Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[O:21][C:11](=[O:13])[C@@H:10]1[CH3:14]
Reactant: C[C@@H](C(=O)O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H]1C(=O)O[C@@]1(Cn1cncn1)c1cc(F)ccc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
10 g (27 mmol) of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-[1,2,4]-triazol-1-yl-butyric acid (oxalate salt) were dissolved in 200 ml of tetrahydrofuran and after addition of 5.8 g (35 mmol) 1,1′-carbonyldiimidazole stirred at 60° C. for 3 hours. After evaporation of the solvent the reaction mixture was poured onto 300 ml of aqueous 0.5N-HCl and extracted 3 times with each 300 ml of ethyl acetate. The extract was dried over Na2SO4 and evaporated. 7.1 g (94% yield) of (3R,4R)-4-(2,5-difluoro-phenyl)-3-methyl-4-[1,2,4]triazol-1-ylmethyl-oxetan-2-one resulted.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8]O)=[CH:5][CH:4]=1.Cl.[H][H].[OH-].[Na+]>CO.CCOCC>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: NCc1ccc(C(F)(F)F)cc1
Yield: 93.6 %

Procedure:
The first and second steps of the process of the present invention were conducted as follows. At first, 8.79 g (50.5 mmol) of 4-trifluoromethylbenzaldehyde and 3.83 g (55.1 mmol) of hydroxylamine hydrochloride were dissolved in 12.5 ml of ethanol and 34 ml of water followed by the addition of 2,5 g of sodium hydroxide and stirring for 1 hour at room temperature. After adding ether and washing with dilute hydrochloric acid, the reaction liquid was further washed with saturated brine followed by drying with mirabilite and concentrating to obtain 9.25 g (48.2 mmol) of 4-trifluoromethylbenzylaldehyde oxime (yield: 95.5%). 5.00 g (26.4 mmol) of this 4-trifluoromethylbenzaldehyde oxime were dissolved in methanol followed by the addition of 4.0 g (109.7 mmol) of hydrogen chloride gas and 252 mg of the same catalyst as that of Example 1 and stirring for 3 hours in a hydrogen atmosphere at 10 atm and room temperature (approx. 250° C.). After removing the catalyst, ether was added to the reaction liquid, and the reaction liquid was neutralized with aqueous sodium hydroxide solution. As a result of analyzing the separated ether layer by gas chromatography, 4-trifluoromethylbenzylamine was formed at a yield of 93.6%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10](OC(C)C)[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].BrC1C=[CH:19][C:20]([OH:26])=[C:21](C=1)C(O)=O>>[C:1]([C:3]1[CH:11]=[CH:10][C:9]([O:26][CH:20]([CH3:21])[CH3:19])=[C:5]([CH:4]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Product: CC(C)Oc1ccc(C#N)cc1C(=O)O

Procedure:
Prepared in an analogous fashion to 3-cyano-5-isopropoxybenzoic acid starting from 5-bromo-2-hydroxybenzoic acid. LCMS-ESI (m/z) calculated for C11H11NO3: 205.2; found 206.1 [M+H]+, tR=2.70 min.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]3[B:11]([OH:14])[O:12][CH2:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[OH:14][B:11]1[C:10]2[CH:15]=[CH:16][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (68 mg, 0.28 mmol, 1.0 eq.) in DCM (3.0 mL) was added Et3N (47 μL, 0.33 mmol, 1.2 eq.), followed by acetyl chloride (22 μL, 0.31 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-acetamide as a white solid. LCMS (m/z) 284 (M+H); 1H NMR (DMSO-d6) δ: 10.17 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.58-7.63 (m, 2H), 6.94-6.99 (m, 2H), 6.88 (dd, J=8.0, 2.1 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 4.85 (s, 2H), 3.12 (s, 1H), 2.00 (s, 3H).
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[C:20]([NH2:26])=[CH:21][CH:22]=[C:23]([F:25])[CH:24]=2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:7]([C:6]2[C:2]([I:1])=[N:3][N:4]([CH3:10])[CH:5]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Cn1cc(C(=O)O)c(I)n1
Reactant: Nc1ccc(F)cc1-c1ccc(Cl)c(Cl)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(F)cc2-c2ccc(Cl)c(Cl)c2)c(I)n1
Yield: 56.5 %

