Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[Li+].[CH:12]([Mg]Cl)([CH3:14])[CH3:13].C(Br)C=C>C1COCC1.[Cu]I>[CH2:14]([C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1)[CH:12]=[CH2:13]
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CC(C)[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cnc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
In a dry 3-necked flask flushed with argon containing a solution of 5-bromo-2-chloro-3-fluoro pyridine (4.0 g, 19.05 mmol) at 0° C. was added isopropyl magnesium chloride lithium chloride complex (1.3 M THF solution, 24.8 mmol, 19.1 mL) over 10 min. After additional 10 min of stirring at 0° C., CuI (0.73 g, 3.81 mmol) was added, and the mixture was stirred for 10 minutes at 0° C. and then a solution of allyl bromide (38.1 mmol, 3.3 mL) in THF (4.0 mL) was added at 0° C. over 10 min. After further stirring for 1 h at 0° C., the reaction was quenched with 10% citric acid and extracted with ethyl acetate (100 mL×2). The organic layers were washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with hexane and 10% ethyl acetate in hexanes to afford 2.5 g of 2 (77%) as a colorless oil. 1H NMR (CDCl3) δ 3.40 (2 H, d, J=6.60 Hz), 5.16 (2 H, m), 5.91 (1 H, m), 7.32 (1 H, dd, J=2.20, 9.00 Hz), 8.06 (1 H, d, J=1.76 Hz); LC/MS (M+1) 172.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:27][C@H:26]([CH2:28][O:29]CC3C=CC=CC=3)[C@@H:17]([O:18]CC3C=CC=CC=3)[C@@H:8]2[O:9]CC2C=CC=CC=2)[C:5]2[CH:37]=[C:38]([Cl:42])[C:39]([Cl:41])=[CH:40][C:4]=2[N:3]=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:17]([OH:18])[C@@H:8]2[OH:9])[C:5]2[CH:37]=[C:38]([Cl:42])[C:39]([Cl:41])=[CH:40][C:4]=2[N:3]=1
Reactant: Clc1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2cc1Cl
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@@H]1O
Reaction time: 4.5 h

Procedure:
Compound 133 (1.25 g 2 mmole) was dissolved in dry CH2Cl2 (20 ml) and this solution was cooled in an acetone-dry ice bath. A 1 M solution of BCl3 in CH2Cl2 (10 ml) was added and the mixture was stirred at -70° for 4.5 hr. At this point TLC showed no starting material. CH3OH (10 ml) was added and the solution was made neutral with NH4OH. The solution was evaporated in vacuo to dryness. H2O (20 ml) was added and the solution was extracted with EtOAc. The EtOAc layer was washed with H2O, dried (Na2SO4) and evaporated in vacuo to obtain a syrup. This syrup was subjected to flash column chromatography on silica gel (Kieselgel 60, 230-400 mesh) with CH2Cl--MeOH (20:1) as eluent solvent to give 134. Yield 0.551 g, 77.9%.
Reaction SMILES: [OH:1][C:2]1([C:15]([N:17]2[CH2:34][CH2:33][CH2:32][C@H:18]2[C:19]([NH:21]CC2C=C(Cl)C=CC=2CN)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(O[CH:38](O)[CH:39]([F:41])[F:40])C.[O-]S([O-])(=O)=O.[Mg+2].[CH2:49]([Cl:51])Cl>C1(C)C=CC=CC=1>[Cl:51][C:49]1[CH:9]=[CH:14][C:2]([CH2:15][N:17]=[CH:38][CH:39]([F:40])[F:41])=[C:3]([CH:4]=1)[CH2:8][C@@:18]1([C:19]([NH2:21])=[O:20])[CH2:32][CH2:33][CH2:34][N:17]1[C:15]([C:2]1([OH:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16]
Reactant: NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Reactant: CCOC(O)C(F)F
Reactant: ClCCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: NC(=O)[C@]1(Cc2cc(Cl)ccc2CN=CC(F)F)CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 1-((9-hydroxy-9H-fluoren-9-yl)carbonyl)-N-(2-aminomethyl-5-chlorobenzyl)-L-prolinamide (65 mg, 0.14 mmol) in anhydrous toluene (1.0 mL) at 0° C. was added difluoroacetaldehyde ethylhemiacetal (20 mg, 0.16 mmol, 1.1 eq). The mixture was heated to 100° C. under nitrogen atmosphere for 40 min and was then treated with MgSO4. Heating was continued for another 2 h. The mixture was then cooled to room temperature and diluted with CH2Cl2. The solution was dried over MgSO4, filtered and concentrated to an orange oil which yielded N-(5-chloro-2-{[(2,2-difluoroethylidene)amino]-methyl}benzyl-1-[(9-hydroxy-9-H-fluoren-9-yl)carbonyl]-L-prolinamide as a foam on prolonged drying under high vacuum. (66 mg, 90%).
