Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([C:30](=[O:36])[CH2:31][CH2:32][CH:33]([OH:35])[CH3:34])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([C:30](=[O:36])[CH2:31][CH2:32][CH:33]([OH:35])[CH3:34])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCC(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCC(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A solution of 0.150 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(4(RS)-hydroxyvaleryl)-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was treated with 0.015 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.027 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-(4(RS)-hydroxyvaleryl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[CH:5]1[O:7][CH2:6]1.[CH2:16]([CH2:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH2:23][NH:24][CH2:6][CH:5]([C:4]1[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[OH:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(S(N)(=O)=O)cc1C1CO1
Product: COc1ccc(S(N)(=O)=O)cc1C(O)CNCCc1ccccc1

Procedure:
2-Methoxy-5-sulphamoylstyrene oxide obtained in step 1 of Example 5, treated with benzylmethylamine under the conditions described in step 2 of Example 5, gives α-benzylmethylaminomethyl-2-methoxy-5-sulphamoylbenzenemethanol in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:1])([F:14])[F:15])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(OC(F)(F)F)ccc1O
Yield: 100 %

Procedure:
A mixture of 4.53 g of 4-trifluoromethoxy-2-nitrophenol, 35 ml of ethyl acetate and 1.0 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for 1.7 hours. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 3.92 g of 2-amino-4-trifluoromethoxy phenol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]([NH:31][C:32](=[O:44])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:45][O-:46].[Na+]>CO>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:31][C@@:9]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:46][CH3:45])=[CH:8][CH:7]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:44])=[CH:34][C:35]=1[C:40]([F:43])([F:41])[F:42]
Reactant: C[O-]
Reactant: O=C(N[C@](Cc1ccccc1)(c1ccc(CBr)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CO
Product: COCc1ccc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Reaction time: 0.67 h
Yield: 67 %

Procedure:
(R)—N-(1-(4-(bromomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (prepared as described in Procedure 3, 4, 5, 6, 7, 56, 57, 100 and 32, 24 mg, 0.035 mmol) was dissolved in 0.5 mL of methanol. To this solution was added sodium methoxide (25% by wt, 0.5 mL) and the reaction mixture was stirred for 40 min. The reaction was quenched with 1.0 M HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified by flash chromatography (4 g silica gel column, 0-100% EtOAc/hexane gradient over 11 min., flow rate 18 mL/min) to provide (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-(methoxymethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 321) as a white solid (15 mg, 67% yield). LC/MS: RT=1.62 min [M+H] 642 (Chromolith Performance 18e 4.6×100 mm column, 50-90% acetonitrile, water with 0.1% trifluoroacetic acid gradient over 2 min, 5 mL/min); 1H NMR (400 MHz, CDCl3) ppm 7.91 (1H, d, J=7.15 Hz), 7.77-7.87 (1H, m), 7.08-7.44 (7H, m), 6.97-7.05 (2H, m), 6.92 (1H, d, J=8.79 Hz), 6.66-6.75 (3H, m), 5.87 (1H, tt, JHH=2.75 Hz, JHF=53 Hz), 4.47 (2H, s), 4.09 (1H, d, J=13.2 Hz), 3.81 (1H, d, J=13.2 Hz), 3.42 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[NH:29]([CH3:31])[CH3:30].CCN(CC)CC>C1COCC1>[CH3:30][N:29]([CH2:2][C:3]1[N:4]=[C:5]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH3:31]
Reactant: O=C(Nc1nc(CCl)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Into a solution of Compound 70 (50 mg, 0.12 mmol) in 5 mL of THF was added NH(Me)2 (40% solution in water, 0.1 mL) and NEt3 (0.1 ml) at room temperature. The solution was stirred at room temperature for 1 hour. The solution was washed with 5 mL of water and dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with 5-100% ethyl acetate in hexane) to give Compound 71 (44 mg, 84%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+].Cl>C(N(CC)CC)C.C(O)(=O)C.C1(C)C=CC=CC=1>[OH:9][C@@H:7]1[CH2:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[C@@H:4]([C:3]([OH:19])=[O:2])[CH2:8]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1C[C@H](O)CN1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To 10 ml of anhydrous toluene, there were added 0.93 g of the (2R, 4R)-4-hydroxy-1-(2-nitrophenyl) proline methyl ester prepared in Reference Example 6, 1.8 g of triphenyl phosphine, 0.42 g of acetic acid and 0.25 g of triethylamine and then 1.4 g of diisopropyl azodicarboxylate was dropwise added to the resulting mixture over one hour with ice-cooling. After stirring the mixture for 16 hours with heating to 60° C. and cooling it to room temperature, 8 ml of a 1.3N sodium hydroxide solution was added to the mixture, followed by stirring the mixture for additional 4 hours at room temperature. The pH of the reaction solution was adjusted to 7 with concentrated hydrochloric acid, the insolubles precipitated were filtered off, the resulting filtrate was fractionated and the aqueous phase obtained was washed with ether. Then the aqueous phase was acidified with hydrochloric acid, followed by extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. After concentration of the ethyl acetate extract, the resulting residue was recrystallized from ethyl acetate-chloroform to give 0.66 g (yield 74.8%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]=[C:8]1[C:12]2=[CH:13][C:14]3[CH:15]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:21]([O:20][C:16]1[CH:17]=[CH:18][C:19]2[N:11]3[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[C:12]3=[CH:13][C:14]=2[CH:15]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccccc3)ccc12