Procedure:
At room temperature, 273 mg (1.0 mmol) of 3-iodo-1-methyl-1H-pyrazole-4-carboxylic acid, 213 mg (0.83 mmol) of 3′,4′-dichloro-5-fluorobiphenyl-2-amine, 0.3 ml (1.67 mmol) of N,N-diisopropyl-ethylamine and 583 mg (1.25 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate were stirred in 5 ml of methylene chloride for 3 days. The mixture was washed with saturated sodium bicarbonate solution and then with water. Removal and concentration of the organic phase gave 910 mg of crude product. Purification by column chromatography on silica gel 60 using methylene chloride/diethyl ether 5:1 gave 230 mg (53.5% of theory) of N-(3′,4′-dichloro-5-fluoro-1,1′-biphenyl-2-yl)-3-iodo-1-methyl-1H-pyrazole-4-carboxamide (compound No. 6 from table 1) of log P (pH 2.3)=3.42.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3C[CH:7]([CH2:9]C(C3)C1)[CH2:8]2.C12(CCCC=C1)CC(CN1C=CN=C1)C2.CC1(C)C2CC1CC=C2CN1C=CN=C1.CC1(C)C2CC(CC2)C1=CCN1C=CN=C1.N12CCC(CC1)C(CN1C=CN=C1)C2.CN1C2CCC1CC(CN1C=CN=C1)C2>>[CH:1]12[CH2:8][CH:7]([CH:5]=[CH:10]1)[CH2:9][CH:11]2[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1cn(CCC23CC4CC(CC(C4)C2)C3)cn1
Agent: C1=CC2(CCC1)CC(Cn1ccnc1)C2
Agent: CC1(C)C(=CCn2ccnc2)C2CCC1C2
Agent: CC1(C)C2CC=C(Cn3ccnc3)C1C2
Product: C1=CC2CC1CC2Cn1ccnc1

Procedure:
1-[2-(adamantan-1-yl)ethyl]imidazole, 1-(2-cyclohexenespirocyclobutan-3'-ylmethyl)imidazole, 1-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-ylmethyl)imidazole, 1-[2-(3,3-dimethylbicyclo[2.2.1]heptan-2-ylidene)ethyl]imidazole, 1-(1-azabicyclo[2.2.2]octan-3-ylmethyl)imidazole, 1-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylmethyl)imidazole.
Reaction SMILES: [Li]C(C)(C)C.[C:6]12([C:16]3[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:21]=3[O:22][CH3:23])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.FC(F)(F)S(O[C:31]1[C:40]2[C:35](=[CH:36][C:37]([Br:41])=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)(=O)=O>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:6]12([C:16]3[CH:17]=[C:18]([C:32]4[CH:31]=[C:40]5[C:35](=[CH:34][CH:33]=4)[CH:36]=[C:37]([Br:41])[CH:38]=[CH:39]5)[CH:19]=[CH:20][C:21]=3[O:22][CH3:23])[CH2:7][CH:8]3[CH2:9][CH:10]([CH2:11][CH:12]([CH2:14]3)[CH2:13]1)[CH2:15]2
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)(Oc1cccc2cc(Br)ccc12)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(Br)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 34.4 %

