Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C@H:6]2[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14]3[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:15]=3)[CH2:8][CH2:7]2)[CH2:3]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[N+:20]([C:19]1[C:14]([NH:13][CH2:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([N:4]3[CH2:5][CH:2]([NH:1][C:36](=[O:38])[CH3:37])[CH2:3]3)[CH2:7][CH2:8]2)=[N:15][C:16]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][C:32]([F:34])([F:35])[F:33])=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N4-{[Trans-4-(3-aminoazetidin-1-yl)cyclohexyl]methyl}-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (20 mg, 0.04 mmol) was dissolved in CH2Cl2 (1.0 mL). To this solution was added acetic anhydride (0.057 mL, 0.06 mmol) followed by triethylamine (0.084 mL, 0.06 mmol). The reaction was allowed to stir at 25° C. for 18 h. The volatiles were removed and the crude was redissolved in CH2Cl2 and extracted with 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The resultant residue was purified via flash chromatography (SiO2, 10-30% (2:18:80, NH4OH:CH3OH:CH2Cl2)—CH2Cl2) to afford 16 mg (74%) of the target compound, m/z 538.46 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: OCCBr
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(COC(=O)c2ccc(OCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methoxybenzyl 4-hydroxybenzoate (7.0 g, 27 mmole) in dry NN-dimethylformamide (50 ml) was added potassium carbonate (4.15 g, 30 mmole) and 2-bromoethanol. The mixture was stirred 48 hours at 80° C., evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed five times with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1.O.[H][H]>[OH-].[Na+].[Pd]>[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccc2c(c1)OCO2
Yield: 97 %

Procedure:
To a solution of 10.0 g of 3,4-methylenedioxycinnamic acid dissolved in 130 ml of 10% NaOH and 80 ml of distilled water was added 1.0 g of 5% Pd-C. This mixture was reacted at 40 psi until the consumption of hydrogen gas was ceased and then filtered through a Celite layer. The filtrate was acidified with concentrated hydrochloric acid, allowed to be cooled and filtered to give solids. The obtained solids were washed twice with 100 ml of cold water and dried to provide 9.8 g(yield 97%) of 3-(3,4-methylenedioxyphenyl) propanoic acid, having the characteristics of: NMR(CDCl3, 200 MHz) δ2.62(t, J=7 Hz, 2H, CH2), 2.88(t, J=7 Hz, 2H, CH2N), 5.93(s, 2H, CH2O2), 6.63-6.76(s, 3H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8](/[CH:15]=[CH:16]/[C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]=[CH:16][C:17]([C:18]([F:21])([F:20])[F:19])=[C:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(/C=C/C(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a solution of (E)-ethyl 2-((4-chlorophenyl)(4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)acetate (0.95 g, 2.83 mmol) in EtOAc (20 mL) was added DBU (0.85 mL, 5.66 mmol) and the resulting mixture heated in a sealed tube for 90 min at 120° C. The resulting mixture was cooled to room temperature, diluted with EtOAc (80 mL) and washed with 5% KHSO4 (2×80 mL) and brine (80 mL). The organic layer was concentrated and the residue purified by elution from a 25-g silica cartridge with 0-20% EtOAc/heptane to yield ethyl 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:23][C@H:13]2[CH2:14][C@H:15]([CH2:20][CH:21]=C)[S:16](=[O:19])(=[O:18])[NH:17][C@H:12]2[CH2:11][CH2:10]1.[O:37]=[O+][O-].[BH4-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:23][C@H:13]2[CH2:14][C@H:15]([CH2:20][CH2:21][OH:37])[S:16](=[O:19])(=[O:18])[NH:17][C@H:12]2[CH2:11][CH2:10]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@H]1C[C@@H]2C[C@](c3cc(F)ccc3F)(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC[C@@H]2NS1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Product: O=S1(=O)N[C@H]2CC[C@@](c3cc(F)ccc3F)(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]2C[C@@H]1CCO

Procedure:
Prepared from the product of Example 56 by treatment with ozone followed by sodium borohydride using the procedure described in Example 55 Step 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(NCC)C.[OH-].[Na+]>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.O1CCCC1>[C:22]1([C:28]#[C:29][C:2]2[CH:3]=[C:4]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(C#Cc3ccccc3)c2)CC1

