Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]>O1CCCC1.C(N)CN>[CH2:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: NCCN
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC1=C2CCCC1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
Fluorene (100 g, 0.6 mole) was dissolved in a mixture of 600 ml tetrahydrofuran (THF) and 600 ml ethylenediamine (1:1 by volume). The fluorene solution was degassed with nitrogen and cooled to 0° C. 4.25 equivalents of lithium metal (17.7 g, 2.55 mole) were added in 2 g portions every 10 minutes and the reaction temperature was maintained at 10° C. The reaction mixture was warmed to room temperature. The reaction mixture was then quenched with degassed water; the separated organic phase was extracted with a mixture of aqueous NaCl (300 ml) and cyclohexane (500 ml). The organic phase was washed with aqueous NaCl (300 ml), the water phase was removed, and the cyclohexane was stripped from the solution leaving 95 g (0.56 moles) of tetrahydrofluorene (93% yield). 9-trimethylsilyl-1,2,3,4-tetrahydro-9H-fluorene. 1,2,3,4-tetrahydro-9H-fluorene (50 grams (g), 0.294 mol) was dissolved in 1 liter (L) of anhydrous THF and cooled to -78 ° C. To this solution 123 ml (0.307 mol) of n-BuLi (2.5M solution in hexane) was added via syringe within 25 minutes (min). The reaction mixture was stirred for few minutes at -78° C. until the lithium salt precipitated from the solution. After precipitation, the cold bath was removed and the reaction mixture was and stirred for 2 hours (hr) at room temperature. The flask was cooled to -78° C. and 40 ml (34.24 g, 0.315 mol) of trimethylsilyl chloride (TMSCI) was added through syringe within 1 hr. After addition was completed the reaction mixture was stirred for 3 hr at -78 ° C. and then it was slowly warmed up to room temperature and stirred overnight. THF solvent was removed in vacuum and the residue was extracted with 150 ml of hexane. The hexane solution was filtered to another flask and hexane was removed leaving 70.39 g of 9-trimethylsilyl-1,2,3,4-tetrahydro-9H-fluorene (about 95% pure). Yield 99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH:11]([N:15]=[N+]=[N-])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=O>C1COCC1>[NH2:15][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13][C:12]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2N=[N+]=[N-]
Solvent: C1CCOC1
Product: NC1CCCc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-azido-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (35 g, 151 mmol, 1.0 eq) in THF (100 mL) was added dropwise in 30 min. The reaction was warmed to RT spontaneously and stirred at RT overnight. The reaction was quenched with THF and H2O mixture (30 mL, THF:H2O=2:1), followed by the sequential addition of 5 N NaOH (10 mL) and H2O (100 mL) while keeping the temperature of the reaction lower than 5° C. The reaction was stirred at RT for additional 5 h. The precipitate was filtered and washed with THF. The concentration of the filtrate afforded the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 161 (M−NH3+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:11][C@H:10]1[CH2:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-].C([O-])(O)=O.[Na+]>CO>[CH2:1]([N:8]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:11][C@H:10]1[CH2:20][CH:21]([OH:25])[CH:22]([CH3:23])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Examples 11p and 11q, Step 8: To a solution of 1-((1S,2S,5R)-2-(dibenzylamino)-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-one (168 mg, 0.39 mmoles) in 3 ml of methanol was added sodium borohydride (29.2 mg, 0.78 mmoles), the mixture was stirred for 2 hours at room temperature. At the end of the stirring was added saturated NH4Cl, and then the mixture was made basic with saturated NaHCO3. It was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated to give 166 mg of 1-((1S,2S,5R)-2-(dibenzylamino)-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-ol as a mixture of the two isomers (ratio ˜2:1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[CH2:16][O:15][CH:14]2[CH:9]([C@:10]3([CH2:28][CH2:27][C@H:26]4[C:17](=[CH:18][CH2:19][C:20]5[CH2:21][C:22](=[O:29])[CH2:23][CH2:24][C:25]=54)[C@@H:12]3[CH2:13]2)[CH3:11])[O:8]1>C(OCC)C>[CH2:7]1[CH2:16][O:15][CH:14]2[CH:9]([C@:10]3([CH2:28][CH2:27][C@H:26]4[C:17](=[CH:18][CH2:19][C:20]5[CH2:21][CH:22]([OH:29])[CH2:23][CH2:24][C:25]=54)[C@@H:12]3[CH2:13]2)[CH3:11])[O:8]1
Reactant: C[C@]12CC[C@H]3C(=CCC4=C3CCC(=O)C4)[C@@H]1CC1OCCOC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@]12CC[C@H]3C(=CCC4=C3CCC(O)C4)[C@@H]1CC1OCCOC12
Reaction time: 1.5 h

