Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]>CS(C)=O>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19]2[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:4]=1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 85 %

Procedure:
p-Hydroxybenzotrifluoride (0.22 g, 1.36 mmol), powdered potassium carbonate (0.185 g, 1.34 mmol), and methyl 5-chloro-2-nitrobenzoate (0.288 g, 1.34 mmol) were heated at 70° C. under a nitrogen atmosphere in 3 ml of dimethyl sulfoxide. After 50 minutes, an aliquot was quenched in methanolic HCl. (By gas chromatography, the reaction is 45% complete.) After 18 hours (overnight), the reaction mixture was cooled to room temperature, diluted with water, and extracted with ether. The organic extracts are shaken with brine, dried (MgSO4) and concentrated to afford methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate in 85% yield. Gas chromatography showed no starting phenol remained. Step B--Methyl 5-(2-chloro-4-trifluoromethylphenoxy) -2-nitrobenzoate
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[C:27]1[NH:32][C:31](=[O:33])[C:30]2=[C:34]([CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:35]=[C:36]([CH3:37])[N:29]2[N:28]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[C:27]1[N:32]([CH2:2][C:3]([O:5][CH3:6])=[O:4])[C:31](=[O:33])[C:30]2=[C:34]([CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:35]=[C:36]([CH3:37])[N:29]2[N:28]=1
Reactant: CCC(CC)c1cc(C)n2nc(-c3ccc(OC)cc3Cl)[nH]c(=O)c12
Reactant: COC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)n2nc(-c3ccc(OC)cc3Cl)n(CC(=O)OC)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl bromoacetate (0.14 mL), potassium carbonate (66 mg) and tetrabutylammonium iodide (12 mg) were added to the N,N-dimethylformamide solution (3 mL) of the compound prepared in Example 36 (109 mg), and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (with an automatic purifying equipment made in Yamazen corporation) to obtain a title compound (95 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:34]=[CH:35]\[CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28](/[CH:34]=[CH:35]\[CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC/C=C\[C@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC/C=C\[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 22 h
Yield: 43 %

Procedure:
To a stirred solution of 35.2 (0.047 g, 0.09 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting reaction mixture was stirred for 22 hours, and then was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted EtOAc, dried over MgSO4, filtered and concentrated. The product thus obtained was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 35 (19 mg, 42% yield) as a colorless oil. MS ESI (neg.) m/e: 979.5 (2M−H)+, 489.2 (M−H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:7][CH:8]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:16][C:15]1[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1csc(Nc2ncccc2OCc2ccccc2)n1)c1ccccc1
Reaction time: 2 h
Yield: 21.8 %