Reaction SMILES: C(O)(=[O:3])C.[CH2:5]([O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[CH2:5]([O:12][C:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:3])=[O:21])=[CH:18][CH:19]=1)=[O:22])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To 50 ml of an acetic acid solution containing 7.34 g (30.5 mmol) of 4-formylbenzoic acid benzyl ester were dropwise added 4.53 g (4.35 mmol) of chromic acid anhydride, 40 ml of acetic acid and 1.3 ml of water with stirring at room temperature for a period of 2 hours. The oxidation of a formyl group was further carried out overnight at room temperature. The reaction mixture was put into water, and the deposited black-green crystal was collected by filtration, followed by drying. The resultant crystal was recrystallized from acetone to obtain 4.08 g of 4-benzyloxycarbonylbenzoic acid as a white needle crystal (isolated yield: 49%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:42])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][O:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])(=[O:27])=[O:26])[N:21]=[C:8]2[N:7]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[C:6]=1[CH3:53])=[O:4]>CN(C)C.C(O)C>[C:38]1([CH3:41])[CH:37]=[CH:36][C:35]([S:32]([O-:34])(=[O:31])=[O:33])=[CH:40][CH:39]=1.[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:10]2[N:9]3[C:19](=[O:42])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][N+:7]([CH3:43])([CH3:8])[CH3:6])(=[O:26])=[O:27])[N:21]=[C:8]3[N:7]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:50])([F:51])[F:52])[CH:44]=3)[C:6]([CH3:53])=[C:5]2[C:3]([O:2][CH3:1])=[O:4])=[CH:12][CH:13]=1)#[N:18]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCOS(=O)(=O)c3ccc(C)cc3)c(=O)n2C1c1ccc(C#N)cc1
Agent: CN(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCC[N+](C)(C)C)c(=O)n2C1c1ccc(C#N)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 136.1 %

Procedure:
Intermediate 23 (68 mg, 0.09 mmol) was dissolved in 31% trimethylamine in ethanol (3 ml) and stirred at RT for 16 hours. The solvent was evaporated in vacuo, and the resulting residue repeatedly azeotroped with diethyl ether until a solid formed. The solid was collected and dried in vacuo to yield the title compound as an off-white solid (51 mg).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22][CH2:23][N:24]2[C:29]3[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=3[O:27][CH2:26][C:25]2=[O:36])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]2[O:27][CH2:26][C:25](=[O:36])[N:24]([CH2:23][CH2:22][C@H:12]3[CH2:11][CH2:10][C@@H:9]([OH:8])[CH2:14][N:13]3[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:29]=2[CH:30]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Reaction time: 5 h

Procedure:
To a solution of tert-butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (Intermediate 186, 1.01 g) in THF (10 mL) was added tetrabutylammonium fluoride (TBAF) (4 mL). After 5 hours, the reaction was diluted with ethyl acetate, washed with NaHCO3 and brine, dried over sodium sulfate and concentrated. The crude reaction mixture was used without further purification in the next step.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:6]=1[NH:13][CH3:14])C.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[Cl:11][C:9]1[CH:8]=[C:7]([F:12])[C:6]([NH:13][CH3:14])=[C:5]([CH:10]=1)[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)c1cc(Cl)cc(F)c1NC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CNc1c(F)cc(Cl)cc1C(=O)O
Yield: 93.2 %

Procedure:
To a solution of 5-chloro-3-fluoro-2-methylaminobenzoic acid ethyl ester (135 mg, 0.58 mmol) in MeOH was added 1N NaOH (1165 μl, 1.17 mmol) and the reaction mixture was refluxed for 2 h. The reaction mixture was diluted with ethyl acetate and water and then extracted. The aqueous layer was acidified to pH3 using 1N HCl and the aqueous layer was extracted with EtOAc (2×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the desired product (110 mg, 93%) which did not require further purification. MS (ISP) 202.1 (M−H)−.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH2:19][NH2:20].O>C1C=CC=CC=1>[OH:3][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH3:15])=[CH:9][CH:8]=1
Reactant: NCC(O)c1ccccc1F
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1ccccc1F
Reaction time: 2 h

Procedure:
A mixture of 1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.22 g) and 2-hydroxy-2-(2-fluorophenyl)ethanamine (1.55 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water using a Dean and Stark trap, for 2 hours. The solution was cooled, evaporated to dryness, the residue dissolved in methanol and sodium borohydride (500 mg) added. After 30 minutes, the methanol was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was dried (magnesium sulphate) and evaporated to leave an oil which was chromatographed on silica gel 60 eluting with 2% methanol/chloroform. N-[2-(4-(2-hydroxyethoxy)phenyl-1-methylethyl]-2-hydroxy-2-(2-fluorophenyl)ethanamine (300 mg) crystallised from hexane, m.p. 80°-95°, as a 55:45 mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=[O:12])[CH2:8]2.Cl.[Cl-].[NH4+:17].[C-:18]#N.[K+]>O>[C:18]([C:7]1([OH:12])[CH2:6][CH:5]2[N:4]([CH2:3][C:2]([F:1])([F:13])[F:14])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)#[N:17]
Reactant: O=C1CC2CCC(C1)N2CC(F)(F)F
Reactant: [NH4+]
Reactant: [C-]#N
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.1 %

Procedure:
A 50 ml 2-necked round bottom flask was fitted with a pressure equalised dropping funnel, bubbler and magnetic stirrer. 8-(2,2,2-Trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (5.23 g, 25 mmol) was charged to the reaction flask and suspended in water (5 ml). Hydrochloric acid (5 ml, 5M) was added followed by solid ammonium chloride (2.15 g) and the mixture stirred until the ammonium chloride had dissolved. The mixture was cooled to 0° C., a solution of potassium cyanide (5.031 g, 75 mmol) in water (7.5 ml) was added over 1 hour and the resulting mixture was then stirred at 0° C. for 2 hours during which time a solid precipitate formed. The precipitate was isolated by filtration and sucked dry for 10 minutes, to give 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane as an off-white solid (6.62 g).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH2:18][NH:19][C:20](=[O:23])[CH2:21]C.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[C:45]1[CH2:53][NH:54][CH3:55].C(Cl)CCl>CN(C=O)C>[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:15])[N:54]([CH3:55])[CH2:53][C:45]2[N:44]([CH3:43])[C:52]3[C:47]([CH:46]=2)=[CH:48][CH:49]=[CH:50][CH:51]=3)=[CH:11][C:10]=1[CH2:18][N:19]([CH3:2])[C:20](=[O:23])[CH3:21]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(=O)NCc1cc(C(=O)O)ccc1N
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N(C)Cc1cc(C(=O)N(C)Cc2cc3ccccc3n2C)ccc1N
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To a stirred solution of 4-amino-3-[(N-methylacetylamino)methyl]benzoic acid trifluoro acetate (0.73 g, 2.17 mmole), from Procedure 3, in DMF (20 mL) at RT was added diisopropylethyl amine (0.83 ml, 4.78 mmole), HOBt (0.32 g, 2.39 mmole), 1-methyl-2-(methylaminomethyl)indole (0.40 g, 2.39 mmole) and finally EDC (0.45 g, 2.39 mmole). After 12 hr, the reaction contents were poured onto H2O (100 mL) and extracted with EtOAc (2×100 mL). The organic phases were combined and sequentially washed with H2O (100 mL) and brine. Drying over Na2SO4 and purification on silica (CHCl3/CH3OH. 95:5) afforded the title compound (0.73 g, 89%) as a light yellow solid: MS (ES) m/e 379 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH4+:15].[OH-:16].CC([O-])=O.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[N:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: [OH-]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(=NO)CCC2
