Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[C:9]([Br:21])[CH:10]=[CH:11][C:12]=2[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=1)=[O:5])[CH3:2].[CH3:22]C(C)=O.COS(OC)(=O)=O>N>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH3:22])[C:13]2[C:8](=[C:9]([Br:21])[CH:10]=[CH:11][C:12]=2[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2c(OC(C)C)ccc(Br)c2c1
Reactant: CC(C)=O
Agent: N
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1cc(OC)c2c(OC(C)C)ccc(Br)c2c1
Yield: 98 %

Procedure:
To a solution of 4.92 g (13.9 mmol) ethyl-8-bromo-4-hydroxy-5-isopropoxy-2-naphthoate in 150 mL acetone 4.80 g (34.8 mmol) K2CO3 and dropwise 4.90 g (38.7 mmol) dimethylsulfate at room temperature were added. Subsequently the reaction mixture was refluxed for 10 h and after that 60 mL of concentrated ammonia was added. Solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The combined organic phases were washed three times with 2N NaOH solution and two times with water. The organic phase was dried (MgSO4) and concentrated under vacuum. The residue was recrystallized from diethylether to give 5.00 g (99%) ethyl-8-bromo-5-isopropoxy-4-methoxy-2-naphthoate as colorless needles (m.p. 62° C.).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[OH:29][C:26]([CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:34]3[CH:35]=[N:36][C:31]([CH3:30])=[CH:32][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:28])[CH3:27]
Reactant: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C(C)(C)O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 142.1) and (6-methylpyridin-3-yl)boronic acid to afford an off-white foam. HPLC (Condition 4) tR=4.37 min, UPLC-MS (Condition 7) m/z=487.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 6H) 2.49 (s, 3H) 3.31 (br. s, 1H) 3.54-3.66 (m, 4H) 4.36 (d, J=0.78 Hz, 1H) 7.22-7.43 (m, 3H) 7.73 (dd, J=7.82, 2.35 Hz, 1H) 7.79-7.88 (m, 2H) 7.95 (d, J=2.35 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H) 8.72 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Cl:19][Si](C)(C)C>C(#N)C>[Cl:19][CH2:10][C:9](=[O:11])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)OC
Reactant: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C(C(=O)CCl)C(=O)OC
Temperature: -30 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
In 15 ml of acetonitrile was dissolved 795 mg of methyl 2-methoxyimino-3-oxobutyrate, followed by addition of 2.1 ml of triethylamine. Then, 1.9 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 1 hour for silylation. The reaction mixture was concentrated under reduced pressure and the residue was suspended in 15 ml of tetrahydrofuran. The suspension was filtered in a nitrogen gas stream to remove insolubles. The filtrate was cooled to -30° C. and 0.405 ml of sulfuryl chloride was added dropwise. After the temperature of the system was increased to 20° C., the mixture was concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and elution was carried out with 100 ml of hexane-ether (1:1, v/v). The eluate was concentrated under reduced pressure to give 813 mg of methyl 4-chloro-2-methoxyimino-3-oxobutyrate as colorless oil. Yield 84.1%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:2]1C=CC=CC=1.[CH2:26]([NH:33]CCN)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][CH2:2][CH2:1][NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: NCCNCc1ccccc1
Product: O=C(NCCNCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 61 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using N-benzylethane-1,2-diamine instead of benzylamine and obtained in 61% yield. 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.41 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.19-8.14 (m, 1H), 7.75 (d, J=5.5 Hz, 1H), 7.38-7.18 (m, 7H), 6.46-6.43 (m, 1H), 3.73 (s, 2H) 3.37 (dd, J=12.4, 6.6 Hz, 2H), 2.89 (t, J=6.6 Hz, 2H); MS (m/z) 393 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH2:10].C[Li].CI.O1CC[CH2:25][CH2:24]1>CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:24][CH3:25])[CH3:10]
Reactant: C1CCOC1
Reactant: C=C(c1ccccc1OC)c1ccccc1OC
Agent: [Li]C
Solvent: CI
Solvent: CCOCC
Product: CCC(C)(c1ccccc1OC)c1ccccc1OC
Reaction time: 2 h

