Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>ClCCl>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 1-(bromomethyl)-4-nitro-benzene (250 mg, 1.157 mmol) in dichloromethane (5 mL) was treated with triethylamine (200 μL, 1.39 mmol) and morpholine (110 μL, 1.27 mmol) then stirred at room temperature for 1.5 hrs. The solution was diluted with dichloromethane (20 mL) then washed with water (2×20 mL). The organic extract was dried (MgSO4), filtered and concentrated to give (i) which was used in subsequent reactions without further purification. 1H NMR (400 MHz, CDCl3) δ 8.21-8.16 (m, 2H), 7.56-7.50 (m, 2H), 3.76-3.69 (m, 4H), 3.59 (s, 2H), 2.49-2.42 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(C(=O)O)c(Cl)c1
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
1.2 g of 4-(2-chloroethyl)morpholine and 2.5 g of Cesium Carbonate were added to 334 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 7 mL of DMF and stirred in the microwave at 150° C. for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated to give crude methyl 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate. 476 mg of methyl 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M and purified by reverse phase HPLC to yield 460 mg of crude 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-morpholinoethyl)methylsulfonamido)benzamide. MS (Q1) 549 (M)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28](#[N:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]#[N:31])=[O:15])[CH3:14]
Reactant: C=CC#N
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCC#N)CCCCc1ccccc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.341 ml, 0.0024 mole), trimethyl silylchloride (0.303 ml, 0.0024 mole) and acrylonitrile (0.17 ml, 0.0024 mole). The reaction mixture was stirred at reflux temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a thick oil (0.6 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[ClH:1].[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C:19]4[O:18][CH:22]=[CH:21][N:20]=4)=[CH:30][CH:29]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cc2ncco2)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: Cl
Product: Clc1cccc(-c2cc(Nc3ccc(Cc4ncco4)cc3)c3c(n2)CCC3)c1
Yield: 20.1 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.075 g, 0.25 mmol) was reacted with 4-(oxazol-2-ylmethyl)aniline (0.065 g, 0.37 mmol) followed by the formation of the hydrochloride salt to afford the title compound (0.022 g, 30%) as an off-white solid. MW=438.35. 1H NMR (DMSO-d6, 300 MHz) δ 14.14 (s, 1H), 9.86 (s, 1H), 8.05-8.03 (m, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.75-7.57 (m, 3H), 7.40 (s, 4H), 1.16 (s, 1H), 7.04 (s, 1H), 4.20 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.32-2.61 (m, 2H), 2.74 (t, J=7.6 Hz, 2H); APCI MS m/z 402 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH3:17])[N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](=[O:28])(=[O:27])[NH:25][CH3:26])[C:9]2=[O:29])=[O:5])[CH3:2].C(O[C:34](=O)[C:35]1C(C)=CC(NC(=O)C)=C(C(O)=O)[C:36]=1C)C.NC1C=CC=CC=1S(NC)(=O)=O.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH:2]1([CH2:1][O:3][C:4]([C:6]2[C:7]([CH3:30])=[C:8]3[C:13](=[CH:14][C:15]=2[CH3:16])[N:12]=[C:11]([CH3:17])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24](=[O:28])(=[O:27])[NH:25][CH3:26])[C:9]3=[O:29])=[O:5])[CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)c1c(C)cc(NC(C)=O)c(C(=O)O)c1C
Reactant: CCOC(=O)c1c(C)cc2nc(C)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Agent: CNS(=O)(=O)c1ccccc1N
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1ccccc1-n1c(C)nc2cc(C)c(C(=O)OCC3CCC3)c(C)c2c1=O
Temperature: 140 °C