Procedure:
t-BuLi (159 μl, 1.4 M, 0.22 mmol) was added, dropwise, onto a mixture of 3-(1-adamantyl)-1-bromo-4-methoxybenzene (50 mg, 0.16 mmol) and anh. THF (1 ml) under atmosphere of Ar and at −78° C., and the mixture was kept in stirring for 1 hour. After this time, the reaction was allowed to evolve at room temperature, a solution of ZnCl2 (21 mg, 0.16 mmol) in anhydrous THF (0.4 mL) was added and was stirred for 1 more hour. Next, a solution of 6-bromonaphthalenyl trifluoromethanesulphonate (40 mg, 0.13 mmol), Pd(PPh3)4 (9 mg, 0.008 mmol) and anh. THF (0.2 ml) was added and the reaction was kept at room temperature for 16 h. Finally, the reaction was neutralized with HCl (1 M) and extractions with Et2O (3×2 ml) were carried out. The organic phase was washed with sat NaCl (3×3 ml) and H2O (3×3 ml), was dried with MgSO4 and was evaporated to dryness. A crude (58 mg) in form of a yellow solid was obtained, which was recrystallized with the minimum volume of toluene at reflux (0.2 ml), giving the title compound (20 mg, 29%) as a pale yellow powder. The spectroscopic data coincide with those of the Example 4.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][C@@H:16]1[CH2:44][O:43][C@@:19]2([O:23][C@H:22]3[CH2:24][C@H:25]4[C@@H:30]5[CH2:31][CH2:32][C@@H:33]6[CH2:38][C@H:37]([OH:39])[CH2:36][CH2:35][C@:34]6([CH3:40])[C@H:29]5[CH2:28][CH2:27][C@:26]4([CH3:41])[C@H:21]3[C@@H:20]2[CH3:42])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:64](O)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1COCC1>[CH3:15][CH:16]1[CH2:44][O:43][C:19]2([O:23][CH:22]3[CH2:24][CH:25]4[CH:30]5[CH2:31][CH2:32][CH:33]6[CH2:38][CH:37]([O:39][C:64]([C:65]7[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=7)=[O:71])[CH2:36][CH2:35][C:34]6([CH3:40])[CH:29]5[CH2:28][CH2:27][C:26]4([CH3:41])[CH:21]3[CH:20]2[CH3:42])[CH2:18][CH2:17]1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC2(OC1)OC1CC3C4CCC5CC(OC(=O)c6ccccc6)CCC5(C)C4CCC3(C)C1C2C
Temperature: 25 °C

Procedure:
A solution of diisopropylazodicarboxylate (0.81 g, 4.0 mmol) in dry THF (2 ml) was added to a stirred solution of episarsasapogenin (0.83 g, 2.0 mmol), triphenylphosphine (1.05 g, 4.0 mmol) and benzoic acid (0.49 g, 4.0 mmol) in dry THF (20 ml). The mixture was stirred at room temperature and monitored by TLC. After 2 h all the starting material had been consumed. The solvent was removed in vacuo, the residual syrup dissolved in ether (30 ml) and the solution washed with aqueous saturated sodium hydrogen carbonate (25 ml). The organic layer was dried over MgSO4 and passed down a short silica pad, the pad being washed with ether. The combined washings and filtrate were concentrated in vacuo to afford sarsasapogenin benzoate as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>O>[CH:1]([C:4]1[C:12]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)c2c(C(C)C)nn3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1nn2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Temperature: 220 °C

Procedure:
A mixture of 0.012 mol of 2-isopropyl-3-(4-methoxybenzenesulphonyl) pyrazolo[1,5-a]pyridine and 0.054 mol of pyridine hydrochloride was heated at 220° C. for & hour. Water was then added and the mixture was distilled in the presence of ethyl acetate. The medium was dried on sodium sulphate, filtered and concentrated. The solid so obtained was then recrystallized from isopropyl ether to provide a white crystalline product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:39]([NH:42][CH2:43][CH2:44][CH3:45])[CH2:40][CH3:41]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[N:42]([CH2:43][CH2:44][CH3:45])[CH2:39][CH2:40][CH3:41])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCCNCCC
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (2.0 g, 7.72 mmol) and HATU (3.52 g, 9.27 mmol) in DMF (70 mL) was stirred at room temperature for 10 min. Then dipropylamine (0.78 g, 1.1 mL, 7.72 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (2.6 g, 99.5% yield): 1H NMR (CD3OD, 500 MHz) δ ppm 0.78 (3H, t, J=5 Hz), 1.01 (3H, t, J=5 Hz), 1.60 (2H, m), 1.74 (2H, m), 3.21 (2H, m), 3.49 (2H, m), 3.96 (3H, s), 7.79 (1H, m), 7.94 (1H, m), 8.23 (1H, m). HPLC retention time: 2.018 min (method B). MS (ESI) (M+H)+ 342.09.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13]CC)=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccncc2)nc2c1c(C)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)C)c2nc(-c3ccncc3)cc(C(=O)O)c12

