Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:17]([OH:19])=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.CC[N:22](CC)CC.C(Cl)(=O)OCC(C)C.[OH-].[NH4+]>C1COCC1>[CH3:1][C:2]1([C:17]([NH2:22])=[O:19])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC1(C(=O)O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C(N)=O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: -3 °C
Reaction time: 1.25 h
Yield: 29.4 %

Procedure:
To a solution of 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylic acid (2.65 g, 10.03 mmol) in THF (45 ml) cooled at −5° C. (ice/NaCl bath) was added Et3N (1.537 mL, 11.03 mmol), followed by dropwise addition of isobutyl carbonochloridate (1.443 mL, 11.03 mmol). After addition, the resulting yellow suspension was stirred at −3° C. for 75 min and then 6.25 mL of a 28% aqueous ammonium hydroxide solution (50 mmol, 5.0 equiv.) was added. The reaction mixture was stirred at ˜0° C. for 1.5 hrs. The reaction was quenched with water, the resulting mixture (pH>10) was extracted with EtOAc (3×). The combined organic phase was washed with water (2×), saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The crude product was crystallized from EtOAc to give the title compound, 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxamide (777 mg, 2.95 mmol, 29.4% yield), as a brown solid. Anal. Calcd. for C13H17N3O3 m/z 263.2, found: 264.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.20-8.02 (m, 2H), 7.06-6.85 (m, 2H), 3.91 (d, J=13.19 Hz, 1H), 3.64-3.49 (m, 1H), 3.16 (ddd, J=12.64, 8.25, 4.40 Hz, 1H), 3.09 (s, 2H), 3.06 (d, J=13.19 Hz, 1H), 2.09 (d, J=13.74 Hz, 1H), 1.91-1.72 (m, 2H), 1.62-1.48 (m, 1H), 1.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:13])=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=O.O.[NH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:7]([CH3:13])[NH:23][N:22]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccccc1
Reactant: NN
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccccc1
Yield: 51.4 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-2-methyl-3-phenyl-chromen-4-one (0.5 g, 1.75 mmol), Hydrazine hydrate (5 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-Chloro-6-(5-methyl-4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a white solid (0.27 g, 51.4%); Rf 0.55 ethyl acetate/hexane (80/20)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[CH:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:5]=[CH:6][CH:7]=1.[B-](F)(F)(F)[F:28].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C.O>>[F:28][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:9]=1[CH:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18]
Reactant: F[B-](F)(F)F
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2cccnc2n1-c1cccc(F)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)c1c(F)c2cccnc2n1-c1cccc(F)c1
Temperature: 50 °C
Yield: 15.3 %

Procedure:
A mixture of tert-butyl {1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl}carbamate (0.10 g, 0.28 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (0.10 g, 0.28 mmol) in acetonitrile (1.5 mL, 29 mmol) and water (0.15 mL, 8.3 mmol) was heated at 50° C. overnight. The reaction was cooled and extracted with dichloromethane. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-20% EtOAc/hexane) to give the desired product (16 mg, 15%). LCMS calculated for C20H22F2N3O2(M+H)+: m/z=374.2. Found: 374.1.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:37][C:38]1([OH:42])[CH2:41][NH:40][CH2:39]1>CC(O)C>[OH:42][C:38]1([CH3:37])[CH2:41][N:40]([C:11]2[C:30]([C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[O:16])=[CH:13][N:12]=2)[CH2:39]1
Reactant: CC1(O)CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ncc[nH]2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ncc[nH]2)C1
Temperature: 140 °C

Procedure:
DIPEA (0.139 mL, 0.794 mmol) was added to a mixture of 6-chloro-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 69.1, 76 mg, 0.199 mmol) and 3-methylazetidin-3-ol HCl (27 mg, 0.218 mmol) in iPrOH (1 mL) and the RM was stirred at 140° C. 4.5 h. The solvent was evaporated off under reduced pressure and the residue was treated with water, extracted with EtOAc and the combined extracts were washed with water and brine, dried over MgSO4/charcoal and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 15 g, EtOAc/EtOH from 95:5 to 9:1) and crystallized from n-hexane/EtOAc to give the title product as white crystals. UPLC-MS (Condition 3) tR=0.7 min, m/z=434.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 3H) 3.54-3.67 (m, 4H) 5.47 (s, 1H) 7.05 (s, 1H) 7.26 (s, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.87 (d, J=9.03 Hz, 2H) 8.15 (d, J=2.07 Hz, 1H) 8.76 (d, J=2.07 Hz, 1H) 10.25 (s, 1H) 12.39 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[S:7])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([NH2:20])=[O:19])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[S:7][CH:12]([C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[O:16][CH2:17][C:18]([NH2:20])=[O:19])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)COc1ccccc1C=O
Reactant: NNC(=S)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)COc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Reaction time: 0.17 h

