Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[CH3:9][O:10][C:11]1[C:12]([O:41][CH3:42])=[CH:13][C:14]2[N:20](COCC[Si](C)(C)C)[C:19](=O)[C@@H:18]3[CH2:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:32][N:17]3[C:16](=[O:39])[C:15]=2[CH:40]=1.CCO.C1COCC1>C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>[CH3:9][O:10][C:11]1[C:12]([O:41][CH3:42])=[CH:13][C:14]2[N:20]=[CH:19][C@@H:18]3[CH2:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:32][N:17]3[C:16](=[O:39])[C:15]=2[CH:40]=1
Reactant: COc1cc2c(cc1OC)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(c3ccccc3)=CN1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)N1C=C(c3ccccc3)C[C@H]1C=N2
Yield: 101.3 %

Procedure:
Solid sodium tetraborohydride (287 mg, 7.6 mmol, 10 equiv.) was added in one portion to a rapidly stirred solution of 180 (365 mg, 0.76 mmol) in a mixture of anhydrous EtOH (8 mL) and anhydrous THF (8 mL) at 0° C. The reaction mixture was allowed to stir at room temperature for 1 hour at room temperature at which time TLC (5% methanol; 95% chloroform) revealed the complete consumption of starting material. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×100 mL), brine (100 mL) and dried over magnesium sulphate. Filtration and evaporation of excess solvent afforded the crude product as a brown viscous oil. Flash chromatography (silica gel, 70% 40-60° petroleum ether, 30% ethyl acetate yield the final product (181) (271 mg, 0.77 mmol, 74%). 1H NMR (270 MHz, CDCl3) δ7.89 (d, 1H, J=4.03 Hz), 7.53 (s, 1H), 7.51 (s, 1H), 7.40-7.20 (m, 5H), 6.83 (s, 1H), 4.50-4.35 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.66-3.36 (m, 2H). 13C NMR (67.8 MHz, CDCl3) δ162.6, 161.5, 151.9, 147.8, 140.4, 133.3, 128.8, 127.6, 127.1, 124.9, 123.6, 119.0, 111.6, 109.8, 56.2, 53.9, 35.4. HRMS (FAB) calcd for C20H19N2O3 (M+.+1) 335.1398, found 335.1396.
Reaction SMILES: [S:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([OH:4])(=[O:3])=[O:2].OO.[OH:27]P(O)(O)=O>>[S:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][OH:27])=[O:15])([OH:4])(=[O:3])=[O:2]
Reactant: O=P(O)(O)O
Reactant: CCCCCCCCC(CCCCCCCCC(=O)O)S(=O)(=O)O
Agent: OO
Product: CCCCCCCCC(CCCCCCCCC(=O)OO)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a 2.0 g mixture of 9 or 10-Sulfostearic acid was added 2.0 g of 50% H2O2. The mixture was stirred at room temperature until all the solid was dissolved. Then, 2.0 g of 75% H3PO4 was added, and the resulting solution was stirred at room temperature overnight. No attempt was made to isolate the pure 9 or 10-sulfoperoxystearic acid from solution. 13C NMR (D2O) of the solution showed a peracid peak (COOOH) at 174 ppm and the parent the carboxylic acid peak at 178 ppm. The iodometric titration (QATM-202) indicated 18.96% of sulfoperoxystearic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one at −78° C. then rt.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([S:35]([CH2:37][C:38]5[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][CH:39]=5)=[O:36])=[CH:31][CH:30]=4)=[O:27])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:47]1([CH:50]=O)[CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:50][CH:47]4[CH2:49][CH2:48]4)[CH2:24][CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([S:35]([CH2:37][C:38]5[N:42]([CH2:43][CH2:44][CH3:45])[CH:41]=[N:40][CH:39]=5)=[O:36])=[CH:33][CH:34]=4)=[O:27])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CC1CC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of (−)-8-(4-(2-butoxyethoxy)phenyl)-N-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (120 mg) in 1,2-dichloroethane (10 ml), cyclopropanecarboxaldehyde (65.6 mg) and sodium triacetoxyborohydride (119 mg) were added. The mixture was stirred at room temperature for overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, and dried over MgSO4. The volatile materials were removed in vacuo and the residue was purified by column chromatography (basic silicagel, ethyl acetate) to give (−)-8-(4-(2-butoxyethoxy)phenyl)-1-(cyclopropylmethyl)-N-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (55 mg)(compound 57) as a yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16](SC)[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N[N:29]([CH2:33][CH2:34][CH2:35][CH3:36])NCC)C>>[CH2:14]([N:21]([CH2:22][CH3:11])[CH2:36][CH2:35][CH2:34][CH2:33][NH:29][C:16]1[N:17]=[N:18][C:13]2[CH:12]=[C:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:14]=2[N:15]=1)[CH3:13]