Procedure:
1,1-Bis(2-methoxyphenyl)ethene (5.6 g) was dissolved in 25 ml of tetrahydrofuran and 25 ml of a 1.3 M solution of methyl lithium in ether was added dropwise with stirring. The solution became dark red and exothermed After 2 hours, 5.0 ml of methyl iodide was added slowly with stirring. The solution again exothermed. When all of the methyl iodide had been added the starting material was found to be completely consumed and replaced by a single product by gas-liquid chromatography. About 300 ml of ether was added and the resulting solution was extracted with 100 ml of water and then 100 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.46 g (88 percent of theory) of the title compound as a pale yellow crystalline solid melting at 49°-52° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CO.CC#N>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CO
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Cl)cc4)nc3n2)CC1
Yield: 62.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.344 g of 4-chlorophenyl isocyanate according to the general procedure of Example 37 to give 0.8424 g of 1-(4-Chloro-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH+DMSO): M+ +H=601; mp 175.5°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[F:10].ClC(Cl)(Cl)C[O:14][C:15](=O)[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:14])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:24]([CH3:26])[CH3:25])=[O:27])=[CH:19][CH:18]=2)=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Nc1ccc(Br)c(F)c1F
Reactant: CN(C)C(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)c(F)c2F)cc1
Temperature: 105 °C
Yield: 36.6 %

Procedure:
To a 50 mL round bottom flask, 4-bromo-2,3-difluoroaniline (0.5 g, 0.0024 mol), 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (0.978 g, 0.00288 mol; from Preparation 5), TEA (1.01 mL, 0.0072 mol) and toluene (20 mL) were added. The reaction mixture was maintained at 105° C. for 12 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude was purified by column chromatography using 3% MeOH in chloroform to get the title compound [0.35 g, 36%]. 1H NMR (300 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.96 (s, 1H), 8.0-7.92 (m, 1H), 7.52-7.42 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 397.0; Observed mass: 400.0 (RT: 1.49 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](Cl)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=C([C@@H](CC2CCCC2)[C:49]([NH:51][C:52]2C=CN(CC3C=C(C=CC=3)C(N)=O)N=2)=O)C=CC=1S(C)(=O)=O.CNC.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([N:51]([CH3:52])[CH3:49])=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(N)=O)c3)n2)cc1Cl
Agent: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a 0.166 M solution of crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride in methylene chloride (prepared in Example 63, 1.71 mL, 0.28 mmol) was added a 40% solution of dimethylamine in water (250 μL, 0.22 mmol) and the reaction stirred at 25° C. for 30 min. The solution was diluted with methylene chloride (40 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to an off white foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N,N-dimethyl-benzamide (72 mg, 46%) as a white powder: ESI-LRMS m/e calcd for C28H33ClN4O4S [M+] 556.19, found 557.27 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.19 (m, 2H, CH2), 1.36-1.78 (m, 8H, 4×CH2), 2.02-2.17 (m, 1H, CH), 2.84 (s, 3H, NCH3), 2.94 (s, 3H, NCH3), 3.32 (s, 3H, SO2CH3), 3.82-3.91 (m, 1H, CH), 5.21 (s, 2H, NCH2), 6.45 (d, J=2.3 Hz, 1H, Ar), 7.17-7.32 (m, 3H, Ar), 7.33-7.40 (m, 1H, Ar), 7.55 (dd, Jo=8.3, Jm=1.7 Hz, 1H, Ar), 7.65 (d, Jm=1.7 Hz, 1H, Ar), 7.73 (d, J=2.3 Hz, 1H, Ar), 7.97 (d, Jo=8.3 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: [C:1]([NH:5][C@H:6]([C:17]([O:19]C)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)(=[O:4])[CH:2]=[CH2:3].[OH-].[Na+:22]>CO>[C:1]([NH:5][C@H:6]([C:17]([O-:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)(=[O:4])[CH:2]=[CH2:3].[Na+:22]
Reactant: C=CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Reaction time: 2 h
Yield: 87 %

