Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[CH3:12][NH:13][C:14]1(C#N)[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1>O1CCCC1>[CH3:12][NH:13][C:14]1([C:11]2[N:7]([CH3:6])[N:8]=[CH:9][N:10]=2)[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1
Reactant: Cn1cncn1
Reactant: CNC1(C#N)CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC1(c2ncnn2C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Butyllithium (2.5 M in hexane, 9.2 ml, 23.0 mmole) was added to a reaction vessel under an argon atmosphere and cooled to −78° C. 1-methyl-1,2,4-triazole (1.30 ml, 23 mmole) was dissolved in absolute tetrahydrofuran (60.0 ml) and added dropwise at −78° C. while cooling with ice. The reaction mixture was then stirred for 10 minutes at this temperature. 8-methylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (2.12 g, 10.8 mmole) in absolute tetrahydrofuran (15 ml) in a cooling bath maintained at −78° C. was then quickly added dropwise to the formed solution. After the addition the reaction solution was stirred for 1 hour in the cooling bath and was then slowly heated to 0° C. The reaction mixture was stirred overnight at room temperature. The mixture was then hydrolysed at 0° C. with water (10 ml), the aqueous phase was extracted with chloroform (3×50 ml), and the organic phase was washed with water (50 ml) and saturated NaCl solution (50 ml), dried over Na2SO4 and concentrated by evaporation in vacuo. The product was purified by means of flash chromatography with chloroform/methanol (15:1).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:10][C:4]=2[CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCOCC1)c1cccc3c1N2CC3
Temperature: 25 °C

Procedure:
A mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 21.8 g (0.250 mole) of morpholine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filterd, and concentrated in vacuo to 8.6 g (90%) of product. Recrystallization from a hot solution of dichloromethane (80 ml) to which methanol (80 ml) was added provided the analytical sample, mp 216°-218° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine HCl salt (0.040 g, 0.13 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (55 uL, 0.26 mmol), and cesium carbonate (120 mg, 0.38 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 50 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[OH:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27]([C:29]3[N:37]4[C:32]([CH:33]=[CH:34][CH:35]=[CH:36]4)=[C:31]([O:38][CH3:39])[C:30]=3[CH3:40])=[O:28])[CH:23]=2)[NH:18][C:17]1=[O:41]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:15][N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27]([C:29]3[N:37]4[C:32]([CH:33]=[CH:34][CH:35]=[CH:36]4)=[C:31]([O:38][CH3:39])[C:30]=3[CH3:40])=[O:28])[CH:23]=2)[NH:18][C:17]1=[O:41])[CH3:7]
Reactant: COc1c(C)c(C(=O)c2ccc3[nH]c(=O)n(O)c(=O)c3c2)n2ccccc12
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)COn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Reaction time: 18 h
Yield: 48.6 %

Procedure:
0.11 ml (0.99 mmol) of ethyl bromoacetate and then 0.14 ml (0.99 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 0.36 g (0.99 mmol) of 3-hydroxy-6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]quinazoline-2,4(1H,3H)-dione in 12.5 ml of ethanol. The reaction medium is stirred for 18 hours and then 0.14 ml (0.99 mmol) of triethylamine and 0.11 ml (0.99 mmol) of ethyl bromoacetate are added. After stirring for 18 hours at ambient temperature, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol mixture. 217 mg of a yellow powder are obtained.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].C(OCC)C.[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=O)[CH2:17][C:18]([CH3:23])([CH3:22])[O:19]2)=[CH:14][CH:13]=1.CN1CCCN(C)C1=O>C1COCC1>[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH:1]([CH3:3])[CH3:2])=[CH:17][C:18]([CH3:23])([CH3:22])[O:19]2)=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=O)c2ccc(Br)cc2O1
Reactant: CC(C)[Mg]Cl
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C1=CC(C)(C)Oc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2.0 M solution of isopropyl magnesium chloride in diethyl ether (15.5 mL, 31 mmol) was added slowly to a solution of 7-bromo-2,2-dimethyl-chroman-4-one (Compound 65, 1.58 g, 6.2 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro 2(1H) pyrimidone (DMPU) (7.5 mL, 30 mmol) in 30 mL THF at −30° C. The reaction mixture was warmed to room temperature and stirred for 15 hours. The reaction was then quenched with water (20 mL), saturated NH4Cl (aq) (15 mL) and 10% HCl (20 mL) at −78° C. The mixture was warmed to room temperature, was extracted with ethyl acetate (3×30 mL), the combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was then refluxed in 40 mL methanol with p-toluenesulfonic acid (160 mg) for 20 hours. The reaction mixture was made basic by addition of solid K2CO3, the solvent was removed and the residue was dissolved in diethyl ether (50 mL). The ether solution was washed with water (2×50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (hexane) to give the title compound as a clear oil: (650 mg, 37%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23]C(=O)C)=[C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32]C(=O)C)[CH:15]=[CH:14][C:11]=1[CH:12]=O)(=O)C.C(O)(=O)[CH2:37][C:38]([OH:40])=[O:39].N1CCCCC1.[OH-].[K+].Cl>O.N1C=CC=CC=1>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:15]=[CH:14][C:11]=1[CH:12]=[CH:37][C:38]([OH:40])=[O:39]