Procedure:
Crude 4-(2-aminoethyl)-N-(3-(benzyloxy)pyridin-2-yl)thiazol-2-amine (Example 134, Step A; 0.25 g, 0.766 mmol) was dissolved in DMF (10 mL), and triethylamine (0.427 ml, 3.06 mmol) was added, followed by benzoyl chloride (0.215 g, 1.53 mmol). The reaction mixture was stirred 2 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 2:3 hexane:ethyl acetate to provide the title compound (0.072 g, 21.8% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.85 (t, 2H), 3.58 (m, 2H), 5.26 (s, 2H), 6.69 (s, 1H), 6.89 (m, 1H), 7.32-7.59 (m, 9H), 7.82-7.87 (m, 3H), 8.55 (t, 1H), 9.95 (s, 1H).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:59])[CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:40]2[C:39]3[C:34](=[CH:35][C:36]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=3)[NH:33][C:32]=2[N:31]=[C:30]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52](=[N:57][OH:58])[C:53]([F:56])([F:55])[F:54])[CH:47]=2)[N:29]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:59])[CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:40]2[C:39]3[C:34](=[CH:35][C:36]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=3)[NH:33][C:32]=2[N:31]=[C:30]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52](=[N:57][O:58][S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:53]([F:54])([F:56])[F:55])[CH:47]=2)[N:29]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NOS(=O)(=O)c4ccc(C)cc4)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Ts-Cl (0.060 g, 0.315 mmol) was added portion-wise to a mixture of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.184 g, 0.274 mmol), DMAP (3.35 mg, 0.027 mmol) and triethylamine (0.048 mL, 0.342 mmol) in DCM (12 mL) to give a tan solution. After 1 hour, the reaction mixture was diluted with DCM (12 mL), washed with water (3×12 mL) and the organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (217 mg, 96% yield) as a tan foam: MS m/z 826.2 (M+H)+; HPLC 93.2% @ 220 nm and 91.3% @ 254 nm, RT=2.20 minutes.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=1.CN1CCOCC1>CN(C=O)C>[Br:35][C:33]1[CH:34]=[C:29]([NH:28][C:1](=[O:5])[CH2:2][CH3:3])[CH:30]=[N:31][CH:32]=1
Reactant: CCC(=O)O
Reactant: Nc1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of propionic acid (Sigma-Aldrich, St. Louis, USA) (1.5 eq, 8.4 mmol, 0.63 ml) in DMF (15 ml), HOBt (1.2 eq, 6.7 mmol, 0.910 g) and EDC hydrochloride (1.5 eq, 8.4 mmol, 1.65 g) are added. The resulting mixture is stirred for 1 h at r.t. Then 3-amino-5-bromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 5.6 mmol, 1.00 g) and N-methyl-morpholine (3 eq, 16.8 mmol, 1.85 ml) are added and stirring is continued for 18 h at r.t. The solvents are evaporated and the residue is purified by column chromatography (hexane/EtOAc) yielding the title compound; [M+H]+=230.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([Cl:26])=[CH:23]3)=[CH:18]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO>ClCCCl>[Cl:26][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][N:17]([S:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:16])=[O:15])[CH:18]=2)[CH:23]=1
Reactant: O=S(=O)(N1CCN(Cc2ccccc2)CC1)n1cc2ccc(Cl)cc2c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: O=S(=O)(N1CCNCC1)n1cc2ccc(Cl)cc2c1
Reaction time: 0.25 h

Procedure:
To a solution of 1-benzyl-4-[(5-chloroisoindol-2-yl)sulfonyl]piperazine (222 mg) in 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (81 mg) was added under ice cooling. The resulting mixture was stirred for 15 minutes and then heated under reflux for 1 hour. After cooling, anhydrous methanol was added to the residue obtained by distilling off the solvent under reduced pressure. The mixture was heated under reflux for 11 hours. After cooling, the residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (ethanol:dichloromethane=1:50 to 1:10), whereby the title compound (120 mg, 70%) was obtained.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:39]([CH:40]([OH:51])[C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)=[C:38]([CH:52]([CH3:54])[CH3:53])[CH:37]=[C:36]3[C:31]=2[C:32](=[O:57])[CH2:33][C:34]([CH3:56])([CH3:55])[O:35]3)=[CH:26][CH:25]=1>ClCCl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:39]([C:40](=[O:51])[C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[C:38]([CH:52]([CH3:53])[CH3:54])[CH:37]=[C:36]3[C:31]=2[C:32](=[O:57])[CH2:33][C:34]([CH3:55])([CH3:56])[O:35]3)=[CH:26][CH:25]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 4 h

