Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(CC1C(=O)N(Cc2ccccc2)c2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 70 mg of 50% sodium hydride (in oil) were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 1 hour. Then a mixture containing of 0.17 ml of benzyl chloride in 3 ml of dimethylformamide was added dropwise slowly into the reaction mixture, and the whole reaction mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into a large volume of water, and the organic material was extracted with chloroform, then the chloroform layer was dried and chloroform was removed by evaporation. There was obtained 110 mg of 2-(4-chlorobenzoylamino)-3-(1-benzyloxindol-3-yl)propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Yield: 96 %

Procedure:
A solution of 4-chloro-3-nitro-phenol (0.5 g, 2.88 mmol), 1-chloromethyl-4-methoxy-benzene (0.496 g, 3.17 mmol), potassium carbonate (1.19 g, 8.64 mmol) and tetrabutylammonium iodide (0.005 g, 0.0135 mmol) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Afterwards ice water (10 mL) was added to the solution and the resultant solid was collected by filtration and dried in a vacuum oven to provide the title compound (0.812 g, 96%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[NH:18][N:17]=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][C:28]([CH3:31])=[N:27]3)=[C:22]([F:32])[CH:21]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:32][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]3[N:17]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[N:29][C:28]([CH3:31])=[N:27]1
Reactant: Cc1ncn(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(F)cc4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ncn(-c2ccc(Nc3nc4n(n3)CCCCC4c3ccc(F)cc3)cc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A solution of 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (1.75 g, 3.81 mmol), sodium iodide (2.86 g, 19.1 mmol), and diisoproplylethylamine (3.33 mL, 19.1 mmol) in acetone (50 mL) was heated in a sealed vessel at 100° C. for 4 h. The reaction was concentrated in vacuo. Water (250 mL) was added and the mixture was extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. Ethanol (50 mL) was added to the residue. The mixture was stirred at rt for 30 min. The solid was collected by vacuum filtration to afford 720 mg (43% yield) of the titled compound as an off-white solid. LC-MS (M+H)+ 422.5. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=2.4 Hz, 1H), 7.68 (dd, J=13.9, 2.3 Hz, 1H), 7.59 (t, J=8.5 Hz, 1H), 7.14 (dd, J=8.5, 5.2 Hz, 2H), 6.97-7.11 (m, 3H), 6.90 (s, 1H), 4.19-4.39 (m, 3H), 2.49 (s, 3H), 2.16-2.32 (m, 1H), 2.06-2.15 (m, 1H), 1.84-2.03 (m, 4H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:16][C:15]1[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=1[Cl:19]
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1ccc2scnc2c1
Product: Clc1ccc(Br)cc1Cc1nc2ccccc2s1

Procedure:
Benzothiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give the target compound. APCI-Mass m/Z 338/340 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]=[C:15]3[N:10]([CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14]3)[C:9]=2[CH2:18][C:19](N(C)C)=[O:20])=[CH:6][CH:7]=1.[OH-:24].[Na+]>Cl>[CH3:17][C:12]1[CH:13]=[CH:14][C:15]2[N:10]([C:9]([CH2:18][C:19]([OH:20])=[O:24])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:16]=2)[CH:11]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a magnetically stirred solution of zolpidem (8.0 g, 26.0 mmol) at 0° C. under Ar atmosphere was added 6N HCl (80 mL). The reaction mixture was refluxed for 18 h. The mixture was cooled to 0° C., and 20% NaOH was added slowly to a pH of 6.5. The white solids were filtered in vacuo to provide the title compound (6.9 g, 94%) as a white solid. 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 2.35 (s, 3H), 3.94 (s, 2H), 7.10 (d, J=9.1 Hz, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.48 (d, J=9.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 2H), 8.18 (s, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 18.4, 21.4, 30.8, 114.8, 116.6, 121.6, 122.9, 127.9, 128.2, 129.8, 132.4, 137.3, 143.0, 143.5, 171.8.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28].O([CH2:40][CH:41]([F:43])[F:42])S(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.O>C(#N)C>[F:31][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:40][CH:41]([F:43])[F:42])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29]
Reactant: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)[nH]c2nccnc12
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)n(CC(F)F)c2nccnc12

