Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=[O:2].[Na+:7].[Na+].S([O-])([O-])(=[O:11])=S.[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+].S(=O)(O)[O-].[Na+].[S:27]([S:30]([O-:32])=[O:31])([O-:29])=[O:28]>>[OH2:2].[OH2:11].[S:27]([S:30]([O-:32])=[O:31])([O-:29])=[O:28].[Na+:7].[Na+:7]
Reactant: O=S([O-])([O-])=S
Agent: O=S([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: O=S([O-])[O-]
Product: O

Procedure:
The process of EXAMPLE 1 was run continuously with a sodium hydrosulfite solution feed containing 144.8 g/l of Na2S2O4, 11.6 g/l of sodium thiosulfate, 23.8 g/l of sodium sulfite, and 81.1 g/l of sodium bisulfite. The hydrosulfite solution was fed at a rate of 12 gallons per minute to the crystallizer of EXAMPLE 1 to produce a slurry of sodium hydrosulfite dihydrate crystals which was continuously fed to the hydrocyclone series. Product sized crystals were continuously conveyed to the centrifuge at a rate of 1.4 gallons per minute. After dissolving the crystalline cake recovered from the centrifuge, a product solution containing 130.4 g/l of sodium hydrosulfite, and 4.1 g/l of sodium thiosulfate was continuously recovered.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:16]1[CH:23]2[CH:19]([O:20][CH:21]([CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22]2)[CH:18]([CH2:32]O)[O:17]1)=[O:5])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:56][O:57][C:58]([CH:60]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:59]>C(#N)C.C(OCC)(=O)C>[CH3:56][O:57][C:58](=[O:59])[CH:60]=[CH:32][CH:18]1[CH:19]2[CH:23]([O:22][CH:21]([CH:24]=[CH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:20]2)[CH:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[O:17]1
Reactant: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CO)C2OC(C=Cc3ccccc3)OC21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ncnc2c1ncn2C1OC(C=CC(=O)OC)C2OC(C=Cc3ccccc3)OC21
Reaction time: 2 h
Yield: 52 %

Procedure:
1-Ethyl-3-[9-(6-hydroxymethyl-2-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-urea (5.0 g, 11 mmol) was suspended in dry acetonitrile (50 mL) and Dess-Martin periodinate (6.7 g, 16 mmol) was added. The suspension was stirred 2 h, after which time proton NMR of an aliquot showed complete conversion to the aldehyde. (Methoxycarbonylmethylene)triphenylphosphorane (3.9 g, 12 mmol) was added and stirring was continued overnight. The reaction mixture was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate/thiosulfate solution (100 mL), dried with sodium sulfate and filtered. The filtrate was evaporated and the solid was dissolved in hot isopropyl alcohol (50 mL). It was allowed to cool, then heptane was added and it was stirred overnight. The resulting precipitate was washed with heptane and dried under vacuum, affording the desired product (2.9 g, 71%). 1H-NMR (300 MHz, d6DMSO) δ1.15 (t, 3H, J=7 Hz), 3.21 (q, 2H, J=7 Hz), 3.59 (s, 3H), 4.98 (m, 1H), 5.28 (ψt, 1H, J=6 Hz), 5.51 (dd, 1H, J=6 Hz, <2 Hz), 5.70 (d, 1H, J=16 Hz), 5.90 (d, 1H, J=6 Hz), 6.30 (dd, 1H, J=6 Hz, 16 Hz), 6.45 (d, 1H, J<2 Hz), 6.95 (d, 1H, J=15 Hz), 7.35 (m, 3H), 7.45 (d, 2H, J=7 Hz), 8.50 (s, 1H), 8.60 (s, 1H), 9.30 (t, 1H, J=6 Hz), 9.60 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13](=[O:44])[CH2:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18](=[O:32])[C@H:17]([CH2:33][C:34]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][N:35]=4)[C:16]3=[O:43])[C:6]=2[CH:5]=[C:4]([CH3:45])[CH:3]=1>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13](=[O:44])[CH2:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:18](=[O:32])[C@H:17]([CH2:33][C:34]4[C:42]5[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=5[NH:36][N:35]=4)[C:16]3=[O:43])[C:6]=2[CH:5]=[C:4]([CH3:45])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)N(C(=O)CN1C(=O)[C@@H](Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3ccccc31)CCCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(c1)N(C(=O)CN1C(=O)[C@@H](Cc3n[nH]c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc31)CCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 13.1 %

