Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][OH:37])=[CH:31][CH:30]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][OH:37])=[CH:31][CH:30]=3)[C:8]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(Nc3ccc(CCO)cc3)c21
Yield: 87.2 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.124 g, 0.28 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.042 g, 0.31 mmol) to afford the title compound (0.105 g, 87%) as a white solid. MW=429.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.77 (s, 1H), 8.22-8.17 (m, 2H), 7.65-7.61 (m, 1H), 7.58-7.52 (m, 3H), 7.29 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.77-3.71 (m, 2H), 3.67-3.61 (m, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 430 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].[C:12]([C:14](C#N)=[C:15]([C:18]#[N:19])[C:16]#[N:17])#[N:13]>C(O)C>[NH2:19][C:18]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:14]([C:12]#[N:13])[C:15]=1[C:16]#[N:17]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C#N
Yield: 41.7 %

Procedure:
A mixture of 2,4,6-trichlorophenylhydrazine (21.1 g) and tetracyanoethylene (13.3 g) in ethanol (100 ml) was heated at reflux for 15 minutes. The reaction mixture was cooled and the solid precipitate was filtered off and washed with diethyl ether to give 5-amino-3,4-dicyano-1-(2,4,6-trichlorophenyl)pyrazole (13 g), as a buff colored solid, m.p. 267°-271° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17]1[N:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([N+:30]([O-])=O)[CH:24]=3)=[CH:19][CH:18]=1)[CH2:9]2.CC#N.O>CO.[OH-].[OH-].[Pd+2]>[NH:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:20]3[N:21]=[N:22][C:17]([O:16][C@@H:10]4[CH:11]5[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]5)[CH2:9]4)=[CH:18][CH:19]=3)=[CH:24][C:25]=2[N:30]=[CH:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: c1nc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The product of Example 29B (29 mg, 0.064 mmol) was dissolved in 2.0 mL of methanol and 6 mg of Pd(OH)2/C (Aldrich, 10 wt %) was added. The mixture was stirred under 50 psi of H2 for 30 min. The solution was filtered through a nylon membrane and concentrated. The residue was dissolved in DMF (0.25 mL) and treated with excess triethylorthoformate (0.1 mL). The solution was heated at 80° C. for 2 h, then cooled down to ambient temperature and stirred for 4 h. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (13 mg, 0.04 mmol, 63%). 1H NMR (300 MHz, CD3OD) δ 1.57 (m, 1H), 1.73-1.94 (m, 2H), 2.08 (m, 1H), 2.34 (td, J=6.4, 3.6 Hz, 1H), 2.80-3.03 (m, 6H), 3.50 (ddd, J=14.5, 8.1, 1.5 Hz, 1H), 5.32 (m, 1H), 7.28 (d, J=9.2 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 8.11 (d, J=9.2 Hz, 1H), 8.22 (s, 1H), 8.25 (s, 1H) ppm; MS (DCI/NH3): m/z 322 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[C:25]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:26]=[C:27]([F:29])[CH:28]=2)OC1>>[F:29][C:27]1[CH:28]=[C:23]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)[CH:24]=[C:25]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=1
Reactant: CC1(C)COB(c2cc(F)cc(-c3cccnc3)c2)OC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1cc(-c2cccnc2)cc(-c2ccnc3nc(C(F)(F)F)ccc23)c1
Yield: 23.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 3-[3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-5-fluorophenyl]pyridine (80 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(3-fluoro-5-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (19 mg, 24%). δH (360 MHz, CDCl3) 7.24-7.63 (1H, m), 7.41-7.45 (1H, m), 7.48-7.52 (2H, m), 7.63 (1H, d, J 4.6), 7.86 (1H, d, J 8.8), 7.92 (1H, dt, J 8.1 and 1.9), 8.55 (1H, d, J 8.8), 8.69 (1H, dd, J 1.6 and 4.7), 8.90 (1H, d, J 1.8), 9.32 (1H, d, J 4.6). m/z (ES+) 370 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[CH:7]2.O=P(Cl)(Cl)[Cl:25].[Cl-].C([NH+](CC)CC)C>C(#N)C>[Cl:25][C:9]1[C:8]([CH3:13])=[CH:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(OCCN3CCCCC3)ccc(Cl)c2[nH]c1=O
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc2c(OCCN3CCCCC3)ccc(Cl)c2nc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
