Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N+:16]([CH3:19])([O-:18])=[O:17].N1CCCCC1>C1C=CC=CC=1.O>[CH2:8]([S:15][C:4]1([CH2:19][N+:16]([O-:18])=[O:17])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: SCc1ccccc1
Reactant: O=C1CCOCC1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])CC1(SCc2ccccc2)CCOCC1
Reaction time: 192 h

Procedure:
2,3,5,6-Tetrahydropyran-4-one (5 g), benzyl mercaptan (6.2 g), nitromethane (2.7 cm3), and piperidine (1 cm3) were dissolved in benzene (50 cm3), and the mixture heated under reflux with azeotropic removal of water. After 8 days the reaction mixture was allowed to cool and washed first with dilute hydrochloric acid, then with water. The remaining solution was dried and the solvent then removed under reduced pressure to give the nitro system (8g, 60%). This material was sufficiently pure to be used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:23]=[CH:24][C:25]=1[NH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)nc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)nc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 109.9 %

Procedure:
A mixture of 2-[3-(benzyloxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine (45.56 g), iron powder (31.7 g), calcium chloride (1.26 g), ethanol (400 mL) and water (100 mL) was stirred at 80° C. for 3.5 h. The mixture was filtered through celite and the filtrate was concentrated. The residual solid was washed successively with water, ethanol, and diethyl ether to give the title compound (46.31 g, 100%) as a brownish-yellow solid. MS 371 (MH+).
Reaction SMILES: [CH:1]1([SH:4])[CH2:3][CH2:2]1.[H-].[Na+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.O>C1COCC1.C(OCC)C>[CH:1]1([S:4][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: SC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A 4% strength solution of 3.00 g (40.5 mmol) of cyclopropanethiol (preparation according to: E. Block et al., J. Am. Chem. Soc. 1992, 114, 3492) in THF/diethyl ether (1:1) was admixed in portions with 1.78 g (44.6 mmol) of sodium hydride (60%) and stirred for 30 minutes at room temperature. The portionwise addition of 6.00 g (38.7 mmol) of 1-fluoro-4-nitrobenzene was then carried out. The mixture was stirred at 40° C. for 2 hours. After cooling, the mixture was added to water and extracted (3×) with benzene. The combined organic phases were concentrated by evaporation and the residue was purified chromatographically (hexane/ethyl acetate 95:5). This gave 4.6 g (23.6 mmol; yield: 61%) of the product.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC1CCCC1

Procedure:
Prepared by Procedure F and Scheme R using 3-(cyclopentyloxy)-4-methoxybenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 451.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc2nc(Nc3ccccc3Cl)oc2c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.1 %