Procedure:
To methanol (50 mL) solution of the compound obtained in Example 1 (1.0 g, 3.7 mmol) was added I mol/L of an aqueous sodium hydroxide solution (5.6 mL) at room temperature. The mixture was allowed to stir for 2 hours, and thereafter to the residue obtained by distilling off the solvent under reduced pressure was added water, and the pH of the solution was adjusted to about pH 7 with polystyrene bound type p-toluensulfonate beads (2.8 mmol/g) (2.0 g), Beads were filtered off with a Millipore filter, thereafter the filtrate was distilled off under a reduced pressure, and the crystals precipitated were filtered with diethyl ether, to give the captioned compound (0.9 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:20])[N:11]([CH2:18][OH:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[P:21](Cl)(=[O:38])([O:30][CH2:31]C1C=CC=CC=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[P:21]([O:30][CH3:31])([O:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:20])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:38]
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Product: COP(=O)(OCc1ccccc1)OCN1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21

Procedure:
The title compound was prepared from (3Z)-3-[(3,5-Dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1) and benzyl methyl phosphorochloridate (modification of procedure used to prepare {3(Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}methyl acetate (2)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[Na].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO>[CH2:14]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Sc1ccc(Br)cc1
Reactant: CCCCCCCCCCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCSc1ccc(Br)cc1
Reaction time: 1 h
Yield: 91.6 %

Procedure:
4-Bromothiophenol (100 g) was added dropwise to a solution of sodium methoxide prepared from sodium (13.4 g) and dry methanol (400 ml). The solution was stirred for 1 hour and then a mixture of 1-bromodecane (128.6 g) and dry methanol (150 ml) was added over 10 minutes. The oily suspension was refluxed for 4 hours and was then concentrated by distilling off about 300 ml of solvent. Water (750 ml) was added and the mixture was stirred vigorously while cooling. The solid product was collected, washed with water and then crystallized from ethanol to give 4-(decylthio)bromobenzene (159.5 g), m.p. 37°-39° C. [Elemental analysis: C,58.0; H,7.7; Br,24.5; S,9.7%; calculated: C,58.36; H,7.60; Br,24.31; S,9.73%].
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][SH:5].Br[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH3:10][CH2:11][CH2:12][CH2:13][S:5][CH2:4][CH2:3][C@H:2]([NH2:1])[C:6]([OH:8])=[O:7]
Reactant: CCCCBr
Reactant: N[C@@H](CCS)C(=O)O
Product: CCCCSCC[C@H](N)C(=O)O

Procedure:
L-buthionine-SR-sulfoximine is prepared as described in Griffith, O. W., The Journal of Biological Chemistry, Vol. 257, No. 22, pp. 13704-13712, 1982. Such preparation is as follows: L-methionine, obtained commercially, is reductively demethylated using sodium in liquid ammonia to produce L-homocysteine. The L-homocysteine is alkylated with 1-bromobutane to form L-buthionine. The L-buthionine is converted to L-buthionine-SR-sulfoximine by reaction with sodium azide in chloroform/sulfuric acid. The L-buthionine-SR-sulfoximine product is isolated by chromatography on Dowex 50(H+) resin. L-buthionine-SR-sulfoximine. 6 gms, containing approximately equal amounts of the two diastereomers was dissolved in 34 ml of hot water (boiling water bath) to a final concentration of 0.8M. The solution was allowed to cool; crystallization occurred spontaneously. After standing overnight at 4° C., the crystals were collected by filtration. The filtrate was evaporated to dryness under reduced pressure. The solid (4.1 gms) was suspended in 50 ml of absolute ethanol, and 5 ml of trifluoroacetic acid was added dropwise. Hexane, 50 ml, was slowly added over a period of about 10 minutes to the stirred, clear solution. Stirring was then stopped, and crystallization was allowed to occur at room temperature. After 2 hours, the crystals were collected by filtration, washed with hexane and ether, and dried under vacuum. The yield was 2.8 gms. The crystals, 2.8 gms, are added to 35 ml of ethanol with stirring to form a solution. To this solution is added with stirring 3.5 ml of trifluoroacetic acid, followed by 35 ml of hexane (added slowly over a 10 minute period). Then stirring is stopped and crystallization is allowed to occur at room temperature. After 2 hours the crystals are collected by filtration, washed with hexane and ether, and dried under vacuum. The yield is 1.6 gms. The crystals consist of L-buthionine-S-sulfoximine trifluoroacetic acid addition salt (of greater than 99% purity). The yield is about 50% based on the initial L-buthionine-S-sulfoximine content of the starting material. The acid addition salt is converted to pure free zwitterion by dissolving in water, 20 ml, applying the resulting solution to a column of Dowex 50 (H+), 1.5×20 cm, then washing with water to elute trifluoroacetic acid leaving L-buthionine-S-sulfoximine bound to the resin. The resin is washed with 1 liter of 3M ammonium hydroxide, and the eluent collected in 10 ml fractions. The fractions containing amino acid are pooled, evaporated to dryness at reduced pressure and traces of ammonia are removed by treating with water and evaporating.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:37]2[CH2:36][CH2:35][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[CH2:39][CH2:38]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C