Procedure:
At 0° C., 174 mg (410 μmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are added to a solution of 100 mg (207 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)-phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 21A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 4 h. The mixture is then diluted with dichloromethane and washed three times with 1 M aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:38])=[C:21]([NH:25][C:26](=[O:37])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=5)[CH:22]=[CH:23][CH:24]=4)[C:13]=3[CH:12]=[C:11]2[Br:39])(=O)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1COCC1>[Br:39][C:11]1[NH:10][C:14]2[N:15]=[CH:16][N:17]=[C:18]([C:19]3[C:20]([CH3:38])=[C:21]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:35])([CH3:36])[CH3:34])=[CH:29][CH:28]=4)[CH:22]=[CH:23][CH:24]=3)[C:13]=2[CH:12]=1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2c1cc(Br)n2S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 53 (3.82 g, 6.33 mmol) in THF (64 ml) was added a solution of potassium tert-butylate in THF (1 M, 9.49 ml, 9.49 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr, then an additional solution of potassium tert-butylate in THF (1 M, 2.00 ml, 2.00 mmol) was added and stirring was continued for an additional 1 hr. The reaction was quenched by addition of sat. aqueous NaHCO3 solution, and the mixture was extracted with EtOAc. The organic layer was dried, filtered, and evaporated to dryness. Purification by flash chromatography (silica gel, cyclohexane/EtOAc gradient) yielded Intermediate 54.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:28][C:29]([CH3:45])([CH3:44])[CH2:30][O:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33]>>[CH3:28][C:29]([CH3:45])([CH3:44])[CH2:30][O:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:40]=1)(=[O:34])=[O:33]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)COS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-Trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid 2,2-dimethyl-propyl ester was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (1.0 g, 2.5 mmol) and 3-(2,2-dimethyl-propyloxysulfonyl)-benzeneboronic acid (example F.4) (1.09 g, 4.0 mmol) according to the general procedure VI. Obtained as an off-white solid (1.28 g, 86%). MS (ISP) 595.7 [(M+H)+]; mp 168.5° C.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18].S(=O)(=O)(O)O>C(O)(=O)C>[Cl:10][C:11]1[C:12]([F:18])=[CH:13][C:14]([OH:17])=[C:15]([I:1])[CH:16]=1
Reactant: NC(=O)CCC(=O)NI
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1cc(F)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
To a suspension of N-iodosuccinamide (6.1 g, 27.3 mmol) in glacial acetic acid (23 mL) was added 4-chloro-3-fluorophenol (4.0 g, 27.3 mmol) and after 5 minutes sulphuric acid was added (0.5 mL, 8.2 mmol) and the reaction mixture was left to stir at room temperature for 16 hours. The reaction was quenched by addition of water (30 mL) and the compound was extracted into dichloromethane (3×30 mL). The combined organic layers were washed with 10% sodium metabisulphite aqueous solution (2×20 mL), then saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by flash column chromatography (silica, toluene) to afford the desired product as an oil (4.0 g, 54%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH2:34]1[C:37]2([CH2:40][NH:39][CH2:38]2)[CH2:36][O:35]1.C(=O)([O-])[O-].[K+].[K+].CC#N>C(Cl)Cl>[F:31][C:28]([F:29])([F:30])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][N:39]2[CH2:40][C:37]3([CH2:36][O:35][CH2:34]3)[CH2:38]2)=[CH:26][CH:25]=1)([OH:33])[CH3:32]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: C1NCC12COC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC3(COC3)C2)cc1)C(F)(F)F
Temperature: 100 °C
Yield: 31.9 %

Procedure:
A 10-mL microwave vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.140 g, 0.265 mmol, Intermediate B), 2-oxa-6-azaspiro[3.3]heptane (0.026 g, 0.265 mmol. ASW MedChem, Inc. New Brunswick, N.J.), potassium carbonate (0.040 g, 0.291 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 100° C. for 1 h. The mixture was diluted with 5 mL of CH2Cl2, filtered, and the filtrate was concentrated. The resulting oil was purified by column chromatography on silica gel (20-100% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(4-((2S)-2-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.045 g) as a mixture of two isomers:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[N:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=4)[CH:14]=[CH:15][C:16]=3[O:17][Si](C(C)(C)C)(C)C)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[N:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cn2)cc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Yield: 100 %