Procedure:
A solution of (3R)-1-[2-(6,8-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-2-oxoethyl]-3-(1H-indazol-3-ylmethyl)-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (50 mg) in ethyl acetate (8 mL) was treated with 10% palladium on charcoal (300 mg). Placed under H2 environment (by balloon) and stirred at room temperature for 48 hours. Filtered through celite and concentrated to dryness. Chromatographed on silica gel (Hexane:Ethyl Acetate). Lyophilized the residue to yield the title compound as a white solid (6.6 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:21])=[N:9]2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:25][C:26]#[CH:27].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([N:13]([CH2:27][C:26]#[CH:25])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]([CH3:21])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1nn(-c2cncc(F)c2)cc1NC(=O)OC(C)(C)C
Reactant: C#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCN(C(=O)OC(C)(C)C)c1cn(-c2cncc(F)c2)nc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To an ice cold solution of tert-butyl 1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-ylcarbamate (1200 mg, 4.11 mmol) in dry N,N-dimethylformamide (DMF; 4 mL) under nitrogen was added 60% wt sodium hydride (197 mg, 4.93 mmol) and the mixture stirred for 10 minutes (min). 3-Bromoprop-1-yne (733 mg, 6.16 mmol) was then added and the mixture was stirred for additional 0.5 hour (h) at 0-5° C. The mixture was allowed to warm to ambient temperature and then stirred for additional 3 h. The brown reaction mixture was poured into saturated aqueous ammonium chloride (NH4Cl; 20 mL), and diluted with ethyl acetate (EtOAc; 50 mL). The organic phase was separated and the aqueous phase extracted with EtOAc (20 mL). The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated in vacuo to give a brown oil. This oil was purified on silica gel eluting with mixtures of hexanes and EtOAc to give the title compound as a light yellow solid (1103 mg, 81%): mp 81-82° C.; 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.37 (d, J=2.5 Hz, 1H), 7.99 (s, 1H), 7.83 (dt, J=9.5, 2.2 Hz, 1H), 4.31 (s, 2H), 2.29 (t, J=2.4 Hz, 1H), 2.27 (s, 3H), 1.45 (s, 9H); ESIMS m/z 229.84 ([M]+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][NH:7][CH2:8][CH2:9][CH2:10][P:11](=[O:14])([OH:13])[OH:12].C(=O)(O)[O-].[Na+].[OH-].[Na+]>O.CC(C)=O>[Cl:1][CH2:2][C:3]([N:7]([CH2:8][CH2:9][CH2:10][P:11](=[O:12])([OH:14])[OH:13])[OH:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=P(O)(O)CCCNO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N(O)CCCP(=O)(O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Chloroacetyl chloride (4.52 g.) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (2.46 g.) in a mixture of water (15 ml.) and acetone (15 ml.) over a 20 minutes-interval with stirring under ice-cooling and maintaining the pH at around 7-8 by adding 5% aqueous sodium bicarbonate solution. After stirring for further hour, the reaction mixture was adjusted to pH 9 with 1 N aqueous sodium hydroxide solution and stirred at ambient temperature for 35 minutes. After acetone was distilled off under reduced pressure, the aqueous solution was acidified to pH 1.8 with 10% hydrochloric acid and evaporated to dryness under reduced pressure. The residue was dissolved in ethanol (40 ml.) and heated for 10 minutes at 60° C. The insoluble substance was separated out and the ethanolic layer was allowed to stand overnight at ambient temperature to give crystalline 3-(N-chloroacetyl-N-hydroxyamino)propylphosphonic acid (1.85 g.), mp: 163°-165° C. (dec.).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][C:8]2[N:9]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[CH3:30])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1.C1N=C[N:33](C(N2C=NC=C2)=O)C=1.O.[NH4+]>C1COCC1>[NH:4]1[C:5]([CH2:6][CH2:7][C:8]2[N:9]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:33])=[O:26])=[CH:23][C:22]=3[CH3:30])[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)=[N:1][N:2]=[N:3]1
Reactant: COc1ccc(-c2ccc(CCc3nnn[nH]3)n2-c2ccc(C(=O)O)cc2C)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(CCc3nnn[nH]3)n2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (130 mg, 0.332 mmol) was dissolved in anhydrous THF (3 mL). CDI (68 mg, 0.419 mmol) was added in three portions at room temperature and stirred at this temperature for 1 h. The resultant yellow solution was added dropwise to 25% ammonium hydrate (3 mL) at 0° C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was evaporated in vacuo and the residue was purified by prep-HPLC to afford 2H, R2=4-methoxyphenyl as a yellow solid (7 mg, 5.4%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:7][C:8](=[O:17])[C:9]3[C:14]([CH:15]=2)=[C:13]([CH3:16])[CH:12]=[CH:11][CH:10]=3)[CH2:2]1.Br[CH:19]([OH:21])[CH3:20].C(=O)([O-])O.[Na+].C(C(C)=O)C>O>[OH:21][CH2:19][CH2:20][N:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:7][C:8](=[O:17])[C:9]3[C:14]([CH:15]=2)=[C:13]([CH3:16])[CH:12]=[CH:11][CH:10]=3)[CH2:2]1
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNC3)cc12
Reactant: CC(O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCO)C3)cc12
Yield: 43.1 %

