Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2.Cl>ClCCl>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(O)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c1
Yield: 79.6 %

Procedure:
To a suspension of 32.26 g (0.115 mol) of 2-(5-hydroxy-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione in 320 ml of dichloromethane, a solution of 43.54 g (0.288 mol) of TBDMS chloride in 150 ml of dichloromethane was added. The resulting mixture was treated dropwise with 35.5 ml (0.23 mol) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature, obtaining a clear solution. After 3 hours the reaction mixture was poured in 300 ml of a solution 0.1 N of hydrochloric acid. The aqueous layer was separated and extracted with 200 ml of dichloromethane. Organic extracts were dried over sodium sulfate and the solvent evaporated under vacuum. The raw product was purified by flash chromatography over silica gel eluiting with dichloromethane-cyclohexane-ethyl acetate (4:4:2). 36.03 g of product as white solid were obtained. Yield=79.2%. mp=225-228° C. HPLC r.t. 8.3 [M+H]+=394 [2M+H]+=787
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (71 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[C:8]([OH:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.[Br:14]Br>CC(O)=O>[Br:14][C:11]1[CH:12]=[C:7]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[N:6]=2)[C:8]([OH:13])=[N:9][CH:10]=1
Reactant: Cc1noc(-c2cccnc2O)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1noc(-c2cc(Br)cnc2O)n1

Procedure:
A solution 3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-ol in AcOH (0.2M) and bromine (1.2 eq) was stirred 18 h at 20° C. and then concentrated. The residue was co-evaporated with benzene (2×) and used as such in the next step.
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[N+:14]([O-:27])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH:21]([CH2:25][OH:26])[CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:29].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[N+:14]([O-:27])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH:21]([CH2:25][OH:26])[CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:29])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C(O)C(F)(F)F
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CC(CO)C3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CC(CO)C3
Temperature: 20 °C
Reaction time: 17 h
Yield: 60.9 %