Reactant: CC(=O)OCCCCOc1ccc(C=O)c(OCCCCOC(C)=O)c1OCCCCOC(C)=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(OCCCCO)c(OCCCCO)c1OCCCCO
Temperature: 110 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
Into a three-neck flask, 2,3,4-tri(4-acetyloxy-butyloxy)benzaldehyde (40.0 g), malonic acid (10.6 g), piperidine (1 ml) and 100 mL of pyridine were added and stirred at 110° C. for 5 hours. After cooling, water (500 ml) and potassium hydroxide (26.0 g) were added and stirred at 60° C. for 2 hours. After cooling, concentrated hydrochloric acid was added until the reaction solution became acidic, and the resulting reaction solution was extracted with ethyl acetate and washed with water. The extract was concentrated and then purified by column chromatography to obtain the titled compound (30.1 g). Yield: 90%.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[H-].[Na+].[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2[CH:44]=O)[CH2:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2/[CH:44]=[CH:15]/[C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:13]=[CH:12][S:11]3)[CH2:38][CH2:39]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OCC2CC2)nc2sccn12
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Step 3 intermediate (2.0 g, 3.626 mmol) was added NaH (0.160 g, 3.989 mmol) in anhydrous DMSO (10 mL) and stirred for 30 min. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (0.82 g, 3.989 mmol) in anhydrous DMSO (10 mL) was added drop wise to this solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), brine and dried (Na2SO4) to yield a crude solid which was purified by column chromatography using 5% ethyl acetate in petroleum ether to afford 0.776 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.50-0.53 (m, 2H), 1.17-1.23 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 3.75 (d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.37 (q, J=6.9 Hz, 2H), 6.95-6.99 (m, 2H), 7.08 (t, J=7.8 Hz, 1H), 7.18-7.22 (m, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.69 (d, J=16.2 Hz, 1H), 7.92 (d, J=16.5 Hz, 1H), 8.10 (d, J=4.2 Hz, 1H); ESI-MS (m/z) 399.20 (MH)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:31]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]([N:42]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH2:43][CH2:44]C[Cl:46])=[O:41])[CH2:36][CH2:35]1)(=[O:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>ClCCl.C(OCC)(=O)C>[ClH:46].[C:31]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]([N:42]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH2:43][CH2:44][CH2:6][N:8]2[CH2:9][CH2:10][CH:11]([S:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:12][CH2:13]2)=[O:41])[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCC(C(=O)N(CCCCl)c2cccc(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2nc3ccccc3s2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Sc3nc4ccccc4s3)CC2)c2cccc(Cl)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(2-benzothiazolylthio)piperidine (505 mg, 1.44 mmol) in dry dichloromethane (4 ml) was added trifluoroacetic acid (4 ml) and stirred at room temperature for 30 min. After the solvent was removed in vacuo, the residue was dissolved in methanol (4 ml) and evaporated. The residue was dissolved in dry acetonitrile (12 ml) followed by addition of 1-acetyl-N-(3-chlorophenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide (400 mg, 1.12 mmol), potassium carbonate (0.77 g, 5.6 mmol), and potassium iodide (186 mg, 1.12 mmol). After stirred at 80° C. for 8 h, the mixture was diluted with ethyl acetate (60 ml), washed with brine (60 ml), dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by preparative HPLC eluting water-acetonitrile containing 0.1% TFA. To the TFA salt was added 5% aqueous solution of potassium carbonate, extracted with ethyl acetate (30 ml), washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue dissolved in ethyl acetate (20 ml) was treated with 4N hydrogen chloride in ethyl acetate (0.72 ml). After the solvent was removed in vacuo, the residue was washed with ether and dried in vacuo to give the title compound (230 mg, 34%) as a white solid.