Procedure:
To a solution of 6-[3-(1-adamantyl)-4-t-butyldimethylsilanyloxyphenyl]-pyridin-3-carboxaldehyde (24.673 g, 0.0511 mol) in 330 mL of dry THF cooled to 0° C. was added dropwise 60.6 mL of 1.0 M solution of tetrabutylammonium fluoride in THF. After 10 minutes from the completion of the addition, the dark red solution was partitioned between EtOAc and 1 M HCl. The mixture was separated the organics were washed with brine, dried (MgSO4), filtered and evaporated. The resulting solid was dried under high vacuum to give 6-[3-(1-adamantyl)-4-hydroxy-phenyl]-pyridin-3-carboxaldehyde (100%). 1H NMR (300 MHz; CDCl3): δ 1.79 (brs, 6H), [2.09 (brs), 2.20 (s), 9 H], 6.47 (brs, 1H), 6.86 (d, J=8.1 Hz, 1H), 7.76 (dd, J1=8.1, J2=2.4 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 8.17 (dd, J1=8.1, J2=2.4 Hz, 1H), 9.06 (d, J=2.4 Hz, 1H), 10.09 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42]CC)[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.[Na+:48].[I-]>CCC(C)=O>[CH2:40]([O:39][P:38]([CH2:37][C:36]1[CH:46]=[CH:47][C:33]([NH:32][C:24]2[N:23]=[C:22]([NH:21][C:13]3[CH:12]=[CH:11][C:10]([C:8]4[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=4)=[C:18]4[C:14]=3[C:15](=[O:20])[N:16]([CH3:19])[CH2:17]4)[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][N:25]=2)=[CH:34][CH:35]=1)(=[O:42])[O-:45])[CH3:41].[Na+:48]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOP(=O)([O-])Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1

Procedure:
A mixture of Example 156 (172 mg, 0.255 mmol) in MEK (6 mL) was treated with of NaI (165 mg, 1.102 mmol) and irradiated on the microwave at 120° C. for 6 hours. The cooled reaction mixture was filtered, the solids were washed with ice cold acetone and dried in vacuo to afford the title compound as alight brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (br s, 1H), 9.72 (s, 1H), 9.19 (br s, 1H), 8.47 (br s, 1H), 8.40 (s, 1H), 8.19 (br s, 1H), 7.75 (br s, 1H), 7.28 (br s, 4H), 6.34 (br s, 1H), 4.63 (s, 2H), 4.20 (t, J=6.2 Hz, 2H), 3.60 (quin, J=7.1 Hz, 2H), 3.42-3.51 (m, 2H), 3.11 (s, 3H), 2.73 (d, J=19.5 Hz, 2H), 1.94 (quin, J=6.1 Hz, 2H), 0.94 (t, J=6.9 Hz, 3H). MS (ES+): m/z 646.20 (100) [MH+]; HPLC: tR=1.12 min (UPLC TOF, polar—3 min).
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[C:14]1([C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][NH2:1])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=NCc1sc2ccccc2c1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1sc2ccccc2c1-c1ccccc1
Temperature: 60 °C
Yield: 130.8 %

Procedure:
A solution of 2-azidomethyl-3-phenylbenzo[b]thiophene (244 mg, 0.92 mmol) in THF (10 mL) was treated with a solution of triphenylphosphine (302 mg, 1.15 mmol) in water (1 mL) under a nitrogen atmosphere. The mixture was heated to 60° C. for 2 h and then cooled to RT. Volatile were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording (3-phenylbenzo[b]thiophen-2-yl)methanamine (288 mg, quantitative). LCMS: RT 2.15 min [M-N3]+ 223.0
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COc1cc(NC(=O)Nc2cccc([N+](=O)[O-])c2)ccc1-c1cnco1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 600 mg (3.2 mmol) of 1D in 20 ml of methylene chloride was added, as a solid, 525 mg (3.2 mmol) of m-nitrophenylisocyanate. A voluminous precipitate was obtained. Stirring was continued overnight. The precipitate was filtered and washed with methylene chloride to afford 1.1 g (3.1 mmol, 97%) of 49A as a yellow solid.