Reactant: CCCCN(NCC)NCC
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2nnc(SC)nc21
Product: CCN(CC)CCCCNc1nnc2cc(-c3cc(OC)cc(OC)c3)c(=O)n(CC)c2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 166.6 %

Procedure:
To 300 mg (0.84 mmol) of 7-(3,5-dimethoxy-phenyl)-5-ethyl-3-methylsulfanyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-one was added 1.25 g (8.7 mmol) of N,N-diethylaminobutylamine. The reaction mixture was warmed at 70° C. for 1.5 hours and cooled to room temperature. A seed crystal was added to the solution, and it was set overnight. The resulting crystalline material was collected, washed with 1:1 diethyl ether/hexane and dried under house vacuum to give 318 mg (83%) of the title compound as pale yellow solid. Mp=120-121° C.(dec); when placed in a 119° C. melting point apparatus. MS (APCI) (m+1)/z 455.2.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([O:22]C)=[CH:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.Cl.C>>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([CH2:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1)=[O:22]
Reactant: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Cl
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Yield: 89.2 %

Procedure:
In this Example, 8,14-dihydro-thebaine (6.00 g, 19.14 mmol) was mixed with 50 ml of approx. 2.45 N hydrochloric acid (122.5 mmol, prepared by mixing concentrated hydrochloric acid (10 ml) with DI water (40 ml)) at room temperature with stirring. The homogeneous light yellow colored solution was stirred overnight. Decolorizing charcoal (Darco, 0.3 g) was added to the mixture and the reaction was stirred for 1 hour and then filtered. The charcoal was washed with DI water (2×5 ml). The combined acid phases were cooled to <5° C. and the pH was adjusted to 9.65 with concentrated (28.0-30.0%) ammonium hydroxide solution (approx. 13 ml). The solid was filtered and washed with 2×5 ml of DI water. The product was dried at 60° C. under 22″ Hg vacuum until constant weight to give hydrocodone as a white amorphous solid (5.11 g, 89.2% yield, 96.3 wt % by assay).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)C>[CH2:23]([NH:2][CH2:3][CH2:4][C:5]1[N:9]([C@@H:10]2[CH2:19][C:18]3[C:13](=[C:14]([F:21])[CH:15]=[C:16]([F:20])[CH:17]=3)[O:12][CH2:11]2)[C:8](=[S:22])[NH:7][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2

Procedure:
A 250 L reactor was charged with 12.25 kg of (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride, 114.82 kg of 2-propanol was added and the mixture was stirred at maximum speed (140 rpm). Through a dropping funnel 1.856 kg of benzaldehyde was added followed by 3.945 kg of sodium triacetoxyborohydride in five portions at Ti=20-25° C. according to the following addition order:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
In DMF (100 ml) was dissolved 4-(2-bromoethyl)nitrobenzene (25.0 g), and to the solution were added piperidine (12.9 ml) and potassium carbonate (18.0 g). The mixture was stirred at 70° C. for 15 hours, and to the mixture was added water (900 ml), and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-[2-(4-nitro-phenyl)ethyl]piperidine (24.8 g) as orange oil.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[CH2:31]1COC[CH2:32]1.[Cl-].[NH4+]>C(OCC)C.[N+]([O-])([O-])=O.[Ag+]>[CH2:31]([CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH2:4][CH2:3]1)[CH3:32]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCC1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture comprising tert-butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (200 mg, 0.429 mmol) and silver nitrate (0.728 mg, 4.29 μmol) in diethyl ether (4 ml) under nitrogen at RT was added 1-Methylmagnesium bromide in THF (0.557 ml, 0.557 mmol). The reaction mixture was left to stir at RT for 3 h under an atmosphere of nitrogen. The mixture was poured into a saturated ammonium chloride solution (10 ml) and extracted with EtOAc (2×10 ml). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-30% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[CH3:28][N+:29](C)=[C:30](N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CNC.C1COCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:28][N:29]([CH3:30])[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(O)c1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
