Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[CH:8]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO.C(N(CC)CC)C>[CH:8]([NH:21][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(=O)C(C)(C)Br
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)C(C)(C)NC(c1ccccc1)c1ccccc1

Procedure:
To the above-obtained 3-bromo-3-methylbutan-2-one (5.88 g) in methanol (30 mL), benzhydrylamine (5.0 mL) and triethylamine (7.5 mL) were added. The resultant mixture was stirred at 70° C. for 24 hours, and then cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and to the solid, diethyl ether was added, and then insoluble matter was removed by filtration. The mother liquid was brought to the dryness under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give 3-(benzhydrylamino)-3-methylbutan-2-one as an oily product (3.3 g, 34%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.C([BH-](CC)CC)C.[Li+]>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@H:5]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of compound 4A (4.30 g, 12.0 mmol) in THF (75 mL) at −78° C. under nitrogen was added dropwise a solution of 1.0 M lithium triethylborohydride in tetrahydrofuran (60.0 mL, 60.0 mmol). The reaction was allowed to warm to rt and was stirred for 4 h. The reaction was then quenched by pouring over ice (150 g) and stirring for 30 min. The product was extracted into EtOAc and was washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification via flash chromatography (silica gel, 0-15% EtOAc in hexane) provided compound 5A (3.30 g).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=1>C(Cl)(Cl)Cl>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:1]=[S:2])=[C:14]([F:19])[CH:13]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(Br)ccc1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophosgene (22 mL, 289 mmol) was added to a suspension of sodium carbonate (61.0 g, 579 mmol) and 4-bromo-2-fluoroaniline (50.0 g, 263 mmol) in CHCl3 (1 L). The reaction mixture was stirred overnight at RT, the inorganic salts were filtered off, and the filtrate was concentrated to give 4-bromo-2-fluoro-1-isothio-cyanatobenzene as a tan solid which was converted to 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-bromobenzo[d]thiazole as described in Reference A above.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Li]CCCC.[I:14]I.O>O1CCCC1>[I:14][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: II
Reactant: O=C(O)c1ccoc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccoc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a stirring solution of furan-3-carboxylic acid (5 g, 44.6 mmol) in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere at −78° C. was added BuLi (44.6 ml, 112 mmol) dropwise. After stirring for 0.5 h, cooling was switched off and the mixture allowed to warm to room temperature. During warming, iodine (12.5 g, 49.1 mmol) as a solution in anhydrous tetrahydrofuran (30 ml) and added dropwise to the stirring mixture. Water was added (100 ml) and the organic solvents were removed in vacuo. The aqueous solution was acidified to ca pH 1 using 2M hydrochloric acid (aq) solution (ca 10-20 ml). The precipitated solid was collected by filtration and dried under vacuum and flowing nitrogen for 16 h to afford the title compound (6.21 g, 59%) that was used in the next step without further purification. LCMS RT=0.78 min, M−H−=236.8.
Reaction SMILES: [CH:1]([N:3]([CH3:6])[CH2:4][OH:5])=O.[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([C:14]([NH2:16])=[O:15])[S:10][N:9]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:4]([N:3]([CH2:1][NH:16][C:14]([C:11]1[S:10][N:9]=[C:8]([Cl:7])[C:12]=1[Cl:13])=[O:15])[CH3:6])=[O:5]
Reactant: NC(=O)c1snc(Cl)c1Cl
Reactant: CN(C=O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CN(C=O)CNC(=O)c1snc(Cl)c1Cl
Yield: 47.1 %

Procedure:
At room temperature, 15 g (0.164 mol) of N-formyl-N-hydroxymethyl-methylamine are added with stirring to a mixture of 32.3 g (0.164 mol) of 3,4-dichloro-isothiazole-5-carboxamide and 245 ml of glacial acetic acid. At room temperature, 37 g (0.362 mol) of concentrated sulphuric acid are then added dropwise with stirring, the reaction mixture being cooled with ice. The reaction mixture is subsequently stirred at room temperature for 29 hours and then, with ice-cooling, admixed with 400 ml of water. The resulting mixture is extracted four times with 200 ml of methylene chloride and the combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The oily residue that remains is chromatographed over silica gel using ethyl acetate. Concentration of the eluate gives 20.7 g (42.6% of theory) of N-(N-formyl-N-methyl-aminomethyl)-3,4-dichloro-isothiazole-5-carboxamide in the form of a crystalline solid of melting point 87 to 88° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:13]([CH2:20][CH2:21][NH:22][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:22][CH2:21][CH2:20][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCOc1ccccc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: c1ccc(OCCNc2ccc3nc(NCCOc4ccccc4)ccc3c2)cc1