Procedure:
A mixture of 1-(5-bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (3.5 g, 9.8 mmol), phenylacetylene (2.0 g, 19.6 mmol), tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol), diethylamine (1.4 g, 19.6 mmol) and tetrahydrofuran (50 ml) was refluxed for 5 hours. Aqueous sodium hydroxide (75 ml, 1M) was added. The mixture was extracted twice with ethyl acetate. The mixture was purified by chromatography on silica gel using ethyl acetate:petroleum (1:1) as solvent. Yield 0.54 g, 7.3%.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:10]1([CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=2[OH:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=2[O:25][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(C)c(O)c(CN2CCCCC2)c1
Solvent: c1ccccc1
Product: Cc1cc(C)c(OC(=O)Nc2ccccc2)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
29.75 g (0.25 mol) of phenylisocyanate are introduced dropwise at 0° to 5°C into a solution of 54.75g (0.25 mol) of 2-(piperidinomethyl)-4,6-dimethylphenol in 80 ml of anhydrous benzene. The reaction mixture is stirred at room temperature for 4 hours. The precipitated carbamic acid ester is suction filtered and washed with petroleum ether (b.p. 30°-50°C).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with benzylamine (2.10 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-benzylamino-cyclopentanecarboxylic acid ethyl ester (2.10 g, 8.49 mmol, 44.2%), as a light yellow oil. LC-MS (ESI) calcd for C15H21NO2 247.16, found 248.2 [M+H+].
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][C:18]1[CH:23]=[C:22]([C:24]([NH:16][CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[CH:2][NH:1][C:6]4=[N:7][CH:8]=[CH:9][C:5]=34)[CH2:15][CH2:14]2)=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 2-methyl-4-pyridinecarboxylic acid (63.1 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E12 (72 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.55 (2H, m), 8.17 (1H, s), 7.62 (1H, s), 7.53 (1H, d), 7.18 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.35 (3H, s), 3.25 (2H, dt), 1.90 (2H, m), 1.53 (2H, m), MS(ES+) 337 [M+H]+.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:16]Br>O>[Br:16][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1
Reactant: CSc1ccccc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A one-liter four-necked flask equipped with a stirrer, thermometer, dropping funnel and Liebig condenser was charged with 124.2 g (1.00 mole) of thioanisole, and 0.13 g (0.001 mole) of aluminum chloride and 200 g of dichloromethane, and 160 g (1.0 mole) of bromine was added dropwise with stirring at 5° C. over 4 hours. Thereafter, the reaction was further allowed to proceed for 2 hours. After completion of the reaction, 50 g of water was added, and phase separation was effected, whereby a 4-bromothioanisole-containing organic layer was obtained. The dichloromethane was distilled off from the organic layer obtained, whereby 203.1 g of crude 4-bromothioanisolve was obtained. The purity of the thus-obtained crude 4-bromothioanisole was 90.1% as determined by gas chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1.[H-].[Na+].I[CH3:45]>CN(C=O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[N:15]([CH3:45])[CH2:14][CH2:13]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)NCCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
A solution of 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (INTERMEDIATE V, 0.045 g, 0.072 mmol) in DMF (0.719 mL) was treated with sodium hydride (4.31 mg, 0.108 mmol) to afford a dark brown solution. Iodomethane (6.74 μL, 0.108 mmol) was added dropwise to give a light-yellow solution. The reaction was stirred for 40 minutes. Additional iodomethane (6.74 μL, 0.108 mmol) was added and the reaction was heated to 70° C. and stirred for one hour. The mixture was diluted with water and a small amount of brine (to break up an emulsion) then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (12 g column, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-4-methyl-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. m/z (ESI) 639.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:35][CH3:36])CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:3]=[CH:2]/[C:1](=[O:8])[C:36]2[CH:35]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 120 °C