Procedure:
Methyl 2-(2-chlorophenyl)amino-7-fluoro-6-benzoxazolylacetate (2.12 g, 6.33 mmol) was dissolved in THF/methanol (2:1, 90 ml). To the resulting solution was added 1N NaOH (30 ml) and the mixture was stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure. The residue was acidified with 1N hydrochloric acid. The crystals thus precipitated were collected by filtration, washed with water and dried under reduced pressure, whereby 2-(2-chlorophenyl)amino-7-fluoro-6-benzoxazolylacetic acid (1.83 g, 90%) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:53][CH3:54])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([OH:29])=O)[CH3:19])=[O:17])=[O:12])=[C:6]([C:33]2[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[CH:36]=[CH:35][N:34]=2)[CH:5]=1)[CH3:2].[CH3:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][NH2:80].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][NH:80][C:27]([C@@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][N:18]([CH3:19])[C:16](=[O:17])[C:15]1[CH:30]=[CH:31][CH:32]=[C:13]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:53][CH3:54])[CH2:1][CH3:2])=[CH:5][C:6]=2[C:33]2[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[CH:36]=[CH:35][N:34]=2)=[O:12])[CH:14]=1)=[O:29]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a mixture of (S)-1-(2-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)-N-methylbenzamido)ethyl)pyrrolidine-2-carboxylic acid (1.32 mmol, 1.12 g), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (1.38 mmol, 530 mg) and DIEA (9.21 mmol, 1.19 g) in DMF (4 mL) was added HATU (1.45 mmol, 0.551 g). The mixture was stirred at 60° C. for 1 h and purified by prep. HPLC to give a syrup (1.18 g, 62%). MS (ES, m/z): 1110.42 [M+H]+.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[F:8][CH:9]([F:17])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CO>O>[F:8][CH:9]([F:17])[C:10]1[CH:11]=[C:12]([NH:13][C:1]2[CH2:5][CH2:4][C:3](=[O:6])[CH:2]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(C(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: O
Product: O=C1C=C(Nc2cccc(C(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclopentane-1,3-dione (2.00 g, 20.4 mmol), 3-(difluoromethyl)aniline (2.92 g, 20.4 mmol) and Ytterbium(III) trifluormethanesulfonate (63 mg, 0.10 mmol, 0.5 mol %) is stirred at room temperature for 2 h. Methanol and water are added and the resulting precipitate is filtered and dried. Yield: 2.75 g; ESI mass spectrum: [M+H]+=224; Retention time HPLC: 0.82 min (V012_S01).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[O:4][N:3]=1
Reactant: Cc1cc(N)on1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
To a solution of 3-methyl-5-aminoisoxazole (1.00 g, 10.2 mmol) and pyridine (0.97 ml, 12.2 mmol) in tetrahydrofuran (34 ml) was added 2,2,2-trichloroethyl chloroformate (1.69 ml, 12.2 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 718 mg (26%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:21][CH:22]=[C:23]([Cl:26])[CH2:24]Cl>O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:24][C:23]([Cl:26])=[CH:22][Cl:21])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClC=C(Cl)CCl
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1CC(Cl)=CCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
To a mixture of 10.8 g of 4,5-dichloro-3(2H)-pyridazinone and 9.5 g of anhydrous potassium carbonate were added 65 ml of N,N-dimethylformamide and stirred for 10 minutes at room temperature. Then, 10.0 g of 1,2,3-trichloro-1-propene (mixture of E-from and Z-form) were added to the mixture solution and were stirred for 6 hours at 40° C. The solution was poured into a large quantity of water and extracted with benzene, and freed of solvent by distillation under reduced pressure to give 6.0 g of the intended compound (mixture of E-form and Z-form). The compound thus obtained was separated into isomer (m.p.: 93.7°-94.6° C., 112.8°-114.8° C.) by means of column chromatography (on silica gel, eluting with benzene).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][N:15](C)[C:16]=2F)[CH2:6]1.O.[CH3:25]O>>[CH3:4][C:5]1([CH3:23])[O:9][N:8]=[C:7]([S:10][CH2:11][C:12]2[CH:13]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:25])[NH:15][C:16]=2[O:2][CH3:1])[CH2:6]1
Reactant: CO
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Product: COC1=C(CSC2=NOC(C)(C)C2)C(C(F)(F)F)N(C)N1
Reaction time: 4 h
Yield: 96.7 %

Procedure:
0.77 g (4.0 mmoles) of sodium methoxide (a 28% methanol solution) was added to a solution of 0.5 g (1.6 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 20 ml of methanol. The mixture was stirred for 4 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 96.7%) of 5,5-dimethyl-3-(5-methoxy-2-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]=[CH2:20])[C:16](=[O:17])[C:3]=12>CCO.O.[Rh](Cl)(Cl)Cl>[OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:10])[CH3:11])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][N:15]([CH:18]=[CH:19][CH3:20])[C:16](=[O:17])[C:3]=12
Reactant: C=CCN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Agent: Cl[Rh](Cl)Cl
Solvent: O
Solvent: CCO
Product: CC=CN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 9-hydroxy-7-isopropyl-2-(2-propenyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (3.0 g, 11 mmol) and rhodium trichloride hydrate (200 mg, 1 mmol) in EtOH (75 mL) was heated to reflux for 8 h. The reaction was cooled to ambient temperature and the solvent was removed in vacuo. The reddish solid was triturated in MeOH and collected by filtration to give the title compound as a solid. HPLC RT=2.90 min (Method A); ES MS (M+H)=280; 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.10 (d, J=4.5 Hz, 1H), 5.49 (sextet, J=6 Hz, 1H), 5.04 (septet, J=7 Hz, 1H), 3.97 (m, 2H), 3.79 (m, 2H), 1.76 (d, J=6 Hz, 3H), 1.39 (d, J=7 Hz, 6H).
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: OCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Temperature: 110 °C
Yield: 47.1 %