Procedure:
To a well-stirred suspension of lithium aluminum hydride (0.3 g, 7.9 mmol) in diethyl ether (20 mL) at 0° C. under nitrogen was added a solution of the ketone 3 (0.47 g, 1.52 mmol) in ether (20 mL). After stirring for 1.5 h the reaction mixture was quenched by the sequential addition of water (0.3 mL), 15% aqueous sodium hydroxide (0.3 mL) and water (1 mL) and stirred for 30 min. The inorganic precipitate was filtered out and washed with ether (3×10 mL). The ether extracts and washings were combined and concentrated to afford a mixture (4:1) of the 3α-and 3β-alcohols 4 as a foam (0.47 g, quant).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCCCCCCCCCOS(C)(=O)=O
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCN1CCN(C(=O)OCC)CC1
Temperature: 25 °C

Procedure:
77.3 Grams of decyl methylsulfonate, 44.64 grams of 1-ethoxycarbonylpiperazine, 500 ml. of ethanol, and 39 grams of potassium carbonate are combined and refluxed for approximately 44 hours under a nitrogen atmosphere. After cooling to room temperature the residue is dissolved in a mixture of water and ethyl ether. The organic layer is separated, washed three times with portions of water and dried over anhydrous sodium sulfate. The solvents are removed under reduced pressure to give 1-ethoxycarbonyl-4-decylpiperazine.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH:12](OCC)=[O:13].O>C(OCC)C>[OH:13]/[CH:12]=[CH:9]/[C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CCOC=O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: O=C(/C=C/O)Cc1ccccc1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 1-phenylpropan-2-one (1.78 g, 13 mmol) in anhydrous diethyl ether (50 ml) containing sodium cut in small pieces (299 mg, 13 mmol), ethyl formate (1.4 g, 20 mmol) was added slowly with stirring and ice-cooling. After standing overnight at rt, water was added, and the ether layer was washed with water. The organic phase was dried, concentrated, and purified by flash column chromatography (PE/EtOAc=10:1) to give the title compound (1.2 g, 57%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:16]1[C:17]2[C:12](=[CH:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc3ncccc3cn2)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Oc1ccc(-c2cc3ncccc3cn2)cc1
Temperature: 190 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as yellow solid. 2-(4-Methoxyphenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at rt. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the imine (2.72 g, 97%) which was used in next step without further purification. To a solution of this imine (2.7 g, 9.23 mmol) in 50 mL anhydrous DMF was added (0.190 g, 0.1 mmol) copper (I) iodide. The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with sat. aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark colored solid. Purification by column chromatography (Silica Gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl) [1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl) [1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The crude compound was adsorbed onto silica gel and purified by column chromatography (Silica Gel 230-400 mesh; 20-70% ethyl acetate in hexanes as fluent) to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. MS (ES) m/z: 223.95 (M+1), 222.95 (M); Mp. 219-221° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[C:8]=1[F:19].[C:20](=[O:22])=[O:21].C(O)(C(F)(F)F)=O>CCOCC>[F:19][C:8]1[C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=1[C:20]([OH:22])=[O:21]
Reactant: O=C=O
Reactant: Fc1cc(Br)c(F)c(C(F)(F)F)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(F)c(F)c(C(F)(F)F)c1F
Temperature: 20 °C
Yield: 69 %

Procedure:
A solution of n-butyl lithium (2.6 M in hexanes, 9.6 mL, 25 mmol) was added dropwise through an addition funnel over 15 minutes to a solution of 1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene (7.00 g, 25 mmol) in ether (100 mL) stirred under N2 at -78°. After 5 minutes the rxn mixture was rapidly blown by catheter onto a suspension of dry ice (100 g) in ether (100 mL). After 5 minutes TFA (2 mL) was added to this. When the solution had warmed up to 20° C., it was washed with diluted HCl (0.5 M, 20 mL), and extracted with dilute base (0.5 N, 2×50 mL). The combined basic extracts were washed with ether (25 mL), made acidic with concentrated HCl (≈4 mL) and extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (50 mL), saturated brine (50 mL) and dried (MgSO4) The solvent was removed under reduced pressure to give 2,4,5-trifluoro-3-(trifluoromethyl) benzoic acid (4.21 g, 69%) as white microscopic needles; mp 87°-90° C. Nmr (CDCl3) δ 11.80 (1 H, br s, OH), 8.05 (1 H, d of t, Jd =6 Hz, Jt =9 Hz, aromatic). IR (KBr) 1721, 1636, 1511, 1464, 1424, 1328, 1256, 1154, 928 cm-1. M⊕ 244 (56).
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[C:5]([OH:13])(=[O:12])[CH:6]([CH2:8][C:9]([OH:11])=[O:10])[OH:7]>O>[C:5]([O-:13])(=[O:12])[CH:6]([CH2:8][C:9]([O-:11])=[O:10])[OH:7].[Al+3:2].[C:5]([O-:13])(=[O:12])[CH:6]([CH2:8][C:9]([O-:11])=[O:10])[OH:7].[C:5]([O-:13])(=[O:12])[CH:6]([CH2:8][C:9]([O-:11])=[O:10])[OH:7].[Al+3:2]
Reactant: O=C(O)CC(O)C(=O)O
Agent: [Al+3]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)C(=O)[O-]
Temperature: 69.85000000000002 °C
Reaction time: 70 h