Procedure:
Isobutyric acid 7-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 2.7) (0.335 g), 2,2-difluoroethyl triflate (0.32 g) and Hunigs base (0.2 ml) were stirred in acetonitrile (12 ml) at ambient temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The phases were separated and the organic phase was washed with water, aqueous sodium hydrogen carbonate (saturated) and brine, dried over anhydrous sodium sulfate and concentrated to give Compound No. B24 of Table B (0.280 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1.CS(C)=O>C(#N)C.C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[C:17]=1[S:26]([NH:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1c(F)cccc1C(F)(F)F
Reactant: COc1cnc(OC)n2nc(N)nc12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(F)cccc3C(F)(F)F)nc12
Reaction time: 216 h
Yield: 46 %

Procedure:
2-Amino-5,8-dimethoxy(1,2,4)triazolo[1,5-c]pyrimidine (1.0 g, 5.1 mmol) was suspended in 15 mL of dry acetonitrile in a round bottom flask equipped with magnetic stirring. To this suspension was added crude 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride (3.16 g, 10.2 mmol), dry pyridine (0.8 g, 10.2 mmol), dry dimethylsulfoxide (DMSO, 0.1 g, 1.3 mmol), and the flask was fitted with a CaSO4 drying tube. The reaction was monitored by HPLC analysis over a 9 day period, during which time an additional 4 equivalents of pyridine and 0.1 equivalents of DMSO were added. The dark solution was diluted with methylene chloride (300 mL), washed with 2N hydrochloric acid (2×200 mL), washed with water (2×200 mL), dried (MgSO4), filtered, and the solvent evaporated in vacuo to give a brown residue. The brown residue was triturated 5 with diethyl ether to afford the product as a tan solid: (1.0 g, 46% yield), mp 201-203° C.; Anal. Calcd for C14H11F4N5O4S: C 39.91, H 2.63, N 16.62, S 7.61; found: C 39.77, H 2.46, N 16.34, S 7.64. 1H NMR (DMSO-d6): δ8 3.85 (s, 3H), 4.05 (s, 3H), 7.58 (s, 1H), 7.73 (m, 1H), 7.88 (s, 2H), 12.85 (bs, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:15][CH2:16]O>>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:16]
Reactant: O=C(O)CC1CCCC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1CCCC1

Procedure:
Concentrated sulfuric acid (1 mL) was added to a solution of cyclopentylacetic acid (5.8 mL, 46 mmol) in anhydrous EtOH (15 mL) and heated to reflux for 3 hours. Thereafter, volatiles were removed under reduced pressure and the residue was diluted with water and ethyl acetate. The organic layer was separated, washed with 5% sodium bicarbonate, brine, dried over Na2SO4, and filtered. After evaporation of solvent under reduced pressure, a syrupy cyclopentylacetic acid ethyl ester was obtained and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11]C23C=CC=CC2C(NC3=O)=O)=[CH:5][CH:4]=1.O.[NH2:26]N>C(O)C>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][NH2:26])=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)C2(CC=Cc3ccc(C(F)(F)F)cc3)C=CC=CC12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NCC=Cc1ccc(C(F)(F)F)cc1
Yield: 100.2 %