Procedure:
To the obtained (−)-3-(pyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (3.0 g) were added bromoethanol (8.21 g), sodium hydrogen carbonate (5.6 g), methyl ethyl ketone (84 ml) and water (8.4 ml), and the mixture was stirred under reflux for 2 hr. The reaction mixture was concentrated, extracted with methylene chloride, and the extract was washed with water, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (methanol/ethyl acetate; 2/5) and crystallized from ethyl acetate to give (−)-3-[1-(2-hydroxylethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (1.5425 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])CCC.C1CCCCC1.CN(C)[CH:29]=[O:30]>O1CCCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:29]=[O:30])[C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1Br
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N-(2-Bromo-6-fluorophenyl)pivalamide (25.5 mmol, 7.0 g) was dissolved in tetrahydrofuran (200 mL). Mixture was cooled to −78° C. 2M Butyllithium in cyclohexane (62.0 mmol, 31.0 mL) was added to the mixture drop-wise. Reaction mixture was held at −78° C. for 30 minutes. A solution of N,N-dimethylformamide (129 mmol, 10.0 mL) in tetrahydrofuran (30 mL) was added to the reaction mixture drop-wise. Reaction was held at −78° C. for 30 minutes. Reaction was quenched with aqueous ammonium chloride then the mixture was allowed to warm to room temperature. Mixture was extracted 2× ethyl acetate. Combined organic layers were dried (magnesium sulfate), filtered and concentrated. Silica gel chromatography afforded the desired product as white solid in 80% yield. 1H NMR (300 MHz, CDCl3): δ=9.93 (d, J=1.83, 1H), 9.14 (bs, 1H), 7.56-7.50 (m, 1H), 7.42-7.25 (m, 2H), 1.34 (s, 9H). MS m/e (M+H)+=224.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH:17][C:24](=[O:23])[CH2:25][C:26](=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CCOc1ccc(N)c(NC(=O)OC(C)(C)C)c1
Product: CCOc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-phenyl)-carbamic acid tert-butyl ester (Example J14) (194 mg, 0.77 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (203 mg, 55%).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][N:12]([CH2:17][CH:18]=[CH2:19])[CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:5])C.[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[CH2:17]([N:12]([CH:13]1[CH2:14][CH2:15][CH2:16]1)[N:11]1[C@@H:7]2[C@@H:6]([CH2:10][CH2:9][CH2:8]2)[C:4]([OH:5])=[C:35]([C:30]2[NH:29][C:28]3[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=3[S:32](=[O:33])(=[O:34])[N:31]=2)[C:36]1=[O:37])[CH:18]=[CH2:19]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: C=CCN(NC1CCCC1C(=O)OCC)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: C=CCN(C1CCC1)N1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Yield: 12.8 %