Procedure:
Preparation of 2,5,7-Trimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A heterogeneous mixture of 4-Acetylamino-2,6-dimethyl-isophthalic acid 1-ethyl ester (5.39 g, 1.95 mmol), 2-amino-N-methyl-benzenesulfonamide (3.63 g, 1.95 mmol), and phosphorus trichloride (8.5 mL, 9.7 mmol) in toluene (220 mL) was heated at 140° C. (oil bath temperature) for 3.5 h. The reaction mixture was allowed to cool to room temperature and then evaporated in vacuo. Sufficient ethyl acetate was added to dissolve the residue and the solution was washed with saturated aqueous sodium hydrogen carbonate then brine, dried (Na2SO4) and evaporated in vacuo. Trituration of the residue with dichloromethane gave a white solid, which was removed by filtration. Evaporation of the filtrate solution followed by trituration with ethyl acetate provided a second crop of white solid. The evaporation-trituration procedure was repeated to give two further crops of white solid. The combined white solids were washed with ether and dried in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29].C(Cl)Cl>C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CC2CNCCN2)n1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100-mL round-bottomed flask were added 2-((6-methoxy-2-pyridinyl)methyl)piperazine (373 mg, 1.80 mmol), triethylamine (0.375 mL, 2.70 mmol), 2-thiophenesulfonyl chloride (0.328 mL, 1.80 mmol, Aldrich, St. Louis, Mo., and DCM (5 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((6-methoxy-2-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (135 mg) as viscous oil.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[N+:10]([C:13]1[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-:20].[Na+]>CS(C)=O>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:5][CH2:4][C:3]([CH2:8][CH3:9])([CH2:1][CH3:2])[CH2:6][O:7][C:16]2[CH:17]=[CH:18][C:13]([N+:10]([O-:11])=[O:20])=[CH:14][CH:15]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CCC(CC)(CO)CO
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)(COc1ccc([N+](=O)[O-])cc1)COc1ccc([N+](=O)[O-])cc1

Procedure:
132 g (1 mol) 2,2-diethyl-1,3-dihydroxypropane, 346.5 g (2.2 mols) 4-nitrochlorobenzene and 140 g powdered sodium hydroxide were reacted in the same manner as was described in Example 1 in 600 ml DMSO.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.B(O)(O)O.C1(C)C(C)=CC=CC=1>O>[O:9]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCCCCC(=O)[O-]
Reactant: Nc1ccccc1O
Agent: OB(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCCCc1nc2ccccc2o1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of monoethyl heptanedioate (9.41 g), o-aminophenol (5.46 g), boric acid (3.09 g), and xylene (100 ml) was refluxed with water being azeotropically removed for 16 hours. After cooling to room temperature, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to provide ethyl 6-(benzoxazol-2-yl)hexanoate (10.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]1=[O:15].CN(C=O)C.[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([O:1][CH2:2][CH2:3][N:4]2[CH:9]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[CH:7]=[CH:6][C:5]2=[O:15])=[CH:25][CH:26]=1
Reactant: Clc1ccnc2ccccc12
Reactant: O=c1ccc(-c2cccs2)cn1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2cccs2)cn1CCOc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 1-(2-hydroxyethyl)-5-(thiophen-2-yl)pyridin-2(1H)-one (0.050 g, 0.3 mmol) in DMF (1 mL, 13 mmol) was added sodium hydride (0.080 g, 3 mmol). The resulting mixture was allowed to stir 1.5 hours at ambient temperature. Then 4-chloroquinoline (0.080 g, 0.5 mmol) was added into the mixture and allowed to stir under inert atmosphere overnight. The progress of the reaction was monitored by LC/MS, which showed mostly desired product. The mixture was diluted with CH2Cl2 and water, then extracted the organic layer with CH2Cl2 (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in-vacuo. The crude material was purified by Reverse-Phase HPLC. This gave the desired product as an off-white solid (0.050 g, 45% yield). MS (ESI pos. ion) m/z (MH+): 349. Calc'd exact mass for C20H16N2O2S: 348. 1H NMR (300 MHz, CDCl3): 8.67 (d, J=4.82, 1H), 8.05 (d, J=8.33 Hz, 1H), 7.95 (d, J=8.33 Hz, 1H), 7.73 (s, 1H), 7.56 (d, J=9.79 Hz, 2H), 7.35 (s, 1H), 7.19 (s, 1H), 6.99 (d, J=2.34, 2H), 6.67 (d, J=4.97 Hz, 1H), 6.58 (d, J=9.35 Hz, 1H), 4.48 (s, 4H), 1.74 (s, 1H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:23]=2)[N:20]=[C:19]([CH3:32])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1.O>C(Cl)Cl.CN(C=O)C>[Br:3][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:23]=2)[N:20]=[C:19]([CH3:32])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOP(=O)(OCC)c1cc(-c2ccc(CO)cc2)cc2ccc(C)nc12
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(OCC)c1cc(-c2ccc(CBr)cc2)cc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of POBr3 (150 mg, 0.39 mmol) in CH2Cl2 (4 mL) and DMF (2 mL) was added the product of step 2 (150 mg, 0.39 mmol). The mixture was stirred at r.t. for 0.5 h. H2O was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 159 mg (91%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[C:8]=2[N:9]=1)[CH3:3].FC(F)(F)[C:27]([OH:29])=[O:28]>ClCCl>[C:7]([O:29][C:27](=[O:28])[NH:1][C@@H:2]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=2)[C:6](=[O:15])[C:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[C:8]=2[N:9]=1)[CH3:3])([CH3:13])([CH3:8])[CH3:6]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1ccc(-n2c([C@@H](C)N)nc3c(c2=O)CCCN3C)cc1
Solvent: ClCCl
Product: CCOc1ccc(-n2c([C@@H](C)NC(=O)OC(C)(C)C)nc3c(c2=O)CCCN3C)cc1