Procedure:
A mixture of 2-[3-(4-trifluoromethylphenyl)-2-propenyl]phthalimide (4.57 g, 13.79 mmol) prepared in Reference Example 102 and hydrazine hydrate (897 mg, 17.93 mmol) in ethanol (80 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to return to room temperature and filtered, and the filtrate was concentrated under reduced pressure. To the residue, ethyl acetate was added, and the resulting mixture was washed with 1 N sodium hydroxide aqueous solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(4-trifluoromethylphenyl)-2-propenylamine (2.78 g, quantitative) as a pale brown crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@H:9]([O:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH2:8][NH:7][C@@H:6]1[C:19]([OH:21])=O)=[O:4].[C:22]1([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:22]1([C:28]2[CH2:33][CH2:32][N:31]([C:19]([C@@H:6]3[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][C@H:9]([O:11][C:12]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[O:13])[CH2:8][NH:7]3)=[O:21])[CH2:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2S,3S,5S)-3-(methoxycarbonyl)-5-[(pyrrolidin-1-ylcarbonyl)oxy]piperidine-2-carboxylic acid (90.1 mg, 0.000300 mol) and 4-phenyl-1,2,3,6-tetrahydropyridine (64.6 mg, 0.000330 mol) HCl salt, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (146 mg, 0.000330 mol) in N,N-dimethylformamide (0.44 mL, 0.0057 mol) was added N,N-diisopropylethylamine (0.115 mL, 0.000660 mol) at rt. The mixture was stirred at rt overnight, then quenched with aq. sodium bicarbonate. After separation of the organic layers, the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dry. The crude material was used directly in next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.Br[CH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:24][C:25]5[S:26][CH:27]=[C:28]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:29]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reactant: BrCc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2nc(-c3ccccc3)cs2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A suspension of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.080 g, 0.252 mmol) and 2-(bromomethyl)-4-phenylthiazole (0.128 g, 0.504 mmol) in N,N-Dimethylformamide (3 mL) was maintained under vacuum (10 mbar) for 5 minutes. The flask was then flushed with nitrogen and anhydrous freshly powdered (mortar and pestle) potassium carbonate (0.105 g, 0.756 mmol) was added all at once. The resulting mixture was stirred at room temperature with a few short sonication periods (˜1 min) for 1 hour. The heterogeneous mixture became almost homogeneous (except the potassium carbonate) after 10 min and started to precipitate again to a cream solid. The reaction mixture was quenched with 1N hydrochloric acid (2 mL) and then partitioned between dichloromethane (150 mL) and saturated sodium bicarbonate (20 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The solid pale yellow residue was chromatographed on silica gel (2.5×6 cm, elution dichloromethane-ethyl acetate 0-2-5%) to give the title material (0.116 g, 94%) as a pale yellow solid. Crystallization in ethyl acetate (12 mL) provided the title material (0.086 g) as a pale yellow solid. LC (Method C): 2.474 min. HRMS (ESI) calcd for C24H19N4O4S2 [M+H]+ m/z 491.0842. found 491.0864. 1H NMR (CDCl3, 400 MHz) δ ppm: 3.86 (s, 3H), 4.22 (s, 3H), 5.54 (s, 2H), 6.48 (d, J=1.96 Hz, 1H), 6.75 (broad d, 1H), 7.15 (s, 1H), 7.32-7.39 (m, 1H), 7.41-7.49 (m, 2H), 7.53 (s, 1H), 7.87 (s, 1H), 7.90-7.95 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[NH2-].[Na+].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([NH:21][C:7]1[CH:2]=[C:3]([O:10][CH3:11])[C:4]([CH3:9])=[C:5]([F:8])[CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1c(Cl)ccc(F)c1C
Reactant: NCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(NCc2ccccc2)cc(F)c1C
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a −78° C. cooled solution of 1-chloro-4-fluoro-2-methoxy-3-methylbenzene (470 mg, 2.69 mmol) in THF (5.5 mL) was added sodium amide (95%, 276 mg, 6.72 mmol). After 30 minutes, the solution was warmed to −20 to −30° C. and then benzylamine (441 μL, 4.05 mmol) was added dropwise over 1 minute. The reaction was stirred overnight, and LCMS showed no starting material. The reaction was quenched by cooling in an ice bath followed by dropwise addition of saturated NH4Cl and water. After stirring for 1 hour, the reaction mix was extracted twice with ethyl acetate, and the combined organic phases dried over MgSO4 and concentrated via rotary evaporation. The crude product was purified by silica gel chromatography (0-30% ethyl acetate/hexanes) to yield a 223 mg (34%) of N-benzyl-3-fluoro-5-methoxy-4-methylaniline as an orange oil. 1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 6.06-6.00 (m, 1H), 6.00 (s, 1H), 4.29 (s, 2H), 3.74 (s, 3H), 2.00 (s, 3H); LCMS (m/z): 246 (MH+).
Reaction SMILES: [P](I)(I)(I)I.[Cl:6][C:7]1[CH:8]=[C:9]([S:14][C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[C:16]=2[C:24]2C=CN=C(C)[C:25]=2O)[CH:10]=[C:11]([Cl:13])[CH:12]=1.S(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([S:14][C:15]2[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[C:17]([CH3:23])[C:16]=2[CH2:24][C:25]2[CH:21]=[CH:20][N:19]=[CH:15][CH:16]=2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: Cc1nccc(-c2c(C)nn(C(C)C)c2Sc2cc(Cl)cc(Cl)c2)c1O
Agent: I[P](I)(I)I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 466 mg of phosphorus tetraiodide in 15 mL of benzene was heated at 80° C. for 15 minutes. To this solution was added dropwise a solution of 400 mg of 4-[[5-(3,5-dichloro-phenylsulfanyl)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-hydroxy-methyl-pyridine in 10 mL of benzene. The mixture was then heated at 80° C. for 1 hour then allowed to cool to room temperature. Then 8 mL of 10% aqueous sodium bisulphite solution was added and the biphasic mixture stirred for 1 hour. The aqueous phase was extracted three times with 30 mL of ethyl acetate and combined extracts were washed with brine, dried, filtered and evaporated to give a yellow residue which was purified by flash chromatography on silica gel using ethyl acetate/hexane (1:1 then 2:1) for the elution to give 238 mg of 4-[5-(3,5-dichloro-phenylsulfanyl)-1-isopropyl-3-methyl-1H-pyrazol-4-ylmethyl]-pyridine as a white solid. Mass spectrum (ES) m/z 392 [M+H]+, 433 [M+H+MeCN]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>CO>[CH3:4][C:3]1([CH3:5])[S:6][CH:16]([C:15]2[CH:18]=[CH:19][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: CSc1ccc(C=O)cc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: CSc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)cc1
Reaction time: 6 h
Yield: 97.2 %