8-chloro-3-methyl-5-(2-(piperidin-1-yl)ethoxy)quinolin-2(1H)-one (160 mg, 0.5 mmol, 1 eq.) was placed in acetonitrile (1.2 mL) in the presence of POCl3 (233 μL, 2.5 mmol, 5 eq.) and triethylammonium chloride (570 mg, 2.5 mmol, 5 eq.). The reaction mixture was stirred at 120° C. during 3 hours. The mixture was then concentrated under reduced pressure and, after adding water to the residue (5 mL), was stirred at room temperature during 30 minutes. Then the resulting precipitate was washed with water and filtered to give 2,8-dichloro-3-methyl-5-(2-(piperidin-1-yl)ethoxy)quinoline (170 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH3:10])[C:7]([C:11]2[N:15]3[N:16]=[C:17](Cl)[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].O1CCOCC1.O.[NH2:28][NH2:29]>CO>[N+:1]([C:4]1[N:8]([CH2:9][CH3:10])[C:7]([C:11]2[N:15]3[N:16]=[C:17]([NH:28][NH2:29])[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: NN
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(NN)nn12

Procedure:
3 g. 3-(5-nitro-1-ethyl-2-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were dissolved in 30 ml. of a mixture of dioxan and methanol (1:1) and 3 ml. hydrazine hydrate were added thereto at 20° - 25° C., while stirring. The reaction mixture was further stirred for 45 minutes and the separated crystals were filtered off with suction, washed with a mixture of dioxan and methanol (1:1) and dried in a vacuum at 120° C. There was thus obtained 0.66 g. of the desired 3-(5-nitro-1-ethyl-2-imidazolyl)-6-hydrazino-s-triazolo[4,3-b]pyridazine which melts, with foaming up, at 216° - 223° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[BrH:17]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: Br
Agent: O=S(=O)(O)O
Product: BrCCCCc1ccccc1
Temperature: 0 °C

Procedure:
To 3.2 g of 4-phenyl-1-butanol, were added 1.0 g of concentrated sulfuric acid and 5.5 g of 47% aqueous solution of hydrobromic acid, and the resultant solution was stirred for 5 hours at 140-150° C. while applying heating. After completed the reaction, the solution was then poured into ice-water and extracted with ethyl acetate. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was distillated under reduced pressure, thereby affording 2.7 g of 4-phenyl-1-bromobutane.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:7]([O:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:8]([C:12]([CH3:16])=[C:13]([Cl:15])[CH:14]=1)[C:9]([OH:11])=[O:10])(=[O:5])[CH3:4]>CO>[C:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][O:17][C:7]1[C:6]([CH:3]([OH:5])[CH3:4])=[CH:14][C:13]([Cl:15])=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10])=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CC(=O)c1cc(Cl)c(C)c(C(=O)O)c1OCCNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Cl)cc(C(C)O)c(OCCNC(=O)OC(C)(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Sodium tetrahydroborate (6.1 mg, 0.16 mmol) was added to a mixture of 3-acetyl-2-{2-[(tert-butoxycarbonyl)amino]ethoxy}-5-chloro-6-methylbenzoic acid (40 mg, 0.1 mmol) in methanol (0.50 mL) at 0° C. and the reaction was stirred at room temperature for 1 hour. The solvent was removed and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, adjusted the pH to 5 with 1 N hydrogen chloride solution, washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired compound (30 mg, 70%). LCMS calculated for C17H24ClNO6Na (M+Na)+: m/z=396.1; found: 396.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:14]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:15]1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc(-c2ccoc2)cc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixed solution of 1-(3-bromophenyl)-piperazine (100 mg, 0.415 mmol), 3-furylboronic acid (69.6 mg, 0.622 mmol), tetrakis(triphenylphosphine)palladium (57.5 mg, 0.050 mmol), 2N aqueous solution of sodium carbonate (1.66 ml, 3.32 mmol) in toluene (4.0 ml) was stirred at 95° C. for 14 hours under a nitrogen atmosphere. After cooling to room temperature, water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give the titled compound 45.4 mg (47.9%) as an oil.