Procedure:
Aluminum(III) hydroxide (2.75 g) was suspended with stirring (340 rpm) in water (11.4 g) maintained at 343 K, malic acid (5.82 g) added over 1 minute, and stirring continued at 343 K for 70 hours. A white suspension was obtained, and this was diluted to 6% w/w solids for testing.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:38])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:5][CH:4]=1.[ClH:39]>O>[ClH:39].[NH:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:21]=[CH:20][C:19]([C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:6]3[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=3)=[O:38])=[CH:24][CH:23]=2)[CH2:26][CH2:27]1
Reactant: COc1ccc(C(=O)C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)cn1
Agent: Cl
Solvent: O
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)[nH]c1)c1ccc(C2CCNCC2)cc1

Procedure:
A solution of (R)-tert-butyl 4-(4-(3-(6-methoxypyridin-3-yl)-3-oxo-1-o-tolylpropyl)-phenyl)piperidine-1-carboxylate (260 mg, 505 μmol), hydrogen chloride solution (4.0 M in 1,4-dioxane, 3.03 mL, 12.1 mmol) and water (0.5 mL) was heated to 100° C., then after 90 min the reaction mixture was purged with argon and concentrated to afford (R)-5-(3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropanoyl)pyridin-2(1H)-one hydrochloride (272 mg, light yellow foam, MS (ESI+): m/z=: 401.4 [M+H]+). This was taken up in dichloromethane (4 mL) and N,N-dimethylformamide (0.4 mL), then after addition of N,N-diisopropylethylamine (326 mg, 2.53 mmol) and a solution of di-tert-butyl-dicarbonate (121 mg, 0.56 mmol) at 0° C. After 30 min the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Chromatography (SiO2; gradient ethyl acetate/heptane 1:1 to ethyl acetate) afforded the title compound (204 mg, 81%). Light yellow foam, MS (ESI+): m/z=: 501.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.CCN(C(C)C)C(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)(=[O:34])=[O:33]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2cnn(C3CCN(S(C)(=O)=O)CC3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
A suspension of 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (200 mg, 0.64 mmol) in DCM (4 mL) was cooled to 0° C. and treated with DIPEA (280 μL, 1.6 mmol). Methanesulfonyl chloride (74 μL, 0.96 mmol) was added dropwise slowly and the mixture was stirred at RT for 18 hours. The mixture was concentrated in vacuo, taken up in MeOH and purified by MDP to afford 100 mg (40%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.34 (s, 12H) 2.05-2.22 (m, 2H) 2.22-2.34 (m, 2H) 2.81-2.90 (m, 4H) 2.90-3.04 (m, 3H) 3.86-4.03 (m, 2H) 4.26-4.43 (m, 1H) 7.77 (s, 1H) 7.81-7.90 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[C:7](C(=O)CS(C)(=O)=O)[NH:8]2)=[CH:4][C:3]=1Cl.[BH4-].[Na+].C(O)(=O)C.C>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: CS(=O)(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(-c2c[nH]c3ccccc23)nc1