Procedure:
The title compound, MS: m/e=400.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline and 2-phenoxyethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][N:14]([CH3:31])[C:15](=[O:19])[O:16][CH2:17][CH3:18])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)NCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N(C)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
In tetrahydrofuran (4 ml) was dissolved ethyl N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate (100 mg, 0.239 mmol), followed by the addition of sodium hydride (60% dispersion in mineral oil, 11.5 mg, 0.287 mmol). The resulting mixture was stirred at room temperature for 3 hours. Iodomethane (17.8 μl, 0.287 mmol) was added and the mixture was stirred at room temperature for 15 hours. Sodium hydride (60% dispersion in mineral oil, 5.00 mg, 0.125 mmol) and iodomethane (10.0 μl, 0.161 mmol) were added, followed by stirring at room temperature for 24 hours. Water (5 ml) was added, and the mixture was concentrated. The residue thus obtained was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated, whereby the title compound (83.2 mg, 0.193 mmol, 81%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[OH:5])[CH2:3][CH2:2]1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH:7]=1
Reactant: OC(c1cccnc1)C1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=C(c1cccnc1)C1CC1
Reaction time: 4 h
Yield: 80 %

Procedure:
Dissolve 3.35 g of cyclopropyl(3-pyridyl)methanol, the compound obtained in the preceding step, in 75 ml of dioxane and add 13.66 g of manganese dioxide. After 4 hours of stirring under reflux, filter the reaction medium while hot through Celite. The organic solution yields, after evaporating under vacuum, a residue which is purified by chromatography on a silica column, using a mixture of cyclohexane and ethyl acetate (1:1 V/V) as eluent, to obtain cyclopropyl 3-pyridyl ketone.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:14][CH:12]([S:9]([NH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1])(=[O:11])=[O:10])[CH3:13]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)S(=O)(=O)NC1CCCCC1=O
Temperature: -55 °C
Reaction time: 0.03 h
Yield: 82.2 %

Procedure:
Into a flame dried 250 mL 3 neck flask fitted with a thermometer and magnetic stirrer, DMSO (2.61 mL) in methylene chloride (10 mL) was added dropwise to oxalyl chloride (1.60 mL) in methylene chloride (50 mL) while stirring at −55° C. under a nitrogen atmosphere. After 2 minutes, (2-hydroxycyclohexyl)[(methylethyl)sulfonyl]amine (3.60 g, 16.3 mmol) in methylene chloride (10 mL) was added dropwise at this temperature and the reaction was stirred for an additional 15 minutes. Triethylamine (10.8 mL) was then added dropwise and the reaction was allowed to warm to room temperature. Water (76 mL) was added at room temperature and the layers were separated. The organic layer was washed once with water, dried over potassium carbonate filtered, and concentrated under reduced vacuum to yield 3.90 g as an orange solid. This material was purified via silica gel chromatography employing the Water's Prep. 2000 and eluting with a solvent of methylene chloride/ethyl acetate 19:1 to yield the intermediate title compound (2.94 g, 82%) as a white solid. FD M.S. 219.2 (M*). Calculated for C9H17NO3S: Theory: C 49.29, H 7.81, N 6.39. Found: C 49.18, H 7.84, N 6.39.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[N:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[N:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)nnc1OCC(F)(F)F
Yield: 52 %

Procedure:
The title compound is prepared in 52% yield (37 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (58 mg, 0.15 mmol, Intermediate-65, single enantiomer) and phenyl formate (37 mg, 0.30 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)(=[O:12])=[O:11].[CH3:24][C:25]1[C:29]([CH2:30]O)=[C:28]([CH3:32])[O:27][N:26]=1.FC(F)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCC1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O.CO.O.CN(C=O)C.O1CCCC1>[CH3:24][C:25]1[C:29]([CH2:30][O:19][C:15]2[CH:14]=[C:13]([S:10]([N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=2)=[C:28]([CH3:32])[O:27][N:26]=1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(O)c2)c(C)c1
Reactant: Cc1noc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCc1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(OCc3c(C)noc3C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutylbenzenesulfonamide (76.9 mg, 0.231 mmol), (3,5-dimethylisoxazol-4-yl)methanol (36.7 mg, 0.288 mmol) and (4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)phenyl)diphenylphosphine (204 mg, 0.288 mmol) were added to a 2-5 mL Biotage microwave vessel. Tetrahydrofuran (THF) (4 mL) was added followed by diisopropyl diazene-1,2-dicarboxylate (DIAD) (0.056 mL, 0.288 mmol). The reaction vial was sealed and left to stir overnight at RT. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (25 mL) and water (25 mL). The organic fraction was separated, dried and then concentrated in vacuo to give the crude product. The crude product was dissolved in DMF:H2O (9:1) 1 mL, and loaded onto a fluorous column (preconditioned with 1 mL DMF, followed by 6 mL MeOH:H2O (5:1). The semi purified fraction was eluted with 6 mL MeOH:H2O (5:1). The fraction was concentrated down, and dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product, 37.7 mg.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[N:11]([C:13](Cl)=[O:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:24]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:35][CH2:36][NH2:37])[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>>[Cl:1][C:2]1[C:12]2[N:11]([C:13]([NH:37][CH2:36][CH2:35][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]3[CH2:28][N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27])=[O:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(CCC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccc(Cl)c2N(C(=O)Cl)c2ccccc21
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccc(Cl)c21
Yield: 2.6 %