Procedure:
To a solution of 3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (11.06 g, 0.04 mol) in acetonitrile (180 mL) was added potassium carbonate (26 g, 0.19 mol) followed by 1-(2-methoxy-phenyl) piperazine (7.25 g, 0.04 mol). After completion of addition the reaction mixture was heated to reflux. After 12 h the reaction mixture was cooled down to room temperature and quenched with water. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield an oil. This crude material was purified using silica gel chromatography (7:3:0.05 Hexane:EtOAc:2M NH3 in EtOH) to afford the desired compound in good yield (8.0 g, 55%). C22H35N3O3,LRMS (m/z)=390 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:14]>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4]([NH:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=3)[CH2:21][CH2:22]2)[N:3]=1
Reactant: CC(=O)Nc1cc(Cl)nc(Cl)n1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3cc(NC(C)=O)nc(Cl)n3)CC2)ccc1OC
Yield: 2.5 %

Procedure:
A solution of N-(2,6-dichloro-pyrimidin-4-yl)-acetamide (30.9 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.6 mg (3%) of the title compound. MS (ISP): 434.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:20](=[O:23])[CH:21]=[CH2:22])=[C:8]([S:10]CC2C=CC(OC)=CC=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl>[CH2:1]([C:5]1[NH:6][C:7]2[C:20](=[O:23])[CH2:21][CH2:22][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)c1[nH]c(CCCC)nc1SCc1ccc(OC)cc1
Solvent: ClCCl
Product: CCCCc1nc2c([nH]1)C(=O)CCS2

Procedure:
2.1 g of the product of Stage 4 (6.4 mmoles) were dissolved in 65 ml of dichloromethane (10 ml/mmole) and the following were introduced at about 0° C.:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1 g of ethyl 4-nitrophenylacetate dissolved in 20 ml of dimethylformamide was treated with 3.12 g of cesium carbonate and 0.68 ml of iodopentane. The mixture was stirred at room temperature for 18 hours. The mixture was poured onto 50 ml of iced water and the resulting mixture was extracted with two portions of 50 ml ether. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), yielding a pale yellow oil. 1H NMR (CDCl3): 8.18 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 4.25-4.00 (m, 2H), 3.64 (t, J=7.7 Hz, 1H), 2.20-2.00 (m, 1H), 1.85-1.70 (m, 1H), 1.45-1.15 (m, 6H), 1.22 (t, J=7.2 Hz, 3H), 0.90-0.80 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[C:3]=1[I:13].[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH3:14])[C:3]=1[I:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)c1cc(Cl)c(Cl)c(I)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(C)=O)cc(Cl)c(Cl)c1I
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (4.9 g, 15 mmol), triphenylphosphine (5.5 g, 21 mmol), and methanol (0.91 mL, 22 mmol) in tetrahydrofuran (44 mL) at 0° C. was treated with diisopropyl azodicarboxylate (4.1 mL, 21 mmol) dropwise and stirred at 20° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate, and poured into water. The organic layer was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (5%-30%) gave the desired product (4.1 g, 79%). LCMS for C9H8Cl2IO2 (M+H)+: m/z=344.9, 346.9. Found: 344.9, 346.7.