Reaction time: 2 h
Yield: 92.8 %

Procedure:
7-Nitro-1-tetralone (2.00 g, 10.4 mmol) was dissolved in ethanol (20 mL) and was added to NH4OH (1.64 mL, 16.6 mmol) and NaOAc (1.71 g, 20.8 mmol) in H2O (30 mL). After 2 h at 65° C., the solvent was removed under reduced pressure and the residue was titurated with H2O. The precipitate was removed by filtration and dried under vacuum to give 1.99 g (93%) of the desired material as a white solid. MS (ES-) m/z 205 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[S:16](Cl)(Cl)(=[O:18])=[O:17].CCOC(C)=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:16]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:18])=[O:17])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)Cl
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCOCC1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
To a solution of 5-bromo-2-chloropyridin-3-amine (Small Molecules, Inc.) (1.000 g, 4.82 mmol) in pyridine (8 mL) was added 4-dimethylaminopyridine (Aldrich) (0.147 g, 1.205 mmol) and morpholine (Aldrich) (0.546 mL, 6.27 mmol). The reaction mixture was cooled to −30° C. and allowed the mixture to stir for 10 minutes. Then sulfuryl chloride (Aldrich) (0.586 mL, 7.23 mmol) was added dropwise into the reaction mixture. After the addition, the mixture was allowed to stir an additional 20 min. in the cooling bath then was allowed to warm to rt and continued to stir under N2 for 20 h. The reaction mixture was poured into the beaker which filled with EtOAc (50 mL) and hand stirred for 10 minutes. The organic layer was decanted into a round-bottom flask. The original mixture (black paste) was dissolved into DCM (3 ml) followed by adding EtOAc (20 mL) and hand stirred for 10 min and decanted to the same round-bottom flask that was mentioned earlier. The combined organic layers were concentrated in-vacuo. The crude product was purified by column chromatography (80 g, 10% to 20% acetone in hexanes) to obtain the desired product as light yellow solid (800 mg). MS (ESI pos. ion) m/z: 356.8. 1H NMR (300 MHz, CDCl3) δ ppm 3.15-3.41 (m, 4H) 3.60-3.83 (m, 4H) 6.79 (br. s., 1H) 8.08 (s, 1H) 8.23 (s, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)([C:12]1[S:16][CH:15]=NC=1)[CH3:11].C[N:28]([CH:30]=O)C>C(OCC)(=O)C>[Br:1][C:15]1[S:16][C:12]([C:10]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)([OH:9])[CH3:11])=[N:28][CH:30]=1
Reactant: COC(=O)c1ccc(C(C)(O)c2cncs2)cc1
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(C)(O)c2ncc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
N-bromosuccinimide (0.933 g, 5.24 mmol) was added to a solution of the product of Step 1 (1.15 g, 4.37 mmol) and DMF (8.73 ml). The resulting solution was stirred overnight at room temperature. The reaction was diluted with ethyl acetate and transferred to a separatory funnel. The organic layer was washed with aqueous saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. Flash chromatography (0-65% EtOAc/hexanes) afforded methyl 4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]benzoate (863 mg, 2.52 mmol, 57.7% yield) as a yellow solid. MS ESI: [M+H]+ m/z 343.9.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[OH:3].CCN(CC)CC.