Procedure:
A solution containing 4.48 g (30 mmoles) of D-penicillamine and 3.99 ml (30 mmoles) of 4-methylmercaptobenzaldehyde in 90 ml of 30% aqueous methanol is stirred for 6 hours. The white solid precipitate is filtered out to give 8.26 g (97.1%) of the title product which can be recrystallized from methanol by adding water, m.p.: 150°-152° C., [α]D20 =+74.4° (c=0.516, dimethylsulphoxide).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[I-].[K+].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.[Ag]=O>[OH:3][CH2:2][CH2:1][O:4][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=[Ag]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
621 mg (corresponding to 10.0 mmol) of ethylene glycol was dissolved in 100 mL of methylene chloride. To this solution under an ice bath, 3.49 g (corresponding to 15.0 mmol) of silver oxide, 350 mg (corresponding to 2.1 mmol) of potassium iodide and 2.10 g (corresponding to 11.0 mmol) of p-toluenesulfonylchloride were added. The resulting mixture was stirred at 0° C. for 2 hours. Insoluble matters were filtered out of the reaction mixture, and were washed with ethyl acetate. The washings were combined with the filtrate, and the mixture was concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 643 mg (corresponding to 2.97 mmol) of 2-hydroxyethyl-p-toluenesulfonate (FIG. 1-3, Step 3).
Reaction SMILES: [OH:1][C@H:2]([CH2:19][NH:20][C:21]([CH3:34])([CH3:33])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH3:6].[OH-].[Na+]>CO.O1CCCC1>[OH:1][C@H:2]([CH2:19][NH:20][C:21]([CH3:33])([CH3:34])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH3:6]
Reactant: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Methyl 3-[2-[(1R)-1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]phenyl]propionate (539 mg) obtained in Step 4 was dissolved in methanol (20 ml) and tetrahydrofuran (20 ml), 4N aqueous sodium hydroxide (2.5 ml) was added and the mixture was stirred at 50° C. for 8 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water, neutralized with 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (332 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC(c2ccc(Br)cn2)=NO1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@@H](CO)C3)nc2)c(F)c1
Temperature: 75 °C
Yield: 55.5 %

Procedure:
[(5R)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (intermediate 12, 0.139 g, 0.54 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.2 g, 0.514 mmol), potassium carbonate (0.355 g, 2.57 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.059 g, 0.05 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane (2×10 ml), the solids were further purified by column chromatography, eluted with 5% DMF in dichloromethane to give the title compound as a white solid (0.125 g).