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)([CH3:7])[CH2:3][CH2:4][CH2:5]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12>C1COCC1>[CH3:1][C:2]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]=[CH:9]1)([CH3:7])[CH2:3][CH2:4][CH2:5][N:54]1[C:50](=[O:60])[C:51]2[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:53]1=[O:55]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(CCCO)n1cnc(-c2cccnc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(CCCN1C(=O)c2ccccc2C1=O)n1cnc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 4-Methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentan-1-ol (1 eq) in THF (20 mL) was added dropwise diethyl azodicarboxylate (1.1 eq), triphenyl phosphine (1.1 eq) and phtalimide (1.1 eq). The yellow solution was stirred at room temperature overnight and the solution was concentrated. The crude product was directly purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH and 0.1% TEA to yield 2-[4-Methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentyl]-isoindole-1,3-dione (66%). MH+(375).
Reaction SMILES: [CH2:1]([C:8]1([N:34]([CH3:36])[CH3:35])[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[Si](CC)(CC)CC)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][CH2:16][CH2:15][C:11]2([OH:14])[CH2:12][CH2:13][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([N:34]([CH3:36])[CH3:35])[CH2:9][CH2:10]2)=[CH:19]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(Cc2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1(Cc2ccccc2)CCC(O)(CCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-benzyl-4-dimethylamino-1-[3-(2-(triethylsilyl)-1H-indol-3-yl)propyl]cyclohexanol (2.50 g, 4.95 mmol) in anhydrous tetrahydrofuran (25 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (6.25 g, 19.8 mmol), boiled with reflux for 7 h and then stirred overnight at room temperature. Since the conversion was not yet complete, the reaction mixture was boiled with reflux for a further 7 h and then stirred over the weekend at room temperature. The reaction mixture was concentrated to low volume in a vacuum and the residue purified by means of flash chromatography (400 g, 20×7.5 cm) with dichloromethane/methanol (95:5+1% conc. aqueous ammonia).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C(F)(F)F)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:36][NH:37][CH3:38].C1COCC1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[CH3:36][N:37]([CH3:38])[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CNC
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Yield: 30 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.12 mmol) and 2M dimethyl amine in THF (0.3 mL, 0.60 mmol) were allowed to react in the presence of K2CO3 (84.6 mg, 0.24 mmol) and NaI (Cat. 5 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (17.1 mg, 30%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([F:27])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:28]C(=O)C2C=CC=CC=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:28][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([F:27])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:9]=1
Reactant: CC(C)(O)c1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(C#N)s3)C2)ncc1F
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(O)c1nc(N2C[C@H]3CSC(N)=N[C@@]3(c3ccc(C#N)s3)C2)ncc1F
Temperature: 55 °C
Yield: 89.5 %

Procedure:
To a stirred solution of N-{(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-6-[5-fluoro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl]-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl}benzamide (364 mg, 0.697 mmol) in ethanol (14 mL) is added pyridine (563 μL, 6.96 mmol) and O-methylhydroxylamine hydrochloride (582 mg, 6.96 mmol). The solution is heated to 55° C. under an atmosphere of nitrogen for 21 hours. The resulting solution is allowed to cool for a few minutes then concentrated under reduced pressure. Dichloromethane (30 mL) is added and again the solution is concentrated under reduced pressure. The residue is diluted with ethyl acetate (50 mL), water (25 mL), and saturated aqueous sodium bicarbonate (10 mL). The phases are separated and the ethyl acetate phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, eluting with dichloromethane/ethyl acetate, 70:30 for 20 minutes, and then a gradient to 0:100 to give the title compound (261 mg, 90%) as a white foam. MS/ES (m/z) 419.