Procedure:
To a heterogeneous mixture of 4-chloro-thiobenzoic acid hydrazide (1.3 mmol) in 12 mL of CH2Cl2 is added 2-(2-formylphenoxy)acetamide (1.53 mmol) and DIEA (1.53 mmol). After 10 minutes the mixture become homogenous and the reaction is complete by TLC and LCMS to give 2-(2-(5-(4-chlorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenoxy)-acetamide which is used as such in the next step without evaporation of the solvent.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:41])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:41])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (122 mg, 0.21 mmol) in dry THF (2.0 mL) was treated at 0° C. with TBAF (0.41 mL of a 1M solution in THF, 0.41 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a white solid. TLC:rf (19:1 CH2Cl2-MeOH)=0.26. LC-MS-conditions 02: tR=1.01 min; [M+H]+=479.03.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC4CCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CC4CCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:19]1([C:23]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:2][CH:3]=2)=[O:24])[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)COc1cccc2ccccc12
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)c2cccs2)c2ccccc12
Temperature: -10 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
483 g ethyl 1-naphthyloxyacetate and 308 g thiophene-2-carboxylic acid chloride was dissolved in 3.570 l. methylene chloride. While the mixture is being maintained at about -10° C., 291 g aluminium chloride are introduced slowly; after 2 hours at -10° C., the mixture is brought back to 25° C. and the stirring maintained for 12 hours. The mixture is then poured into 2 Kg iced water, the organic phase decanted off, washed with dilute aqueous sodium hydroxide solution then water and the solvent evaporated. 562 g of the ester are thus obtained. After recrystallisation from isopropyl ether, it melts at 79° C.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:11][C:10]1[C:2]([F:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(C(=O)O)c1F
Reaction time: 2 h

Procedure:
To 2-fluoro-3-nitro-benzoic acid (28, 2.0 g, 11 mmol) in 45 mL of tetrahydrofuran, 20% palladium hydroxide on carbon (150 mg) was added. The reaction was stirred under hydrogen for 2 hours, then filtered and the filtrate concentrated under vacuum to provide the desired compound 29 as a white solid, which was used in the next step without further purification. MS(ESI) [M−H+]−=154.4.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN([CH:18]=[O:19])C>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[N:10]=[C:11]([CH:18]=[O:19])[CH:12]=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: c1cnc(OCC2CCCCC2)nc1
Solvent: C1CCOC1
Product: O=Cc1ccnc(OCC2CCCCC2)n1
Reaction time: 0.25 h

Procedure:
Knochel-Hauser reagent (2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex) is added to a mixture of 2-(cyclohexylmethoxy)pyrimidine in THF at −78° C., stirred for 15 min, then DMF is added. The reaction mixture is stirred at −30° C., quenched by aqueous NH4Cl, extracted with ethyl acetate. Combined organic layers are dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(cyclohexylmethoxy)-pyrimidine-4-carbaldehyde.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S([O:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])(=O)=O.[F:20][C:21]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[CH2:22]O.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:20][C:21]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[CH2:22][O:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Reactant: C[Si](C)(C)COS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)COCC(F)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
Potassium carbonate (6 g) was added to a solution of 3.5 g (0.0148 mol) of trimethylsilylmethyl trifluoromethanesulfonate and 2.3 g of 2-fluoro-2,2-dinitroethanol in 5 ml of methylene chloride, and the mixture was stirred for 16 hrs. This suspension was added with stirring to a mixture of 30 ml of ice water and 30 ml of carbon tetrachloride. The carbon tetrachloride layer was washed with 10 ml of water, dried over magnesium sulfate, and distilled to give 1.56 g (45%) of trimethylsilylmethyl 2-fluoro-2,2-dinitroethyl ether, bp 52° (0.75 mm).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=1)[C:18]#[N:19].O>CN(C)C=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:17]([CH:20]=1)[C:18]#[N:19]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1C#N
Reaction time: 0.5 h
Yield: 105 %