Procedure:
1-Phenylpropenone (58 mg, 0.44 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (200 mg, 0.37 mmol), Pd(OAc)2 (4 mg), triethylamine (372 mg, 0.367 mmol), and acetonitrile (3 mL) are placed in a microwave vial and heated at 120° C. for 15 min. The mixture is filtered over Celite and washed with acetonitrile. The filtrate is evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: C(OC([N:11]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]([NH2:19])([CH3:18])[C:12]1=[O:20])=O)C1C=CC=CC=1.[ClH:21].[H][H].O>C(O)C.[Pd]>[ClH:21].[NH2:19][C:13]1([CH3:18])[CH2:14][CH2:15][C:16](=[O:17])[NH:11][C:12]1=[O:20]
Reactant: [H][H]
Reactant: CC1(N)CCC(=O)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(N)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution allowed to cool to room temperature. To this solution was added 4N hydrochloric acid (3 mL) followed by 10% Pd/C (0.4 g). The mixture was hydrogenated in a Parr apparatus under 50 psi of hydrogen for 3 hours. To the mixture was added water (50 mL) to dissolve the product. This mixture was filtered through a Celite pad which was washed with water (50 mL). The filtrate was concentrated in vacuo to afford a solid residue. The solid was slurried in ethanol (20 mL) for 30 min. The slurry was filtered to afford 1.38 g (93%) of α-amino-α-methylglutarimide hydrochloride as a white solid: 1H NMR (DMSO-D6) δ 11.25 (s, 1H), 8.92 (s, 3H), 2.84-2.51 (m, 2H), 2.35-2.09 (m, 2H), 1.53 (s, 3H); HPLC, Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 1.03 min (94.6%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]([CH3:37])([CH3:36])[CH2:8][C@@:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[OH:6][C:7]([CH3:36])([CH3:37])[CH2:8][C@@:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
MeSO2Cl (29 μL) was added to a solution of (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (150 mg) and triethylamine (100 μL) in dichloromethane (3 mL) at room temperature. After stirring the solution at room temperature overnight, more dichloromethane was added and the resulting solution was washed with aqueous NaHCO3 solution, water, and brine. The organic solution was then dried (MgSO4) and concentrated. The residue was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [I-].O1CCNC1=O.[F:8][C:9]1[CH:10]=[C:11]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:12]=[CH:13][C:14]=1[Sn](C)(C)C.Br[C:31]1[CH:37]=[CH:36][C:35](=[O:38])[C:34]([O:39][CH3:40])=[CH:33][CH:32]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:12]=[CH:13][C:14]=1[C:31]1[CH:37]=[CH:36][C:35](=[O:38])[C:34]([O:39][CH3:40])=[CH:33][CH:32]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Reactant: COc1ccc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1NCCO1
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 80 °C
Yield: 57 %

Procedure:
Alternatively, the oxazolidinone iodide described above can be converted to (S)-N-[[3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, employing conditions disclosed for the corresponding racemic material in TR 7246-92-050. This tin-substituted intermediate (0.180 g, 0.43 mmol) and 5-bromo-2-methoxycyclohepta-2,4,6-trien-1-one (0.103 g, 0.48 mmol) were dissolved in dry DMF (3 mL) and the resultant solution degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.015 g, 0.02 mmol) was added, the reaction again degassed, and the mixture heated to 80° C. for 2 h. TLC revealed some starting material still remained, so additional palladium catalyst (0.015 g) was added and the mixture heated a further 5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed over silica gel, eluting with a methanol/chloroform gradient, to afford 0.096 g (57%) of the title compound, identical in all respects to material prepared via the above protocol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[CH2:10][CH2:11][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:11][CH2:10][C:9]1[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:46]1[CH2:47][CH2:48][N:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:44][CH2:45]1)[CH3:21]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCBr)Cc1ccc(C(=O)OC)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCN1CCN(c2ccccc2)CC1)Cc1ccc(C(=O)OC)cc1

Procedure:
200.0 mg (0.355 mmol) of methyl 4-{[{2-[(5-bromopentyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 107, 69.21 mg of N-phenylpiperazine and 71.95 mg (0.711 mmol) of triethylamine in 2 ml of tetrahydrofuran are heated at reflux for 18 hours. The reaction solution is washed with water, concentrated and chromatographed over silica gel using the mobile phase ethyl acetate/methanol 10/1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[N:27][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCCCC1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(CC2CCCCC2=NO)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(3-benzyloxy-4-nitrobenzyl)-cyclohexanone (1.0 g, 2.95 mmol), hydroxylamine hydrochloride (407 mg, 5.9 mmol) and sodium acetate (726 mg, 8.85 mmol) in MeOH (20 mL)/water (4 mL) is stirred at RT for 18 h. The resulting precipitate is filtered and washed with water to give the title compound as a yellow solid: (M+1)+=355.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:14]([O:16][CH3:17])=[O:15])[C:7]2=[O:12].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([CH:72]([CH3:76])[C:73](O)=[O:74])=[CH:68][CH:67]=1>>[Si:20]([O:19][CH2:18][C@@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:73](=[O:74])[CH:72]([C:69]2[CH:70]=[CH:71][C:66]([Cl:65])=[CH:67][CH:68]=2)[CH3:76])[C:7]1=[O:12])[C:14]([O:16][CH3:17])=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)cc3)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-3-(tert-butyldimethylsilyloxy)propanoate (500 mg, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol), N,N-diisopropylethylamine (0.5 mL, 0.003 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1 g, 0.003 mol) and 2-(4-chlorophenyl)propanoic acid (340 mg, 0.0018 mol) and the reaction stirred at room temperature overnight then for another 12 h. The solvent was removed and the residue purified by flash chromatography to yield the product as a white solid. MS m/z=545.4 (M+H).