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Si:13]([O:3][CH:2]([CH3:4])[C:1]#[N:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a flask containing DL-lactonitrile (36.3 mmol, 2.8 g) in DCM (25 ml), Et3N (54.7 mmol, 8.1 ml) and tert-butyldiphenylsilyl chloride (36.3 mmol, 10 g) were added. The resulting solution was stirred at RT for 24 h. The reaction mixture was quenched with H2O and extracted with DCM. The organic layer was washed with brine, dried, filtered and evaporated. The crude product was purified by flash-chromatography. Yield 4.52 g. 1H-NMR (400 MHz; CDCl3): δ 1.10 (s, 9H), 1.50 (d, 3H), 4.43 (q, 1H), 7.39-7.51 (m, 6H), 7.65 (d, 2H), 7.71 (d, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][NH2:34])[CH:27]=[N:28][CH:29]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:8]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][NH:34][C:1](=[O:3])[CH3:2])[CH:27]=[N:28][CH:29]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OCc3ccccc3)c2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OCc3ccccc3)c2)c1
Reaction time: 1.42 h
Yield: 95.7 %

Procedure:
In a 15 mL round-bottom flask with magnetic stirrer, septum, and balloon (for pressure equalization and exclusion of moisture), neat acetic anhydride (23 μL, 0.24 mmol, 1.5 equiv.) was added with ice cooling in 5 min to a solution of 3-[5-[[1-(benzyloxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]benzylamine (65.3 mg, 162 μmol) and triethylamine (45 μL, 0.32 mmol, 2 equiv.) in anhydrous CH2Cl2 (1 mL). Stirring was continued at room temperature for 85 min, while the septum was replaced with a glass stopper to avoid evaporation losses. After 65 min, TLC (SiO2, CH2Cl2/MeOH 9:1, UV detection) demostrated complete conversion of the starting material (Rf approx. 0.05) to the acetamide (Rf approx. 0.45). Methanol (25 μL) was added, and the reaction mixture was stored at room temperature for 1 h before being directly applied on a SiO2 column (26×1.3 cm; eluent: CH2Cl2/MeOH 94:6 for a forerun, then 9:1). The product-containing fractions were evaporated and dried (50° C./oil pump) to yield 69.1 mg (96%) of the amide as a colorless glass. [α]D−40.7, [α]546−48.3 (c 14.8 g/L, EtOAc). 1H NMR (CDCl3, 500 MHz) δ 8.47 (s, 1H), 8.32 (br, 1H), 7.55-7.48 (m, 2H), 7.47 (t, 1H, J=7.5 Hz), approx. 7.4 (br and overlapping, 1H), 7.30 (d, 1H, J=7.4 Hz), 7.31 (br s, 5H), 5.89 (br, 1H), 5.12, 5.07 (ABq, 2H, J=12.3 Hz), 4.67 (br, 1H), 4.54 (d, 2H, J=5.7 Hz), approx. 4.4-4.5 (br, 1H), 4.22 (br, 1H), 4.09-4.00 (m, 2H), 2.51-2.32 (m, 2H), 2.08 (s, 3H). MS (EI) m/z 445 (M+, 8.46%), 354 (2.2%), 312 (2.8%), 310 (5.9%), 242 (6.5%), 199 (5.0%), 91 (100%), 43 (11%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[C:13](O)=[O:14].[BH4-].[Na+]>CCOCC.CO>[F:16][C:12]([F:17])([C:11]([F:19])([F:18])[F:10])[CH:13]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)[OH:14]
Reactant: Cc1ccc(Br)cc1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(C(O)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
In a three neck flask purged with nitrogen were charged magnesium (12.2 g, 502 mmol) and ether (100 ml). A solution of 4-bromotoluene (56.1 ml, 456 mmol) in ether (200 ml) was added dropwise, and the mixture was heated under reflux for 1.5 hrs. The reaction vessel was cooled in a dry ice-acetone bath. A solution of pentafluoropropionic acid (25 g, 152 mmol) in ether (100 ml) was added dropwise, and the temperature was slowly raised to room temperature. The mixture was heated under reflux for 3 hrs, and stirred overnight at room temperature. The reaction mixture was ice-cooled, and quenched with 3N hydrochloric acid. The mixture was diluted with ethyl acetate, and the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0, 30:1) to give a colorless transparent oil. This was dissolved in methanol, and sodium borohydride was added under ice-cooling. The temperature was raised to, room temperature, and the mixture was stirred for 1 hr. After completion of the reaction, the reaction was quenched with 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, 5:1) to give 2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propan-1-ol (20.28 g, 56%) as a colorless transparent oil.