Procedure:
Prepared analogously to Example 1 from 6-chloro-5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-[(dipropylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 2.6% of theory. Colourless crystals, m.p. 71°-78° C., presumably a mixture of 2 diastereomers.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH2:11][C:12]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:16][C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][N:13]1[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:9])=[O:8])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH2:11][C:12]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:16][C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])=[N:14][N:13]1[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])(=[O:9])=[O:8]
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN=[N+]=[N-])(c2ccccc2)S1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN)(c2ccccc2)S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Next, the resulting optically active N-[5-(3-azidopropanesulfonylamino-methyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide was dissolved in THF (53 mL), and water (10.6 mL) and triphenylphosphine (1.24 g, 4.73 mmol) were added, then the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and water and saturated aqueous sodium hydrogencarbonate were added, then the mixture was extracted with ethyl acetate. The organic layer was extracted with aqueous hydrochloric acid, and the aqueous layer was made basic by adding saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The resulting organic layer was concentrated under reduced pressure to give Compound w {N-[5-(3-aminopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide} (1.29 g, 89%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Cl[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1>CN(C=O)C>[CH3:32][C:31]1[C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=[C:29]([N+:33]([O-:35])=[O:34])[CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
To the solution of benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (3.0 g, 9.89 mmol) in 10 ml of anhydrous DMF was added NaH (0.40 g, 9.89 mmol) in small portions at RT and the final resulting solution was stirred for 15 min. Commercially available 2-chloro-3-methyl-5-nitropyridine (1.37 g, 7.91 mmol) was added in 10 portions over 2 minutes and the resulting mixture was stirred 3 hrs at RT. The reaction mixture was quenched with ice cooled aqueous sat'd NH4Cl solution and extracted with ethyl acetate/ether (1:1) (2×50 mL). The organics were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (40M+ silica gel) using a gradient eluant of 0-60% ethyl acetate in hexane (800 ml) to afford the title compound. LC/MS (m/z): 440 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: NCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
(S)-tert-Butoxycarbonylamino-phenyl-acetic acid (1.00 g, 4 mmol) was dissolved in DCM (15 mL). Benzylamine (0.428 g, 4 mmol) and DIEA (0.65 g, 5 mmol) were added to the above mixture. The mixture which resulted was stirred at room temperature for a few minutes. PyBroP (2.10 g, 4.5 mmol) was added to the above solution in one portion and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (150 mL) and washed with NaHCO3 (50 mL×2, sat.). The organic layer was collected and dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was purified by chromatography to provide the desired product (0.859, 62%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=[O:1]
Reactant: COC(=O)c1ccc(CO)c2ccccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)c2ccccc12
Reaction time: 16 h

Procedure:
To a solution of methyl 4-hydroxymethylnaphthoate above (3.3, 15.3 mmol) in dichloromethane (20 mL) was added MnO2 (6.6 g, 76 mmol). After stirring the dark mixture for 16 hours, the insolubles were filtered through a bed of Celite. Evaporation of the solvent gave the desired product as a white solid in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][NH:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][N:57]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:56]2)=[CH:53][CH:54]=1
Reactant: OC1(c2ccc(F)cc2)CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccc(F)cc3)C2)cc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 3-(4-fluorophenyl)pyrrolidin-3-ol hydrochloride (22 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (30 mg). MS (ESI, pos. ion) m/z calcd for C21H19FN2O3: 366.1380, found 366.1380.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:13]2[CH2:14][O:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 8 g of 3-phenyl-1-propanol, 9.64 ml of epibromohydrin, 2.56 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 100 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.2 g of the title compound as a colorless oil having an Rf value of 0.36 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).