The 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoic acid (0.89 g, 3.1 mol) was treated with N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.8 g, 4.6 mmol), N,N-diisopropylethylamine (1.6 mL, 9.3 mmol) and 2 M dimethylamine in THF (3.0 mL, 6.0 mmol), in N,N-dimethylformamide (20 mL) at r.t. The reaction was complete after stirring for 2 h. This was taken up in ethyl acetate and washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as an oily residue. The product was purified by flash chromatography on a silica gel column eluting hexane: ethyl acetate gradient to give tert-butyl 1-(dimethylamino)-3-(3-hydroxyphenyl)-1-oxopropan-2-ylcarbamate (0.75 g, 78%) as an off white solid. Analytical LCMS (M+H-Boc)+: m/z=208.9.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9]3[N:10]=[C:11]([O:21][CH:22]4[CH2:39][CH:38]5[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]6[C:35]([C:41](O)=[O:42])([NH:36][C:37]5=[O:40])[CH2:34]6)[CH2:23]4)[C:12]4[C:17]([CH:18]=3)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=4)[S:7][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]([C:9]3[N:10]=[C:11]([O:21][CH:22]4[CH2:39][CH:38]5[CH:24]([C:25](=[O:45])[N:26]([CH3:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]6[C:35]([C:41]([NH:64][S:61]([CH:58]7[CH2:60][CH2:59]7)(=[O:63])=[O:62])=[O:42])([NH:36][C:37]5=[O:40])[CH2:34]6)[CH2:23]4)[C:12]4[C:17]([CH:18]=3)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=4)[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3nc(C4CC4)cs3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A mixture of 29 (91 mg, 0.14 mmol) and 1,1′-carbonyldiimidazole (CDI) (47 mg, 0.29 mmol) in dry THF (7 mL) was heated at reflux for 2 h under nitrogen. LCMS analysis shows one peak of the intermediate (RT=5.37). Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (52 mg, 0.43 mmol) was added. Then, DBU (50 μL, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, and then heated at 55° C. for 24 h. The solvent was evaporated, and the residue partitioned between AcOEt ethyl acetate and acidic water (pH=3). The crude material was purified by column chromatography (ethyl acetateAcOEt/CH2Cl2/pPetroleum ether, 1:1:1). The residue was crystallized in diethyl ether, filtered to give the target compound contaminated with the cyclopropylsulfonamide. This material was triturated in 3 mL of water, filtered, washed with water and dried overnight with the high vacuum pump to give 60 mg (57%) of the target compound 30 as a slightly yellow powder: m/z=734 (M+H)+, 1H-NMR (CDCl3): 10.94 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 8.00 (s, 1H), 7.12-7.15 (m, 2H), 6.91 (s, 1H), 6.35 (s, 1H), 5.74-5.77 (m, 1H), 5.63-5.69 (m, 1H), 5.06 (t, J=10.4 Hz, 1H), 4.60 (t, J=12.3 Hz, 1H), 3.93 (s, 3H), 3.35-3.42 (m, 2H), 3.04 (s, 3H), 2.89-2.96 (m, 2H), 2.52-2.52 (m, 2H), 2.37-2.45 (m, 2H), 2.10-2.32 (m, 2H), 1.61-1.93 (m, 4H), 1.3-1.51 (m, 4H), 0.90-1.30 (m, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>CS(C)=O.CCOC(C)=O>[N+:32]([C:29]1[CH:30]=[CH:31][C:22]([NH:14][CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25])([O-:34])=[O:33]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: NCC1CCN(c2ccncc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 17 h
Yield: 42 %

Procedure:
A solution of 1-(4-pyridyl)piperidine-4-methylamine (1.13 g, 5.92 mmol) and potassium carbonate (816 mg, 5.92 mmol) in dimethyl sulfoxide (12 mL) was treated with methyl 2-fluoro-5-nitrobenzoate (1.18 g, 5.92 mmol). After 17 h, the mixture was cooled, diluted with EtOAc, and filtered. The filtrate was concentrated and partitioned between EtOAc and 10% HCl. The aqueous layer was washed with EtOAc (1×), pH adjusted (>10) by addition of NaOH, and washed with EtOAC (3×). The combined extracts were washed with H2O (5×), brine, dried (sodium sulfate), and concentrated. The residue was purified by column chromatography (SiO2, 1 to 3% [2 N NH3 in MeOH]:chloroform) yielding 920 mg (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[O:50]1[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][C@@H:58]([NH:67][C:68]2[CH:73]=[CH:72][C:71]([S:74]([NH2:77])(=[O:76])=[O:75])=[CH:70][C:69]=2[S:78]([C:81]([F:84])([F:83])[F:82])(=[O:80])=[O:79])[CH2:59][S:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:52][CH2:51]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:34])([CH3:35])[CH3:36])=[O:32])[CH:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:77][S:74]([C:71]4[CH:72]=[CH:73][C:68]([NH:67][C@H:58]([CH2:57][CH2:56][N:53]5[CH2:54][CH2:55][O:50][CH2:51][CH2:52]5)[CH2:59][S:60][C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)=[C:69]([S:78]([C:81]([F:83])([F:84])[F:82])(=[O:80])=[O:79])[CH:70]=4)(=[O:75])=[O:76])=[O:26])=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 130, 0.150 g, 0.29 mmol), DMAP (70 mg, 0.57 mmol), and EDC (0.110 g, 0.57 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (4.0 ml) and DIPEA (0.10 ml, 0.57 mmol) were added, and the solution was stirred at r.t for 10 minutes. A solution of (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 0.158 g, 0.29 mmol) in DCM (1.6 ml) was added to the solution and the reaction mixture was stirred at r.t overnight. The mixture was diluted with DCM and washed with 1N sodium bisulfate (aq.) followed by a saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue which was purified by column chromatography (ISCO, silica gel column, eluting with 0→100% DCM/MeOH/NH3 (10:1:0.1 v/v/v)) to provide the title compound (0.21 g, yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.C(OCC)(=O)C>[NH:31]([C:32]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](N1CCN(C(=O)Nc2ccccc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a ice cooled solution of (2R,3R)-2-(2,4-diflurophenyl)-3-(piperazin-1-yl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol 2 (150 mg, 0.44 mmol) in acetonitrile (10 ml) was added phenylisocyanate (60 mg, 0.5 mmol) in acetonitrile (4 ml). The reaction mixture was stirred at 0° C. for 2 h, diluted with 20 ml of ethyl acetate and successively washed with water, brine and dried over sodium sulphate. This organic extract was concentrated and the residue was purified by passing through a column of silica gel (hexane/EtOAc) to give the title compound as a colorless solid (170 mg, 84%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]2[N:17]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[O:19][C:13]=2[CH:12]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[F:7][C:8]1[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]2[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([O:27][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:24]([CH3:26])[CH:25]=3)[O:19][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
110 mg of potassium carbonate were added to a solution of 70 mg of 4-[6-(2-fluorophenoxy)oxazolo[4,5-c]pyridin-2-yl]-2,6-dimethylphenol in 1 ml of dimethylformamide, and 51 mg of tert-butyl bromoacetate were then added. The mixture was stirred at room temperature for 16 h. The reaction mixture was then added to water and extracted twice with ethyl acetate. The collected organic phases were dried and concentrated. This gave 93 mg (100%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: O=S(=O)(c1ccc(F)cc1)n1ccc2ccccc21
Yield: 81 %

Procedure:
The title compound was prepared from 4-fluoro-benzene sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 81%; mp 135-137° C.; 1H NMR (CDCl3) δ 7.86-7.99 (m, 3H), 7.51-7.54 (m, 2H), 7.19-7.35 (m, 2H), 7.05-7.12 (m, 2H), 6.66-6.68 (dd, J=4 Hz, 1H); 13C NMR (CDCl3) δ 168.1, 164.0, 135.2, 134.7, 134.6, 131.2, 130.1, 129.9, 126.6, 125.2, 123.9, 121.9, 117.2, 116.9, 113.9, 110.0; MS (ES+) m/z 275.99 (M++1).