Procedure:
To a solution of 4-(p-fluorobenzoyl)piperidine hydrobromide (0.3 g, 1.04 mmol) in DMF (10 mL) were added 3-bromo-1-propanol (0.11 mL, 1.25 mmol) and potassium carbonate (0.29 g, 2.08 mmol). This heterogeneous solution was heated at 110° C. for 3 h then cooled at 25° C., diluted with water (100 mL) and extracted with EtOAc (3×30 mL). The collected organic phase was washed with water (2×50 mL), dried and concentrated in vacuum. The crude compound was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound as a pale yellow solid (0.13 g, 47%). m.p. =106-108° C. 1H NMR (CDCl3): 1.55-1.68 (m, 2H), 1.68-1.95 (m, 5H), 2.05-2.2 (m, 2H), 2.642 (t, J=5.4 Hz, 2H), 3.13 (bd, J=11.7 Hz, 2H), 3.15-3.3 (m, 1H), 3.808 (t, J=4.8 Hz, 2H), 7.137 (t, J=8.4 Hz, 2H), 7.95 (dd, J=5.4 & 8.4, 2H). Anal. Calcd. for C15H20FNO2:C, 67.90; H, 7.60; N, 5.28; Found: C, 66.71; H, 7.38; N, 5.44.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[O:2]1>[Si]([O-])([O-])([O-])[O-].[Ag+].[Ag+].[Ag+].[Ag+].C1C=CC=CC=1>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: OCc1ccc2c(c1)OCO2
Agent: [Ag+]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: c1ccccc1
Product: O=Cc1ccc2c(c1)OCO2

Procedure:
152 Mg of 3,4-methylenedioxy-benzyl alcohol, 500 mg of silver silicate and 30 ml of benzene were added to the flask described in Example II and the mixture was refluxed for 45 minutes and was then filtered to obtain 139 mg of 3,4-methylenedioxy-benzaldehyde melting at 36.8°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@@H]3CCC(=O)[C@H](F)C3)cnc2N)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@H](F)C3)cnc2N)cc1F
Product: CC(C)(C)OC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F
Reaction time: 2 h
Yield: 43.9 %
Yield: 47 %