Procedure:
H2O2 (70%, 0.46 mL, 7.7 mmol) was added drop-wise (over 5 min) to a stirred solution of 1-oxide 140 (292 mg, 0.77 mmol), TFA (0.32 mL, 3.9 mmol), and TFAA (1.24 mL, 7.7 mmol) in DCM (25 mL) at 20° C. and the mixture stirred at 20° C. for 17 h. Another aliquot of H2O2 (70%, 0.46 mL, 7.7 mmol) and TFAA (1.24 mL, 7.7 mmol) were added and the mixture was stirred for 1 h. Aqueous NH3 solution (2 M, 30 mL) was added at 0° C. and the mixture stirred at 0° C. for 10 min, then stirred at 20° C. for 20 min. The mixture was extracted with DCM (5×80 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 141 (169 mg, 61%) as a dull orange solid: mp (MeOH/DCM) 112-114° C.; 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.73 (d, J=6.4 Hz, 2H, CH2O), 3.45 (br s, 4H, 2×CH2O), 3.21-3.37 (m, 4H, H-8, CH2), 3.00-3.09 (m, 2H, CH2), 2.83-2.92 (m, 1H, H-7), 2.50 (t, J=6.4 Hz, 2H, CH2N), 2.39 (br s, 4H, 2×CH2N), 2.07-2.15 (m, 2H, CH2), OH not observed; 13C NMR [(CD3)2SO] δ 154.1, 153.7, 149.3, 138.7, 133.5, 115.3, 113.3, 66.0 (2), 63.4, 57.2, 53.0 (2), 41.5, 35.6, 35.1, 28.0, 21.0. HRMS (FAB+) calcd for C18H25N4O4 (MH+) m/z 361.1876, found 361.1878.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]([NH:13][NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]1[O:25][C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc([N+](=O)[O-])cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 66.9 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-nitrobenzohydrazide (8.5 g, 15.57 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (8.17 g, 31.13 mmol), iodine (7.90 g, 31.13 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 50 minutes and quenched with sat. aq. sodium thiosulfate (400 mL). The solution was extracted with CH2Cl2 (250 mL). The organic extract was washed with sat. aq. sodium thiosulfate (300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a light yellow solid (5.5 g, 67%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.37 (dm, J=9.0 Hz, 2H), 8.18 (dm, J=9.0 Hz, 2H), 7.36 (d, 8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 5.11 (d, J=9.2 Hz, 1H), 4.87 (dd, J=3.9, 8.8 Hz, 1H), 4.46 (dq, J=3.7, 6.3 Hz, 1H), 2.34 (s, 3H), 1.31 (d, J=6.3 Hz, 3H), 0.93 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([C:23]1([C:26]([F:29])([F:28])[F:27])CO1)[CH2:11][NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16]C=[N:18]2.[C:30](=[O:33])([O-])[O-].[Cs+].[Cs+].C(S)C>CN(C=O)C>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([C:11]1[CH:16]=[CH:15][C:14]2[C:19]([NH2:18])=[CH:20][CH:21]=[CH:22][C:13]=2[N:12]=1)[C:23]1([C:26]([F:29])([F:28])[F:27])[CH2:30][O:33]1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(C(CNc2cccc3ncccc23)C2(C(F)(F)F)CO2)c1F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCS
Product: COc1cccc(C(c2ccc3c(N)cccc3n2)C2(C(F)(F)F)CO2)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
[(2-Fluoro-3-methoxyphenyl)-2-(2-trifluoromethyl-oxiranyl)ethyl]quinolin-5-yl-amine (97 mg, 0.25 mmol) was dissolved in DMF (0.5 mL). Caesium carbonate (161 mg, 0.5 mmol) was added followed by ethanethiol (75 μL, 1 mmol). The mixture was vigorously stirred at ambient temperature for 90 minutes. The reaction mixture was partitioned between diethylether and water. The organic phase was washed trice with water and then with brine and evaporated. The residue was dissolved in methylene chloride, filtered through a plug of glass wool to remove residual NaCl and again evaporated. The crude product was dissolved in methylene chloride and flash-chromatographed on a column of silica using a gradient of heptane-ethyl acetate (10→90% ethyl acetate) to yield the title product (60 mg, 53%) as an amorphous solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]O)=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=1[N+:33]([O-:35])=[O:34]
Reactant: BrBr
Reactant: COc1ccc(CCO)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCBr)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
A suspension of triphenylphosphine (26 g, 1 mol) in DCM (100 mL) under nitrogen atmosphere at 25-26° C. is cooled down to 0-5° C. A solution of bromine (15.9 g, 0.1 mol) in DCM (150 mL) is added over 30 min at the same temperature. The reaction mixture is stirred for 15 min at 0-5° C. A solution of 2-(4-methoxy-2-nitrophenyl)ethanol (14 g, 0.07 mol) and pyridine (7.8 g, 0.1 mol) in DCM (100 mL) is added to the above reaction mixture over 30 min at 0-5° C. The resulting reaction mixture is warmed up to 25-26° C. and stirred for 3 h. The reaction is quenched by addition of cold water (250 mL). The crude product is extracted with DCM (2×200 mL). The organic layer is washed with water and brine (200 mL each), dried over Na2SO4 and concentrated to dryness. The crude residue obtained is purified by column chromatography (60-120 mesh silica gel, eluent: 5% EtOAc in petrol ether) to give 14.7 g (79%) of the title compound as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.51-7.49 (m, 2H), 7.30-7.27 (m, 1H), 3.83 (s, 3H), 3.82-3.68 (m, 2H), 3.32-3.27 (m, 2H).
Reaction SMILES: [F:1][C:2]([C:5]1[C:6](=[O:19])[C:7]([OH:18])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[CH3:11])([F:4])[F:3].[CH2:20]([O:22]CC)[CH3:21]>C(OC(=O)C)(=O)C>[F:3][C:2]([C:5]1[C:6](=[O:19])[C:7]([O:18][C:20](=[O:22])[CH3:21])=[N:8][N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]=1[CH3:11])([F:1])[F:4]
Reactant: CCOCC
Reactant: Cc1c(C(F)(F)F)c(=O)c(O)nn1-c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1nn(-c2ccccc2)c(C)c(C(F)(F)F)c1=O
Temperature: 50 °C
Yield: 70 %