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (36 mg, 0.111 mmol), Ethanol (2 ml) and sodium hydroxide (0.185 mL, 0.555 mmol). The final product was collected as 26 mg 79%). LCMS E-S (M+H)=297.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.4 Hz, 6H), 2.65 (s, 3H), 5.35 (m, 1H), 8.17 (s, 1H) 8.24 (m, 2H), 8.78 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([F:11])=[C:6]([Cl:12])[C:3]=1[CH:4]=O.[Br-].Br[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCCC1.CCCCCC>[Cl:12][C:6]1[C:3]2[CH:4]=[CH:15][O:1][C:2]=2[C:9]([Br:10])=[CH:8][C:7]=1[F:11]
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(O)c(Br)cc(F)c1Cl
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1cc(Br)c2occc2c1Cl
Temperature: 0 °C
Yield: 84.4 %

Procedure:
A suspension of 49.2 gm (0.19 mole) 2-hydroxy-3-bromo-5-fluoro-6-chlorobenzaldehyde and 127 gm (0.29 mole) (bromomethyl)triphenylphosphonium bromide in 230 mL tetrahydrofuran was cooled to 0° C. under a nitrogen atmosphere. To this were added dropwise 330 mL (0.33 mole) potassium tert-butoxide (1M in tetrahydrofuran) over 3 hours. An additional 90 mL (0.09 mole) potassium tert-butoxide (1M in tetrahydrofuran) were then added to react remaining starting material. The reaction mixture was diluted with 700 mL of hexane and the resulting precipitate removed by filtration. The recovered solid was slurried in 300 mL hexane and filtered 4 times. The combined filtrates were washed with 2×500 mL water followed by 500 mL saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to provide a residual solid. This solid was slurried and filtered with 4×300 mL diethyl ether to remove triphenylphosphine oxide. The filtrates were concentrated and the residue subjected to silica gel chromatography, eluting with hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 40 gm (83%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[SH:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CCO>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[S:16][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: Sc1nc2ccccc2s1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C[C@@H](O)CSc1nc2ccccc2s1
Yield: 58.4 %

Procedure:
A suspension of compound N-[(2R)-oxiran-2-ylmethyl]-phthalimide (21.1 g, 104 mmol) and 2-mercaptobenzothiazole (17.4 g, 104 mmol) in EtOH (600 mL) was heated to reflux for 16.5 h. The reaction was then cooled and concentrated under reduced pressure. The crude mixture was crystallized from ethanol and filtered to provide N-[(2R)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide (22.5 g, 59%) as a yellow solid. Data for N-[(2R)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide: 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 4H), 7.45-7.26 (m, 2H), 5.18 (m, 1H), 4.42 (m, 1H), 4.08-3.88 (m, 2H), 3.61 (m, 1H), 3.42 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1.[CH3:14][NH2:15]>O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:15][CH3:14])[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Solvent: O
Product: CNc1c([N+](=O)[O-])c(Br)nn1CCO
Yield: 91 %