Procedure:
(R)-2-(1-Amino-ethyl)-3-(4-ethoxy-phenyl)-8-methyl-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-4-one (G2) To a solution of 110 mg G1 (0.26 mmol, 1.00 equiv.) dissolved in 2 mL dichloromethane cooled by an ice-bath was added 4 mL trifluoroacetic acid all at once. The reaction was equilibrated to room temperature. After 40 min. the reaction was concentrated in vacuo and the concentrate was partitioned between 25 mL each dichloromethane and saturated aqueous sodium bicarbonate. The aqueous separation was extracted again with 25 mL dichloromethane. Combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford G4 as a faint yellow glassy solid, 83 mg. The product was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9](=[O:15])[N:10](CC#C)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O.[CH3:24][C:25]([CH3:27])=O>[N+]([O-])([O-])=O.[Ag+]>[C:1]1([C:7]2[SH:8]([CH2:24][C:25]#[CH:27])[C:9](=[O:15])[N:10]([I:16])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCn1nc(-c2ccccc2)sc1=O
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: C#CC[SH]1C(=O)N(I)N=C1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the solution of 2-phenyl-4-propargyl-1,3,4-thiadiazolin-5-one (1.6 g, 7.4 mmole) in dry acetone (25 ml) under nitrogen with magnetic stirring was added catalytic amount of silver nitrate 0.1 g, 0.58 mmole), followed by N-iodosuccinimide (1.85 g, 8.15 mmole). The reaction mixture was stirred at room temperature for 20 hours. The solid was filtered off by suction-filtration through a Celite filter. The filtrate was diluted with water (200 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was washed with water (2×50 ml), brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated to give a residue. The residue was triturated with hexane and the product was collected by suction-filtration to give 1.75 g as a semicrystalline compound. m.p.=117°-119 C. Proton NMR spectum showed the desired compound.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:16][C:15]=1[C:23]([O:25]C)=O)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C-]#N.[Na+].O>CO>[CH3:1][NH:2][C:23]([C:15]1[S:16][C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:18][C:14]=1[NH:13][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:25]
Reactant: CN
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1sc(C(C)(C)C)cc1NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 20 %

Procedure:
To a saturated solution of methylamine in MeOH (200 mL) in a screw top vessel was added methyl 3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxylate (13.6 g, 39.2 mmol) and NaCN (0.98 g, 20 mmol). The vessel was sealed and the reaction mixture was heated to 50° C. for 8 h. The resulting solution was poured into water (500 mL) and extracted with EtOAc. The organic layer was washed with water and a concentrated NaCl solution, dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc/hexane) affording N-methyl-3-(N-carbobenzyloxyamino)-5-tert-butylthiophene-2-carboxamide (2.76 g, 20%).
Reaction SMILES: O(C1C=CC(N[N:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])=CC=1)C1C=CC=CC=1.[O:21]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(#N)CC#N.O.[NH2:41][NH2:42]>>[O:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][N:15]=[C:16]2[C:17]([NH2:18])=[N:42][N:41]=[C:19]2[NH2:20])=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(Oc2ccccc2)cc1