Procedure:
To 6-bromo-5-chloro-2[(methylsulfonyl)acetyl]-3-(2-pyridyl)indole (2.2 g) in 75 ml of ethanol add 0.175 g of sodium borohydride. After a solution is obtained (about 10 minutes) stir the mixture of another 30 minutes, then slowly add 2 ml of acetic acid. Treat with charcoal, filter and add 100 ml of water to the filtrate to obtain 6-bromo-5-chloro-2[1-hydroxy-2-methylsulfonyl)ethyl]-3-(2-pyridyl)indole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.COC(C)(C)C.CC(C)([O-])C.[Na+].[CH:69]1([C:72]([N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)=[O:73])[CH2:71][CH2:70]1>O1CCOCC1>[CH:69]1([C:72]([N:74]2[CH2:79][CH2:78][N:77]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)(=[O:12])=[O:11])=[CH:4][CH:3]=3)[CH2:76][CH2:75]2)=[O:73])[CH2:70][CH2:71]1
Reactant: CC(C)CN(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)CN(Cc1ccc(N2CCN(C(=O)C3CC3)CC2)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
In a vial, N-[(4-bromophenyl)methyl]-N-isobutyl-1-phenyl-methanesulfonamide (53 mg, 0.13 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (3.2 mg, 0.0067 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2 aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (6 mg, 0.0067 mmol) and sodium tert-butoxide (20 mg, 0.20 mmol) were combined and the vial was purged with nitrogen. 1,4-Dioxane (1 mL) and cyclopropyl(piperazin-1-yl)methanone (31 mg, 0.20 mmol) were then added and the reaction was stirred at ambient temperature for 16 hours. The reaction was then partitioned between water and dichloromethane and the dichloromethane layer was isolated with a phase separator cartridge, concentrated and purified by preparative reverse phase HPLC to yield 27 mg of N-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzyl]-N-isobutyl-C-phenyl-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.38-7.34 (m, 5H), 7.21 (d, J=8.5 Hz, 2H), 6.94 (d, J=6.8 Hz, 2H), 4.40 (s, 2H), 4.16 (s, 2H), 3.82-3.78 (m, 2H), 3.62-3.58 (m, 2H), 3.20-3.05 (m, 4H), 2.80 (d, J=7.5, 2H), 2.12-1.92 (m, 1H), 1.60-1.45 (m, 1H), 0.83-0.69 (m, 4H), 0.67 (d, J=7.1 Hz, 6H); LCMS (m/z) ES+ 470.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31][C:32]([O:34]C)=O)[O:13][C:12](=[O:14])[N:11]([C@H](C3C=CC(C4C=CC(=O)N(C)C=4)=CC=3)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:36]([Mg]Br)[CH3:37]>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:31][C:32]3([OH:34])[CH2:37][CH2:36]3)[O:13][C:12](=[O:14])[NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: O=C1NCCC(CC2(O)CC2)(c2ccc(F)cc2)O1
Reaction time: 2 h
Yield: 2.9 %

Procedure:
To a solution of methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate (150 mg, 0.33 mmol), and tetraisopropoxytitanium (189 mg, 0.66 mmol) in THF (20 mL) was added 3.0 M ethylmagnesium bromide (4 mL, 12 mmol) at rt under nitrogen. Then the mixture was stirred for 2 h. The reaction was quenched with aqueous NH4Cl solution, and the mixture was filtered. The filtrate was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by preparative HPLC to give (S)-3-(S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one (2.51 mg, 2%). 1H NMR (CDCl3): 0.03 (m, 1H), 0.18 (m, 1H), 0.49 (m, 1H), 0.60 (m, 1H), 1.43 (m, 3H), 2.08 (s, 2H), 2.26 (m, 1H), 2.37 (m, 2H), 2.88 (m, 1H), 5.53 (m, 1H), 6.66 (d, 2H), 6.97 (t, 2H), 7.16 (m, 2H), 7.26 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:1]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccccc3OC(F)(F)F)c2)S1

Procedure:
To a solution of 3-formyl-(2′-trifluoromethoxy-1,1′-biphenyl) (0.31 g, 1.16 mmol) and 2,4-thiazolidinedione (0.164 g, 1.4 mmol) in toluene (20 mL) were added piperidine (0.015 mL, 0.152 mmol) and benzoic acid (0.021 mg, 0.175 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(C)(C)C.[K+].COC1C=CC(C[Br:38])=CC=1>CN(C)C=O>[Br:38][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:24])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12](=[O:23])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CBr)cc1
Reactant: COc1ccc(CN2C(=O)COC[C@@]2(C)c2cccc(N)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)COC[C@@]2(C)c2cccc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-5-(3-amino-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one (1.0 g, 3.7 mmol) in N,N-dimethylformamide was added within 5 minutes at 0° C. to a solution of potassium tert-butanolate (0.636 g, 5.7 mmol). After stirring at 0° C. for 30 minutes the light yellow solution was cooled to −4° C. and treated with a solution of 4-methoxybenzylbromide (1.12 g, 5.6 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was left to warm to room temperature, then the solvent was evaporated at reduced pressure, and the residue treated with saturated ammonium chloride solution (50 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with brine (50 ml), dried over sodium sulfate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. The (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one was obtained as colorless oil (1.19 g, 83% of theory). Mass (calculated) C19H20BrNO3 [390.275]; (found) [M+H]+=390, [M+2-H]+=392.