Reaction SMILES: [Mg].CN(CCN(C)C)C.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCCCC>[CH:22]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: CN(C)CCN(C)C
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a 10 L jacketed reactor was added dry THF (2.4 L) and magnesium turnings (81.0 g, 3.33 mol, 1.5 eq.) under N2. In a separate flask FeCl3 (36 g, 0.22 mol, 0.1 eq.) was dissolved in THF (150 mL) (caution, exothermic) under N2. This dark brown solution was allowed to cool to ambient temperature and then added over 10 min to the reactor content under N2 at an internal temperature of about 10° C. TMEDA (402 mL) was added to this yellow/green mixture keeping the internal temperature below about 20° C. (slightly exothermic). The resulting rust brown mixture was stirred at ambient temperature for 1 h under N2 then 1 h at 45° C. The reactor contents were allowed to cool below about 20° C. and a mixture of 1-bromo-2-(trifluoromethyl)benzene (500 g, 2.22 mol) and bromocyclopentane (397 g, 2.66 mol, 1.2 eq.) added dropwise under N2 at a rate as to maintain the internal temperature between about 25-30° C. After the addition, the reaction mixture was stirred at about 25° C. under N2 overnight, allowed to cool to an internal temperature of about 0° C. and quenched with 6 N HCl (2 L) at a rate as to maintain the internal temperature below about 15° C. (caution, exothermic). [Note: IPC's after completing the addition and stirring overnight were similar indicating that the reaction may have been completed much sooner.] After the quench, hexane (3 L) was added and the reactor contents were stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with hexane (1 L). The combined organic layers were dried (Na2SO4), slurried with silica (750 g) and filtered washing the solids with hexane (1 L). The filtrate was concentrated under reduced pressure (100 torr at 37° C.) to give an amber oil (317 g, 97.3 Area % by HPLC, 87.7 wt % by HPLC (contained residual hexane by NMR), corrected yield 58%) which was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][CH2:11]Cl.[Cl:13][SiH:14]([Cl:16])[Cl:15]>>[Cl:13][Si:14]([Cl:16])([Cl:15])[CH2:9][CH2:10][CH2:11][Si:14]([Cl:16])([Cl:15])[Cl:13]
Reactant: ClCCCCl
Reactant: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Product: Cl[Si](Cl)(Cl)CCC[Si](Cl)(Cl)Cl
Yield: 8.9 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.048 g (0.47 mmol) of triethylamine, 0.6 g (4.7 mmol) of 1,3-dichloropropane, and 3.18 g (23.5 mmol) of trichlorosilane were reacted at 200° C. for 15 hrs. The resulting mixture was distilled to give 0.13 g of 1,3-bis(trichlorosilyl)propane (yield; 9%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[CH:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CCCC(=O)OCc1ccccc1
Reactant: FC(F)(F)Oc1cccc(I)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCC#Cc1cccc(OC(F)(F)F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a degassed (Ar) solution of 1-iodo-3-trifluoromethoxy-benzene (0.54 ml, 3 mmol) in acetonitrile (30 ml) was added pent-4-ynoic acid benzyl ester (719 mg, 4 mmol; A. Rosowsky, R. A. Forsch, F. S. Queener, J. Med. Chem. 2003, 46, 1726-1736), PdCl2(Ph3P)2 (122 mg, 0.17 mmol), cuprous iodide (33 mg, 0.17 mmol) and triethylamine (1.45 ml, 10 mmol). The reaction mixture was stirred for 2.5 h at ambient temperature, poured into a solution of aqueous 10% KHSO4/ice water 1/1 and extracted two times with ether. The combined extracts were washed with aqueous 10% KHSO4 and aqueous 10% NaCl and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 1.13 g (3.2 mmol, 93%) of the title compound as yellow oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:27]OS([O-])=O.