The aqueous slurry was stirred for about 1 hour and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 4.3 g (46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: 1H NMR (DMSO-d6): δ11.1 (s, 1H), 9.2 (s,1H), 8.2 (d,1H), 7.0 (d,1H); APCI−MS m/z 203 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:20][NH:21][CH:22]([CH3:24])[CH3:23].CC(C)([O-])C.[Na+].O>O1CCOCC1.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:22]([N:21]([CH3:20])[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: CNC(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N(C)c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Yield: 92.1 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.915 mmol), N-methyl-N-isopropylamine (0.313 ml, 3.00 mmol), X-phos (26.1 mg, 0.0546 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.6 mg, 0.00187 mmol) and sodium tert-butoxide (131 mg, 1.37 mmol) in dioxane (6 ml) was stirred under an argon atmosphere at 80° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (270 mg, 92.1%) as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:5][N:4]=1.C1C(=O)N([Cl:21])C(=O)C1>CC#N>[Cl:21][C:7]1[C:6]([C:8]([F:9])([F:10])[F:11])=[N:5][NH:4][C:3]=1[C:2]([F:1])([F:12])[F:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Solvent: CC#N
Product: FC(F)(F)c1n[nH]c(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 3,5-bistrifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (296 mg, 0.79 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (289 mg, 0.88 mmol) according to the general procedure M. Obtained as an orange foam (402 mg, 81%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:18])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2. 1]octan-2-one (Description 30; 6.9 g, 21.8 mmol) was taken up a mixture of methanol (100 ml) and THF (30 ml). To this suspension was added sodium borohydride (0.5 g, 13 mmol). The mixture was stirred for 30 minutes then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was separated, dried (MgSO4), filtered and concentrated. Chromatography on silica gel eluting with 35 and 50% ethyl acetate/iso-hexanes afforded the title compound (4.8 g, 70%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:30]([N:27]([CH2:28][CH3:29])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:8](=[O:10])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH3:31]
Reactant: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of diphenylacetic acid (223 mg, 1.05 mmol), 4-Amino-N,N-diethyl-benzenesulfonamide (240 mg, 1.05 mmol), HOBT (213 mg, 1.58 mmol), and EDC (242 mg, 1.26 mmol) in dichloromethane (20 mL) was stirred at 23° C. for 15 hours. The reaction mixture was washed with 1N aqueous sodium hydroxide (10 mL), 1N aqueous hydrochloric acid (10 mL), and saturated aqueous sodium chloride (10 mL). The organics were dried over magnesium sulfate and were concentrated. Flash chromatography (20% THF in hexanes grading to 40% THF in hexanes) provided the title compound as orange oil that solidified upon standing (224 mg). MS 423 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Cl[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[O:18][N:17]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[O:18][N:17]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=1.1 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.75-7.71 (m, 2H), 7.69-7.63 (m, 1H), 7.58 (dd, J=8.7, 1.5 Hz, 1H), 5.83 (s, 2H), 2.47 (s, 3H); MS (ES) m/z 385 (M+1).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[O:15][N:14]=[C:13]([C:16](OCC)=[O:17])[CH:12]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[Si:1]([O:8][CH:9]([C:11]1[O:15][N:14]=[C:13]([CH2:16][OH:17])[CH:12]=1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
8.95 g of ethyl 5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazole-3-carboxylate was dissolved in 60 ml of ethanol, and 2.30 g of sodium borohydride was then added. The mixture was stirred at room temperature for 4 hours. After 30 ml of water was added, the reaction mixture was concentrated to 30 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.35 g of {5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazol-3-yl}methanol.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]1=[O:12].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[O:15]1[C:8]2([CH2:9][CH2:10][C:5]3([CH2:4][CH2:3][C:2](=[O:12])[NH:1]3)[CH2:6][CH2:7]2)[O:11][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: O=C1CCC2(CC1)CCC(=O)N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CCC2(CCC3(CC2)OCCO3)N1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A stirred mixture of 1-azaspiro[4.5]decane-2,8-dione (P1, 2.00 g, 12.0 mmol), ethylene glycol (2.96 g, 47.7 mmol), and 4-methylbenzenesulfonic acid (100 mg, 0.735 mmol) in toluene (100 mL) was refluxed for 20 h with Dean-Stark apparatus to remove water. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was mixed with saturated aqueous sodium bicarbonate (100 mL) and the resulting aqueous mixture was extracted with 5% methanol/ethyl acetate (4×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound P2 as an off-white solid (2.41 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 5.82 (bs, 1H), 3.95 (s, 4H), 2.41 (t, J=8.0 Hz, 2H), 1.99 (t, J=8.0 Hz, 2H), 1.80-1.65 (m, 8H). MS (M+H) 212.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: Clc1ccc([Mg]Br)cc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(Cl)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-chlorophenylmagnesium bromide.