Procedure:
tert-Butyl-2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (1.391 g, 3.70 mmol) was dissolved in THF (25 mL) and 10% palladium on carbon (50% in water, 217 mg) was added. The reaction mixture was placed under 225 psi of hydrogen in a hydrogenation reactor for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The above material was taken up in a mixture of THF (20 mL) and EtOH (20 mL) and Pd(OH)2/C (250 mg) was added. The reaction mixture was placed under 200 psi of hydrogen in a hydrogenation reactor for 2 days. Additional Pd(OH)2/C (250 mg) was added and the reaction mixture was placed under 300 psi of hydrogen in a hydrogenation reactor for 24 h. Pd(OH)2/C (250 mg) was again added and the vessel placed under 500 psi of hydrogen in a hydrogenation reactor for 24 h. The hydrogenation reactor was warmed to 50° C. for 8 h. The reaction mixture was cooled to room temperature and AcOH (5 mL) was added. The reaction mixture was placed under 500 psi of hydrogen for 16 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to provide a mixture of the title compound and tert-butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The title compound (150 mg) was isolated by silica gel column chromatography. tert-Butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (600 mg) was dissolved in toluene (100 mL) and Pd/C (1.0 g) was added. The reaction mixture was warmed to 80° C. and stirred for 2 days. The reaction mixture was filtered through Celite® and the title compound (250 mg) was isolated as a white solid resulting from precipitation during concentration of the filtrate. LCMS m/z=288.3 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][CH:5]([C:7](OCC)=[O:8])[N:4]([C:12](=[O:25])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)[CH2:3]1.OCC1N(C(C2C=C(C)C=CC=2N2N=CC=N2)=O)CC(C)O1>>[OH:8][CH2:7][C@H:5]1[N:4]([C:12]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:25])[CH2:3][C@H:2]([CH3:1])[O:6]1
Reactant: CCOC(=O)C1O[C@@H](C)CN1C(=O)c1cc(C)ccc1-n1nccn1
Agent: Cc1ccc(-n2nccn2)c(C(=O)N2CC(C)OC2CO)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@H](C)O[C@H]2CO)c1

Procedure:
By using ethyl(2RS,5S)-5-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate obtained in Reference Example 5 (0.11 g, 0.33 mmol) as the raw material, the same procedure as in Reference Example 2 was carried out to obtain the diastereomer mixture of [2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (colorless oil). The obtained diastereomer mixture was purified by thin layer chromatography (1 mm, hexane/EtOAc=50/50) to obtain [(2S,5S)-2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (colorless oil). To a solution of the obtained [(2S,5S)-2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (30.2 mg, 0.10 mmol) and TEA (0.021 mL, 0.15 mmol) in CHCl3 (0.8 mL), MsCl (0.011 mL, 0.15 mmol) were added under cooling with ice water and the resulting mixture was stirred for 1 hour. Water was added to the reaction mixture under cooling with ice water, followed by extraction with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. 5-Fluoro-2-(1H-pyrazol-4-yl)pyridine (0.033 g, 0.20 mmol) and Cs2CO3 (0.065 g, 0.20 mmol) were added to a solution of the obtained residue (0.5 mL). The resulting mixture was reacted for 1 hour at 120° C. under irradiation of microwave. The reaction mixture was allowed to cool, water was added thereto, followed by extraction with CHCl3, the extract was passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (0.020 g) (colorless oil).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]#[N:22])=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:23](=[O:25])[CH3:24].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].Cl>O1CCOCC1.O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]3[NH:28][N:27]=[N:26][N:22]=3)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:23](=[O:25])[CH3:24]
Reactant: CCCc1c(OCc2ccc(CSC#N)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1c(OCc2ccc(CSc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 89 °C

Procedure:
1-[2-Hydroxy-3-propyl-4-(4-thiocyanomethylphenylmethoxy)phenyl]ethanone (6.0 g; 0.017 m) was dissolved in dioxan:water (80:20; 100 ml) to which was added sodium azide (4.4 g; 0.068 m) and ammonium chloride (1.8 g; 0.034 m). The resulting solution was heated at 89° C. for 18 hours, cooled and poured onto water. The resulting solution was acidified with concentrated hydrochloric acid, filtered and washed with water to leave a white solid. Recrystallised from methanol to give a cream crystalline solid m.p. 160°-161° C.