Procedure:
2-(N′-Allyl-N′-cyclobutyl-hydrazino)-cyclopentanecarboxylic acid ethyl ester (333 mg, 1.25 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (416 mg, 1.25 mmol) was added followed by N-methylmorpholine (0.29 mL, 2.62 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg, 1.31 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with saturated aqueous brine solution (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (8 mL). A 21% w/w solution of sodium ethoxide in ethanol (1.40 mL, 3.75 mmol) was added. The reaction was refluxed for 16 h. The reaction was quenched via the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The organic layer was further washed with saturated aqueous sodium bicarbonate solution (2×20 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-5% methanol in dichloromethane) afford the desired product, cis-N-{3-[1-(allyl-cyclobutyl-amino)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (83 g, 0.16 mmol, 13%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.50-1.71 (7H, m), 1.80-2.33 (5H, m), 3.06 (3H, s), 3.67 (2H, s), 3.89-4.05 (2H, m), 5.05-5.12 (1H, m), 5.18-5.22 (1H, m), 5.82-5.90 (1H, m), 7.50-7.57 (3H, m), 10.18 (1H, bs). LC-MS (ESI) calcd for C23H29N5O6S2 535.64, found 536.4 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([S:12]([O-:15])(=[O:14])=[O:13])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH2:16]([N+:20]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]([S:12]([O-:15])(=[O:13])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32]
Reactant: CC(c1cccc([N+](=O)[O-])c1)S(=O)(=O)[O-]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCO
Product: CC(c1cccc(N)c1)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.2 g of 5% strength palladium on charcoal is added to a solution of 2.8 g of the laevorotatory isomer of tetra-n-butylammonium 1-(3-nitrophenyl)ethanesulphonate in 50 cm3 of ethanol. The suspension is stirred for 2 hours at a temperature of about 25° C. under a hydrogen atmosphere (100 kPa). The catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 2.8 g of the laevorotatory isomer of tetra-n-butylammonium 1-(3-aminophenyl)ethanesulphonate are thus obtained in the form of an oil, used as such in the subsequent syntheses.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)CC1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (364 mg, 1.31 mmol) was dissolved in DMF (10 ml). To the solution, sodium hydride (58 mg, 1.44 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (300 mg, 1.38 mmol) was added with cooling on ice-bath followed by stirring for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from methylene chloride-diisopropyl ether to afford tert-butyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperidine-1-carboxylate (248 mg, yield 41%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH:16]=O)=[CH:12][C:11]([CH2:18][CH2:19][CH3:20])=[N:10]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH3-]C#N.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([CH2:18][CH2:19][CH3:20])[CH:12]=2)[CH2:30][CH2:29]1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(OC)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(OC)cc2)n1

Procedure:
114 mg (66.0%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (107.73 mg, 0.396 mmol), 1-(2-fluorophenyl)piperazine (82.22 mL, 0.514 mmol), and NaCNBH3 (74.58 mg, 1.187 mmol).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([F:30])[C:14]([F:29])=[C:15]([C@:17]2([CH3:28])[CH2:22][C@@H:21]([C:23]([F:26])([F:25])[F:24])[O:20][C:19]([NH2:27])=[N:18]2)[CH:16]=1>>[F:29][C:14]1[C:13]([F:30])=[CH:12][C:11]([NH:10][C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][C:15]=1[C@:17]1([CH3:28])[CH2:22][C@@H:21]([C:23]([F:24])([F:25])[F:26])[O:20][C:19]([NH2:27])=[N:18]1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: COc1cccnc1Br
Product: COc1cccnc1Nc1cc(F)c(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Method B, Example 8 above, but using 2-bromo-3-methoxypyridine and (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine in step 2. MS m/z=417 [M+H]+. Calculated for C18H17F5N4O2: 416.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:20]4[N:24]([CH3:25])[C:23](S)=[N:22][N:21]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([CH3:34])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[N+]([O-])(O)=O.O>[OH2:19].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([CH3:34])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nnc(S)n3C)ccc2n1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Product: Cc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nncn3C)ccc2n1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 101.3 %

Procedure:
A mixture of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)-2-methyl-6-quinolinemethanol (0.0020 mol), obtained in Example B14a, in THF (5 ml) was added dropwise at 5° C. to a mixture of sodium nitrite (0.0020 mol) in nitric acid (2 ml) and water (2 ml). The mixture was stirred at 5° C. for 5 minutes, poured out into potassium carbonate 10% and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over kromasil 10 μm (eluent: CH2Cl2/CH3OH; 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.5 g (53%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-methyl-α-(4-methyl-4H-1,2,4-triazol-3-yl)-6-quinolinemethanol monohydrate, mp. 150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH:5]=[C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=O)[O:7]1.O.[NH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8](=[O:7])[NH:22][N:21]=1
Reactant: Nc1cc(C=C2OC(=O)C3=C2CCCC3)ccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Temperature: 0 °C

Procedure:
To a solution of EXAMPLE 2B (1.42 g) in ethanol (10 mL) was added hydrazine monohydrate (0.27 mL). The mixture stirred at reflux for 1 hour, cooled to 0° C., and filtered. The solid was washed with water and dried. 1H NMR (CD3OD) δ 1.63-1.75 (m, 4H), 2.36-2.45 (m, 2H), 2.46-2.53 (m, 2H), 3.84 (s, 2H), 6.42-6.49 (m, 1H), 6.64 (dd, J=8.6, 2.2 Hz, 1H), 6.86 (dd, J=11.2, 8.1 Hz, 1H).