Procedure:
Octanol (0.834 g) was dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (60%, 0.256 g) was added. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (0.640 g) was added, and the mixture was further stirred at 40-50° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the object product (1.042 g) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: [Ru]
Solvent: CO
Solvent: ClCCl
Product: CCCCC[C@H](O)CC(=O)OC
Yield: 95.9 %

Procedure:
Into a 100-ml autoclave (made of Hastelloy) were introduced 20 g of methyl 3-oxooctanoate (manufactured by Inoue Perfumery Mfg. Co., Ltd.) and 50 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 140 mg of Ru2Cl4 ((-)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 1.0 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 6 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 19.4 g of methyl (S)-3-hydroxyoctanoate. Yield, 96%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1F.[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:15][CH2:13][CH3:14]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(C(F)(F)F)ccc1Br
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1.5 g of 4-bromo-3-fluorobenzotrifluoride, 0.46 ml of ethanethiol, 851 mg of potassium carbonate and 2 ml of DMF was stirred at 75° C. for 2.5 hours. Water was poured to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 1.15 g of 4-bromo-3-ethylsulfanylbenzotrifluoride.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[OH-].[Li+]>O1CCCC1>[F:27][C:2]([F:1])([F:26])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@H:14]3[CH2:15][CH2:16][C@H:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[CH:4]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with the product from Example 26B (0.520 g, 1.36 mmol) and 6 mL of 20% aqueous tetrahydrofuran. Lithium hydroxide was added (114 mg, 2.72 mmol), and the reaction stirred at room temperature overnight. After 16 hours, the reaction was quenched with 1 N HCl, and the mixture filtered over a bed of celite. Evaporation of the solvents and purification via silica gel chromatography (10-30% ethyl acetate/hexanes with 1% acetic acid) afforded the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.23 (m, 2 H), 1.41-1.57 (m, 2 H), 1.58-1.67 (m, 1 H), 1.69-1.77 (m, 1 H), 1.78-1.88 (m, 4 H), 2.12-2.20 (m, 2 H), 7.05-7.17 (m, 1 H), 7.26-7.41 (m, 2 H), 7.62-7.82 (m, 2 H), 12.00 (s, 1 H), 13.89-14.07 (m, 1H): MS (ESI) m/z 354 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[S:21][CH2:22][CH2:23][N:24]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[N:24]([CH:2]=2)[CH2:23][CH2:22][S:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: NC1=NCCS1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Solvent: CCO
Product: COc1cc(-c2cn3c(n2)SCC3)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (200 mg, 0.65 mmol) and 2-amino-2-thiazoline (67 mg, 0.65 mmol) in ethanol (5 mL) was heated to reflux for 2 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with a solution of saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (2:1) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)-2,3-dihydroimidazo[2,1-b][1,3]thiazole. 1H NMR (CD3OD, 300 MHz) δ 8.86 (d, 1H), 8.67 (t, 1H), 8.35 (d, 1H), 8.17 (s, 1H), 8.04 (m, 1H), 7.84 (m, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 4.60 (m, 2H), 4.26 (m, 2H), 4.07 (s, 3H) ppm. MS (ESI) 310 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[NH:28]C(=O)OCC[Si](C)(C)C)[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][C@@H:18]1[CH2:19][C@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:21][CH2:22][C@@H:17]1[N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:38]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Example 1, Alternative Preparation, Step 6: A stirring solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate (100 mg, 0.183 mmol) in dichloromethane (3 mL) was charged with trifluoroacetic acid (2 mL). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and washed with saturated NaHCO3 (20 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The dichloromethane layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-amino-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (66 mg, 90%). LC/MS found [M+H]+=403.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([NH2:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])[CH3:25]>>[C:24]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([NH:36][C:20]([C:10]2[CH:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:21])[CH2:34][CH2:35]1)=[O:29])([CH3:23])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(N)CC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-amino-1-piperazinecarboxylic acid 1,1-dimethylethyl ester (CAN 118753-66-5) as starting materials; MS (EI) 515.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:1][C:2]1([C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-oxopyrrolidine-1-carboxylate (926 mg, 5.0 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0° C., trimethyl(trifluoromethyl)silane (0.872 mL) and tetrabutylammonium fluoride (TBAF) (176 mg, 0.557 mmol) were added. The ice-bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl solution (8 mL) was added and stirring was continued. After 15 min TBAF (2.36 g TBAF in 7.5 mL THF) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate, washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum spirit) to give the subtitled compound (800 mg).