Procedure:
4-[(4-phenoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 131 mg (0.5 mmol) of 2-[(4-phenoxyphenyl)hydrazono]malononitrile, which was derived from 4-phenoxyaniline (185 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 90 mg (61%) of the compound as an orange solid.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][CH:12]2[C:11](=[O:19])[CH:10]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]3[CH2:31][NH:30]3)=[CH:28][C:23]=2[O:22][CH2:21]1>O1CCCC1>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]3[CH2:31][N:30]3[C:9]3[CH:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][CH:12]4[C:11](=[O:19])[CH:10]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: CC1(C)OC2C(=O)C=C(Cl)C2O1
Reactant: c1cc2c(cc1C1CN1)OCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OC2C(=O)C=C(N3CC3c3ccc4c(c3)OCO4)C2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Triethylamine (0.4 mL, 3.0 mmol, 2.0 equiv) and 13-chloroenone 53 (280 mg, 1.5 mmol, 1.0 equiv) were sequentially added to a stirred solution of aziridine 15 (360 mg, 2.2 mmol, 1.5 equiv) in tetrahydrofuran (10 mL) at 25° C. The resulting white mixture was stirred at 25° C. for 3 h. The crude reaction mixture was loaded directly onto a column and purified by silica gel column chromatography (1% triethylamine and 49% benzene in ethyl acetate) to afford 54 (400 mg, 85% yield) as a yellow foam. Rf=0.68 (1% triethylamine and 49% benzene in ethyl acetate); 1H NMR (500 MHz, C6D6) δ 6.55-6.70 (m, 3H, ArH), 5.24-5.28 (m, 2H, OCH2O), 5.14-5.18 (m, 1H, NCCH), 4.50-4.56 (m, 1H, CH(OR)), 4.19-4.27 (m, 1H, CH(OR)), 2.46-3.18 (m, 1H, ArCHN), 1.84-2.17 (m, 1H, CH2N), 1.63-1.78 (m, 1H, CH2N), 1.28-1.32 (m, 3H, CH3), 1.10-1.12 (m, 3H, CH3); IR (neat film) 2989 (w), 1703 (m), 1586 (s) cm−1; HRMS (ESI) m/z: Calcd for C17H18NO5 (MH+) 316.1185, observed 316.1186.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(OCC)(=O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)c1ccc(C(=O)O)cc1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)Cl)cc1
Yield: 77.9 %

Procedure:
4-Dimethylaminobenzoic acid (250 g, 1.51 moles) was suspended in 2 L of ethyl acetate. Thionyl chloride (359.3 g, 3.02 moles) was added dropwise with stirring. After completion of the reaction, the solvent was removed by rotary evaporation affording a gray solid. The solid was crystallized from ethyl acetate to give 216 g of 4-dimethylaminobenzoyl chloride, yield 78%.
Reaction SMILES: [C:1]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:33]([N:27]1[CH2:28][C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:2]([C:1]([N:11]2[C@@H:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][O:13][C:12]2=[O:23])=[O:10])[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH2:33]([N:27]1[CH2:28][C@@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:2]([C:1]([N:11]2[C@@H:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][O:13][C:12]2=[O:23])=[O:10])[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %
Yield: 43 %

Procedure:
A solution of 402 g (1.3 mol) of 3-((E)-cinnamoyl)-4-(S)-benzyloxazolidin-2-one (from EXAMPLE 1, Step A) and 474 g (2.0 mol) of N-methoxymethyl-N-trimethylsilylmethyl benzyl amine in 4 L of CH2Cl2 at −10° C. was treated with 6 mL of TFA. The resulting mixture was stirred cold for 4 h and then was treated with an additional 4 mL of TFA. The reaction mixture was warmed to rt and stirred for 20 h. The reaction was quenched with 2 L of sat'd NaHCO3 and the layers were separated. The organic layer was washed with 1 L of sat'd NaCl and concentrated. Chromatography on 10 kg of silica gel using 4:1 v/v hexanes/EtOAc (24 L), then 7:3 v/v hexanes/EtOAc (36 L), then 3:2 v/v hexanes/EtOAc (32 L) afforded 260.9 g (45%) of 3-(1-benzyl-4-(S)-phenylpyrrolidine-3-(R)-carbonyl)-4-(S)-benzyloxazolidin-2-one and 247.5 g (43%) of 3-(1-benzyl-4-(R)-phenylpyrrolidine-3-(S)-carbonyl)-4-(S)-benzyloxazolidin-2-one. For 3-(1-benzyl-4-(S)-phenylpyrrolidine-3-(R)-carbonyl)-4-(S)-benzyloxazolidin-2-one: 1H NMR (500 MHz) δ 2.66 (t, J=8.0, 11H), 2.78 (dd, J=13.0, 9.0, 11H), 2.87 (dd, J=9.0, 4.5, 1H), 3.21-3.27 (m, 2H), 3.64 (d, J=11.5, 1H), 3.77 (d, J=11.5, 1H), 4.104.15 (m, 2H), 4.61-4.65 (m, 1H), 7.16-7.38 (15H). For 3-(1-benzyl-4-(R)-phenylpyrrolidine-3-(S)-carbonyl)-4-(S)benzyloxazolidin-2-one: 1H NMR (500 MHz) δ 2.69-2.76 (m, 2H), 2.82 (dd, J=9.5, 5.5, 1H), 3.14-3.22 (3H), 3.64 (d, J=13.0, 1H), 3.74 (d, J=13.0, 1H), 4.074.12 (m, 2H), 4.16 (t, J=9.0, 1H), 4.26-4.30 (m, 1H), 4.654.69 (m, 1H), 7.03-7.40 (15H).