[K+].O>C(Cl)Cl.CO>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:19]([N:21]2[CH2:26][CH2:25][SH2:24](=[O:27])[CH2:23][CH2:22]2)=[O:20])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCSCC2)no1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CC[SH2](=O)CC2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(Thiomorpholine-4-carbonyl)-piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (150 mg; 0.394 mmol) in 50% methylene chloride in methanol (4 mL) is added oxone (122.8 mg; 0.2 mmol) and water (0.1 mL). The reaction mixture is stirred at room temperature for 2 hours. The mixture is quenched with water and extracted with dichloromethane 3 times. The organics are combined and dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 397 [M+H+].
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([F:7])([F:6])[CH2:4]I.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:4][C:3]([F:7])([F:6])[CH:2]([F:8])[F:1])=[N:16][CH:17]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: FC(F)C(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)F)nc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
1,1,2,2-Tetrafluoro-3-iodo propane (0.5 g, 2 mmol) was added to a mixture of 5-nitro-2-hydroxy pyridine (860 mg, 6.1 mmol) and potassium carbonate (1.4 g, 10 mmol) in DMF (10 ml) and the reaction heated at reflux for 6 hr. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (50 ml), washed successively with bicarbonate solution, water, brine, and dried. Concentration to dryness yielded 5-nitro-2-(2,2,3,3-tetrafluoro-propoxy)pyridine (394 mg, 75%) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[C:5]([C:18]([O:20]CC)=[O:19])[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[C:5]([C:18]([OH:20])=[O:19])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)sc1Nc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc(C(=O)O)c(Nc2ccccc2[N+](=O)[O-])s1

Procedure:
Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate (6.0 g) dissolved in ethanol (100 ml) and water (50 ml) and heated to 60° C. with stirring. Sodium hydroxide (5N,50 ml) was then added and the temperature maintained for 16 hours. The reaction mixture was cooled and diluted with water (500 ml), and solid title product filtered off, m.p. 189°-191° C. (EtOAc).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Ic1cnc(N2CCNCC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ncc(I)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-iodo-2-piperazin-1-ylpyrimidine (7.0 g, 24.1 mmol, CAS number 95847-41-9) and triethylamine (10 mL, 72 mmol) in dichloromethane (70 mL) at 0° C. was added methanesulfonyl chloride (1.93 mL, 138 mmol) dropwise over 10 minutes. The reaction was then stirred for 30 minutes at 0° C., before being allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction was then quenched with water (70 mL) and the layers were separated. The organic phase was washed with water (100 mL) and the organics were dried (MgSO4), filtered and evaporated in vacuo. The residue was then triturated with ethyl acetate and the solid residue filtered and dried in vacuo to give 5-iodo-2-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine as an off white solid (8.85 g, 24 mmol, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:39]=[C:40](CO)[CH:41]=[CH:42][CH:43]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:37])[CH:43]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Cc1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4cccc(C)c4)c(C)c3C)c2cc1OC
Yield: 96.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-methylphenyl)methanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (140 mg, yield 89%).