Procedure:
A suspension of Compound 1 (2.36 grams) in acetic anhydride is heated for six hours at 50° C. The recooled solution is concentrated under vacuum. There is obtained, after the addition of diethyl ether, filtration, washing with ether and drying, the Compound 3 (1.91 grams; yield=70%).
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[C:3]1[S:4][C:5]([C:8]23[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:13][C@@H:12]2[CH2:11][O:10][NH:9]3)=[CH:6][N:7]=1.[C:28]([N:36]=[C:37]=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:28]([NH:36][C:37]([N:9]1[C:8]2([C:5]3[S:4][C:3]([Si:2]([CH3:27])([CH3:26])[CH3:1])=[N:7][CH:6]=3)[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:13][CH:12]2[CH2:11][O:10]1)=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)C[C@@H]2CON3)s1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)CC2CON3C(=S)NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of benzyl(3aS)-6a-(2-trimethylsilylthiazol-5-yl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (0.218 g, 0.54 mmol) in THF (3.60 mL) is added benzoyl isothiocyanate (0.088 g, 0.54 mmol). The mixture is stirred for 1 hour at room temperature and more benzoyl isothiocyanate (0.044 g, 0.27 mmol) is added. The reaction is stirred for 3 hours at room temperature, concentrated under reduced pressure, and purified by silica gel chromatography eluting with a gradient of 5% to 100% ethyl acetate in hexanes to give title compound (0.204 g, 67%). ES/MS (m/e): 404 (M+H).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCCN(Cc4ccc(Cl)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-chlorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-chlorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[O:20]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)=[CH:21]1
Reactant: OB(O)c1ccoc1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Product: O=C(Nc1nc2ccc(-c3ccoc3)cn2n1)c1cccnc1
Yield: 21.3 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and furan-3-boronic acid (57 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (15.6 mg, 21%). HPLC, Rt: 1.82 min. (purity 92.2%). LC/MS, M+(ESI): 306.3, M−(ESI): 304.3.
Reaction SMILES: [BH4-].[Na+].O.O=C1CCC(=O)N1[O:11][C:12](=O)[CH2:13][CH:14]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:13][CH2:12][OH:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
A solution of NaBH4 (262 mg, 6.92 mmol) in 4:1 THF:H2O (20 ml) was cooled to 0° C. To this mixture was slowly added a solution of the ester from step (38a) (4.61 mmol) in THF (12 ml). Gas was evolved. When gas evolution ceased, the mixture was quenched by the careful addition of saturated aqueous ammonium chloride. The resulting solution was stirred at 0° C. for an additional 15 min. EtOAc (200 ml) was added and the resulting mixture was washed with saturated aqueous NaCl. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (silica, 0-10% MeOH/CHCl3) gave 2-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (350 mg, 25% for 2 steps) as a clear, colorless oil: 1H NMR (300 MHz, Methanol-D) δ 7.23-7.43 (m, 5 H), 5.06-5.25 (m, 2 H), 4.00-4.57 (m, 2 H), 3.54-3.69 (m, 1 H), 1.67-2.12 (m, 2 H), 1.29-1.50 (m, 9 H). LC-MS (Method A, retention time: 1.25 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:19])[CH2:13][CH2:14][S:15]C(=O)C)([CH3:4])([CH3:3])[CH3:2].N>>[C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:19])[CH2:13][CH2:14][SH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: N
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCS

Procedure:
The product from Example 10, 3-acetylthiopropanoyl-L-proline-t-butyl ester, 0.5 g, was mixed with 4.5 ml of 5.5N methanolic ammonia at room temperature under nitrogen for one hour. The solvent was then removed at 25° C. with a rotary evaporator. After the product was taken up in methanol and reevaporated twice more in the rotary evaporator, the clear oily residue was dissolved in ethyl ether, washed twice with 5% potassium bisulphate and once with saturated NaCl, dried over MgSO4 and filtered. Residual solvent was removed in vacuo to yield a clear oily product, migrating as a single spot on thin layer chromatography in three separate solvent systems.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15](Cl)=[O:16])=[CH:9][CH:8]=1.Cl>[OH-].[Na+]>[N:1]1([C:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=2)=[O:16])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)N1CCSCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of thiomorpholine (2 g) in 1N NaOH (11.6 mL) was added benzyl chloridocarbonate (1.66 mL) under ice water cooling and the mixture was stirred at ambient temperature for 2 hours. The solution was neutrolized with 1N HCl and extracted with EtOAc twice. The combined organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography to give benzyl 4-thiomorpholinecarboxylate as a colorless solid (4.8 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11])[CH:12]=[O:13]
Reactant: OCc1ccc(C(F)(F)F)c(I)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(C(F)(F)F)c(I)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
The product from Example 62C in chloroform (60 mL) was treated with manganese dioxide (1.45 g, 16 mmol). After refluxing for 12 hours, the mixture was allowed to cool to ambient temperature, filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 15% ethyl acetate:hexanes to provide the title compound (0.5 g, 42% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.CN(C)C=O.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:21][CH:22]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:9][CH:5]3[CH2:6][CH2:7][CH2:8][CH:3]([OH:10])[CH2:4]3)[N:19]=2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(-c2nc(CCl)co2)cc1
Reactant: OC1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OC1CCCC(OCc2coc(-c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
With ice-cooling, initially 2.25 g of an 80 percent suspension of sodium hydride and then 5.8 g of 1,3-cyclohexanediol were added to a mixture of 50 ml of dimethylformamide and 50 ml of tetrahydrofuran. The mixture was stirred at about 25° C. for 3 hours. 10.5 g of 4-chloromethyl-2-(4-fluorophenyl)oxazole (1) was then added, the mixture was heated at 70° C. and the reaction was monitored by thin-layer chromatography. After the reaction ended, the mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was separated off, dried and concentrated and the residue was purified on silica gel by flash chromatography (ethyl acetate/n-heptane=1:1). This gave the alcohol 3 as an oil. C16H18FNO3 (291.33) MS(ESI): 292 (M+H+)
Reaction SMILES: O1CCOCC1.Cl[CH2:8][C:9]([NH:11][C:12]1[C:13]([N+:30]([O-:32])=[O:31])=[CH:14][C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)=[O:10].[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36]>O>[CH2:33]([NH:37][CH2:8][C:9]([NH:11][C:12]1[C:13]([N+:30]([O-:32])=[O:31])=[CH:14][C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)=[O:10])[CH2:34][CH2:35][CH3:36]
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CCl)c([N+](=O)[O-])cc1Oc1ccccc1
Reactant: CCCCN
Solvent: O
Solvent: C1COCCO1
Product: CCCCNCC(=O)Nc1cc(NS(C)(=O)=O)c(Oc2ccccc2)cc1[N+](=O)[O-]
Yield: 72 %

Procedure:
To 7 ml of a dioxane solution containing 1.4 g of N-(5-chloroacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide was added 0.77 g of n-butylamine at room temperature, followed by stirring for an hour. Water was added to the reaction solution, the precipitate was collected by filtration and recrystallized from ethanol to give 1.1 g of N-[5-(n-butylaminoacetylamino)4-nitro-2-phenoxyphenyl]methanesulfonamide as yellow needles.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])[CH:3]=1.Cl.I([O-])(=O)(=O)=[O:27].[Na+].[OH-].[Na+]>O>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:27])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCSC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCS(C)=O
Reaction time: 2.5 h
Yield: 49.4 %

Procedure:
To a stirred solution of product from Example 49 (1.496 g, 4 mmoles) in 2N hydrochloric acid (5.0 ml, 10 mmoles) and water (20 ml) was added sodium periodate (856 mg. 4.0 mmoles) and the mixture stirred for 2.5 hours. It was then basified with 4N sodium hydroxide (3 ml) and extracted with methylene chloride (3×30 ml). The extracted was concentrated in vacuo and the residue flash-chromatographed on deactivated silica column using methylene chloride:methanol:ammonia (100:3.5:0.5) solvent system. The appropriate fractions were combined and concentrated to give a yellow oil which crystallized from methylene chloride-ether to give 770 mg of the title product as a light yellow solid, mp. 116°-117° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:12]Br.C(O)(=O)C>C(Cl)(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=2[CH:11]=1
Reactant: BrBr
Reactant: CSc1nc2ccccc2s1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CSc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To the solution of 2-(methylthio)-1,3-benzothiazole (5.00 g, 27.58 mmol) in CHCl3 (85 mL) in a NaCl-ice water bath, bromine (4.24 mL, 82.8 mmol) was slowly added dropwise, followed by acetic acid (30 mL). The mixture was stirred at rt overnight. The white solid was filtered and then dissolved in EtOAc (200 mL). Saturated, aqueous Na2CO3 (200 mL) was added and the organic layer was separated, dried over MgSO4 and concentrated to dryness. Desired product (5.0 g, 70%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ8.30 (s, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 2.79 (s, 3H); LC-MS m/z [M+H]+ 260.2 & 262.1, RT 3.65 min.