Procedure:
3.15 g (10 mmoles) of 3,5-dibromo-1-(2'-hydroxyethyl)-4-nitropyrazole are heated in 70 ml of a 30-percent solution of methylamine in water for 1 hour at 60° C. After cooling, the product precipitates in the form of bright yellow crystals with a melting point of 158° to 160° C. 2.4 g (91 percent of theory) of 3-bromo-1-(2'hydroxyethyl)-5-methylamino-4-nitropyrazole are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][OH:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:30][CH2:29][CH2:28][C@H:15]1[CH2:16][C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[C:14]1=[O:31])(=[O:37])=[O:36]
Reactant: O=C1[C@@H](CCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
To a solution of (3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(2-hydroxyethyl)pyrrolidin-2-one (50 mg, 0.105 mmol) in DCM (2 mL) at 0° C. is added MsCl (26 μL) and TEA (50 μL). The reaction mixture is stirred at room temperature for 45 min before removal of the solvent. The residue is purified on silica gel (0-50% ethyl acetate in hexane) to give 2-{(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}ethyl methanesulfonate (54.3 mg, 93%) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@:6]1([O:19][CH3:20])[C@@H:10](O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+]=[N-].C(N(CC)CC)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:20][O:19][C@:6]12[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C@H:10]1[NH:1][CH2:4][CH2:5]2
Reactant: CO[C@]1(CCN=[N+]=[N-])CN(C(=O)OC(C)(C)C)C[C@@H]1O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CO[C@@]12CCN[C@@H]1CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of tert-butyl (3R,4S)-3-(2-azidoethyl)-4-hydroxy-3-methoxypyrrolidine-1-carboxylate (85 mg) in CHCl3 (5 mL) was added triethylamine (140 mg) and MsCl (50 mg) at room temperature. And the mixture was stirred at room temperature for 1 hour. After the period, the mixture was poured into saturated aqueous solution of NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and concentrated. The residue was dissolved in THF (5 mL). To the solution was added 10% palladium on activated carbon (20 mg). The resulting solution was placed under a H2 atmosphere (balloon pressure) and stirred at room temperature for 15 hours. The solution obtained by filtration through Celite and washing the filter cake with MeOH was concentrated in vacuo. The residue was dissolved in CHCl3 (3 mL) and refluxed for 1 day and then cooled to room temperature. The resulting mixture was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give tert-butyl (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate as a pale yellow foam.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][C:13]#[CH:14]>C1COCC1.CCOC(C)=O.[Cu]I>[Br:8][C:6]1[N:7]=[C:2]([C:14]#[C:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#CC[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CC#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
3,5-Dibromo-pyrazin-2-ylamine (1.70 g, 6.70 mmol), TEA (1.1 mL, 8.04 mmol), PdCl2(PPh3)4 (28 mg, 0.040 mmol), and CuI (15 mg, 0.080 mmol) were dissolved in THF (17 mL), cooled to RT and Trimethyl-prop-2-ynyl-silane (1.0 mL, 6.7 mmol) was added at 0° C., allowed to warm up to RT and stirred overnight. The reaction mixture was diluted with EtOAc, washed with H2O and saturated aqueous NaHCO3, dried (MgSO4) and concentrated, and purified by SiO2 chromatography (80 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 1.66 g of 5-bromo-3-(3-trimethylsilanyl-prop-1-ynyl)-pyrazin-2-ylamine as a yellow semi-solid contaminated by starting material (87% yield, 66% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21](OC)=[O:22])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylate (0.15 g, 0.41 mmol) in 1 ml of THF at −78° C. was added 1M DIBAL-H in toluene (1.03 ml, 1.03 mmol) dropwise. After 5 min, the reaction was allowed to warm to room temperature and stirred for 4 h. Water (0.1 ml), 10% NaOH (0.1 ml) and celite were added to the reaction solution and the mixture was filtered. Washed with THF and the filtrate was dried over Na2SO4, filtered, concentrated and purified by flash chromatography (silica, 20-50% EtOAc/hexanes) to provide {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol as white solid: 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.5 Hz, 1H), 8.05 (m, 2H), 7.56 (dd, J=8.4, 2.5 Hz, 1H), 7.13 (m, 3H), 4.72 (d, J=6.2 Hz, 2H), 2.98 (d, J=6.2 Hz, 1H); LCMS [M+H]+=337.3.