Procedure:
To a solution of (+/−)-tert-butyl 4-(3-amino-6-((1R,3R)-3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (1.9 g, 4.71 mmol) in MeOH (47.1 mL) was added NaBH4 (0.267 g, 7.06 mmol) at 0° C. The reaction mixture was stirred for 2 h. After quenched with sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with flat 35% of EtOAc in heptane to provide (+/−)-tert-butyl 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (839 mg, 2.07 mmol, 43.9%) and (+/−)-tert-butyl 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (900 mg, 2.22 mmol, 47%). LCMS (m/z): 406.3 (MH+), 0.85 min and 406.3 (MH+), 0.85 min respectively.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11]([N:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[N:15]1)[CH2:12][CH3:13])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].[N:45]1([CH2:50][C@@:51]2([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=3[F:75])[O:55][CH2:54][C@@H:53]([CH2:56]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:52]2)[CH:49]=[N:48][CH:47]=[N:46]1>C(O)(C)C.O>[N:45]1([CH2:50][C@@:51]2([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=3[F:75])[O:55][CH2:54][C@@H:53]([CH2:56][O:38][C:35]3[CH:36]=[CH:37][C:32]([N:29]4[CH2:28][CH2:27][N:26]([C:23]5[CH:24]=[CH:25][C:20]([N:17]6[C:18](=[O:19])[N:14]([C@@H:11]([CH2:12][CH3:13])[C@@H:9]([O:8][CH2:1][C:2]7[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=7)[CH3:10])[N:15]=[CH:16]6)=[CH:21][CH:22]=5)[CH2:31][CH2:30]4)=[CH:33][CH:34]=3)[CH2:52]2)[CH:49]=[N:48][CH:47]=[N:46]1
Reactant: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](Cn3cncn3)(c3ccc(F)cc3F)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
Added 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-20 (35 g) to a mixture of dimethylsulfoxide (350 ml) and sodium hydroxide (3.4 g) and water (7 ml) at 25-30° C. and stirred for 45 minutes at 25-30° C. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate compound of formula-10 (31.5 g) was added to the above reaction mixture at 25-30° C. and stirred 5 hours at 25-30° C. After completion of the reaction, water was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% sodium chloride solution. Distilled off the solvent under reduced pressure to get the compound as residue. Dissolved the obtained residue in isopropanol (320 ml) at 45-50° C. Filtered the solid, washed with water and dried to get the title compound. Yield: 98%; Purity by HPLC: 95.1%
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[CH3:10][S:11]([NH:14][C:15]1[CH:16]=[C:17]2[C:40](=[CH:41][CH:42]=1)[O:39][C:20]1([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][CH2:21]1)[CH2:19][C:18]2=O)(=[O:13])=[O:12]>CO.ClCCl>[OH:9][N:8]=[C:18]1[C:17]2[C:40](=[CH:41][CH:42]=[C:15]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])[CH:16]=2)[O:39][C:20]2([CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:22][CH2:21]2)[CH2:19]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCCOCCN1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCN1CCC2(CC1)CC(=NO)c1cc(NS(C)(=O)=O)ccc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Anhydrous pyridine (40 μL, 0.5 mmol) and hydroxylamine hydrochloride (8 mg, 0.11 mmol) were added to a solution of tert-butyl 2-(2-(6-(methylsulfonamido)-4-oxospiro[chroman-2,4′-piperidine]-1′-yl)ethoxy)ethylcarbamate (12, 50 mg, 0.10 mmol) in 5 mL of anhydrous methanol. This solution was stirred at room temperature for ˜1 hour and then at ˜60° C. for ˜1 hour. Additional hydroxylamine hydrochloride (6.2 mg, 0.09 mmol) and anhydrous pyridine (40 μL, 0.5 mmol) were added and stirring was continued at 60-65° C. for ˜1 hour. More hydroxylamine hydrochloride (13.9 mg, 0.20 mmol) was added and stirring was continued at 60-65° C. for ˜80 minutes. Hydroxylamine hydrochloride (7 mg, 0.10 mmol) was added and stirring was continued at 60-65° C. for ˜2 hours. TLC (silica gel, 10% methanol in dichloromethane, UV visualization) showed complete disappearance of starting ketone 12 (Rf=0.35-0.4) and a single new spot (18, Rf=0.18-0.27). The reaction mixture was concentrated to dryness under reduced pressure on a rotary evaporator. The residue was dissolved in 5 mL of ethyl acetate and extracted successively with 10 mL of 0.5 M aqueous hydrochloric acid, mL of water, and 5 mL of saturated aqueous sodium chloride. TLC (as above) showed the product (18) in the combined aqueous extracts, which were adjusted to pH ˜13 by addition of sodium hydroxide pellets and then to pH ˜4 by addition of 3 M aqueous hydrochloric acid. The aqueous solution was extracted with three 20 mL portions of ethyl acetate. The combined ethyl acetate extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure on a rotary evaporator followed by high vacuum overnight to afford 50.3 mg (98% yield) tert-butyl 2-(2-(4-(hydroxyimino)-6-(methylsulfonamido)-spiro[chroman-2,4′-piperidine]-1′-yl)ethoxy)ethylcarbamate (18).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:43])=[C:37]([S:39]([Cl:42])(=[O:41])=[O:40])[CH:38]=1>>[ClH:42].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:39]([C:37]3[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=3[CH3:43])(=[O:41])=[O:40])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 5-fluoro-2-methylbenzenesulfonylchloride (56 mg, 0.269 mmole) to give 7 mg as purple solid. M+1 519.3 Calcd 519.15; 1HNMR δ 7.78–7.18 (m, 8H), 6.72 (d, 1H), 6.45 (dd, 1H), 6.34 (d, 1H), 3.59 (app t, 2H), 3.38 (app t, 2H), 3.21 (app t, 2H), 3.13 (app t, 2H), 2.57 (s, 3H), 2.06–1.98 (m, 2H).