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:24]1[CH2:29][O:28][CH:27]=[CH:26][CH2:25]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][O:12][CH:27]1[CH2:26][CH2:25][CH2:24][CH2:29][O:28]1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(CO)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(COC2CCCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution of (2-fluoro-4-nitrophenyl)methanol (755 mg, 4.42 mmol) in 10 mL of DCM was added TsOH (100 mg, 0.13 mmol) and DHP (408 mg, 4.86 mmol). After stirring at RT for 16 hr, the mixture was concentrated. The residue was partitioned between 100 mL of EA and 100 mL of brine. The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, concentrated and purified by chromatography column on silica gel (elution with PE/EA) to afford 900 mg (80%) of 2-(2-fluoro-4-nitrobenzyloxy)-tetrahydro-2H-pyran as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J=3.0, 6.2 Hz, 1H), 8.26-8.30 (m, 1H), 7.53 (t, J=9.2 Hz, 1H), 4.82-4.76 (m, 2H), 4.62 (d, J=12.0 Hz, 1H), 3.80-3.74 (m, 1H), 3.52-3.47 (m, 1H), 1.76-1.64 (m, 2H) and 1.58-1.45 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([O:11][OH:12])([CH2:4][CH2:5][C:6]([CH3:10])([O:8][OH:9])[CH3:7])[CH3:3].Cl[Si:14](Cl)([CH3:16])[CH3:15].N>CCOCC>[CH3:15][Si:14]1([CH3:16])[O:12][O:11][C:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][C:6]([CH3:10])([CH3:7])[O:8][O:9]1
Reactant: CC(C)(CCC(C)(C)OO)OO
Reactant: C[Si](C)(Cl)Cl
Agent: N
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)OO[Si](C)(C)OO1
Temperature: 5 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
Into a one liter flask equipped with a motorized stirrer is added 0.15 mole (25.17g, 98.47% pure) of 2,5-dimethyl-2,5-dihydroperoxyhexane and 0.15 mole (19.35g) of dichlorodimethylsilane in 400 ml of anhydrous ether. This mixture is cooled to about 5° C., and ammonia gas is introduced cautiously. Reaction temperature is maintained between 5° and 10° C. by use of an ice bath and by adjusting the rate of gas introduction. Ammonia addition is continued for 30 to 40 minutes until the exothermic reaction has stopped. The reaction mixture is then stirred at room temperature for an additional 3 hours. The salts are removed by filtration and the ether is removed by distillation. The crude yield of a colorless solid was 26.7 grams. To purify the crude product hexane is added and the mixture is filtered to remove a small amount of insoluble, unreacted 2,5-dimethyl-2,5-dihydroperoxyhexane. Evaporation of the hexane yields 21.9 grams (62.4%) of 3,3,6,6,9,9-hexamethyl-1,2,4,5-tetraoxa-3-silacyclononane having a melting point of 44.5°-48° C. The product is 95.5% pure based upon active oxygen (A.O.) analysis wherein theoretical A.O. is 13.67% and A.O. found is 13.05%. Analysis of the product supports the structure ##STR4## as follows: (1) I.R. spectrum indicates no terminal hydroperoxy (--OOH) groups; (2) the molecular weight corresponds to a cyclic structure; and (3) various chromatographic analyses verify a very non-polar species.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([C:18](OC)=[O:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH2:18][OH:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a solution of methyl 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate (3.0 g) in absolute tetrahydrofuran (40 mL) was added dropwise a 1.5 mol/L solution (21.0 mL) of diisobutylaluminum hydride in toluene at −78° C. The mixture was further stirred at the same temperature for 2 hr. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as crystals (yield 1.07 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].N[CH2:34][C@H](O)C>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH3:34])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: C[C@@H](O)CN
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 58 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using (R)-(−)-1-amino-2-propanol (0.98 mL, 12.45 mmol) as the amine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (2.70 g, 58%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 7.93 (dd, 1H, J=1.6 Hz), 7.69 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.94 (m, 1H), 3.39 (m, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.9 (d, 3H, J=6.4 Hz); ES-HRMS m/z 478.1322 (M+H C23H23ClF2N3O4 requires 478.1340). Both (+) and (−) atropomers will be resolved and characterized.