Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCCCC(O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of N-[2-fluoro-4-(1-hydroxyhexyl)phenyl]-2,2-dimethylpropanamide (18.5 g, 62.6 mmol) in CH2Cl2 (300 mL) was treated with 4-methylmorpholine N-oxide (7.35 g, 62.6 mmol) followed by tetrapropylammonium perruthenate (TPAP, 0.22 g, 0.63 mmol). The mixture was stirred at room temperature for 30 minutes, then treated with additional TPAP (0.88 g, 2.5 mmol) and stirred an additional 30 minutes at room temperature. The mixture was filtered through a pad of MgSO4 atop a pad of silica gel, washing through with EtOAc (500 mL). The filtrate was evaporated under vacuum to afford N-(2-fluoro-4-hexanoylphenyl)-2,2-dimethylpropanamide (17.8 g, 97%) as a white solid.
Reaction SMILES: C1([C:7](C2C=CC=CC=2)([O:13][Si](C)(C)C)[C@@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)C=CC=CC=1.S(N[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(C1C=CC(C)=CC=1)(=O)=O.C([O-])(=O)C.[Na+].C(=O)/C=C/CC>C(Cl)(Cl)Cl>[CH2:11]([C@@H:12]1[C@@H:8]([CH:7]=[O:13])[N:9]1[C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: C[Si](C)(C)OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Agent: CC(=O)[O-]
Agent: CC/C=C/C=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[C@@H]1[C@@H](C=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a 500 mL round-bottom flask equipped with a stir bar was added (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (2.60 g, 8.00 mmol) and CHCl3 (200 mL). To the solution was added tert-butyl tosylcarbamate (10.9 g, 40.0 mmol). The flask was placed in a room temperature-water bath. To the stirred solution was added sodium acetate (9.84 g, 120 mmol), then (E)-pent-2-enal (4.04 g, 48.0 mmol). The mixture was stirred at room temperature for 40 minutes. The mixture was filtered, washing the filter cake with a small amount of CHCl3. The filtrate was concentrated in vacuo at 30° C. The resulting orange liquid was dissolved in Et2O (400 mL) and transfered to a 1 L separatory funnel. The solution was washed with water:aq. sat. NaHCO3 (200 mL:200 mL). The aqueous phase was extracted with Et2O (100 mL). The combined organics were washed with brine (200 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford (2R,3S)-tert-butyl 2-ethyl-3-formylaziridine-1-carboxylate as a pale orange liquid.
Reaction SMILES: C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:41][CH:42]2[S:46][C:45](=[O:47])[NH:44][C:43]2=[O:48])=[C:24]2[C:29]=1[N:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][CH:32]=1)[C:27](=[O:40])[CH2:26][CH2:25]2.[CH:49]([C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1)([CH3:51])[CH3:50]>O.CN(C=O)C>[CH:49]([C:52]1[CH:58]=[CH:57][C:55]([NH:56][C:37]([C:34]2[CH:33]=[CH:32][C:31]([CH2:30][N:28]3[C:29]4[C:24](=[C:23]([CH2:41][CH:42]5[S:46][C:45](=[O:47])[NH:44][C:43]5=[O:48])[CH:22]=[CH:21][C:20]=4[O:19][CH3:18])[CH2:25][CH2:26][C:27]3=[O:40])=[CH:36][CH:35]=2)=[O:38])=[CH:54][CH:53]=1)([CH3:51])[CH3:50]
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(C(=O)O)cc1)C(=O)CC2
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(C(=O)Nc3ccc(C(C)C)cc3)cc1)C(=O)CC2
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.34 g of triethylamine and 0.28 g of diethyl phosphorocyanidate (DEPC) were added with ice cooling to a DMF solution (10 ml) of 0.5 g of 5-[8-methoxy-1-(4-carboxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione and 0.23 g of 4-isopropylaniline, followed by stirring for 0.5 hours. Water was added to the reaction liquid and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→20:1), and recrystallized from a mixed solvent of ethyl acetate and n-hexane, giving 0.57 g (64% yield) of 5-{1-[4-(4-isopropylphenylaminocarbonyl)benzyl]-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH3:12][C:13]1[CH:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH3:24])[C:14]=1[CH:15]=[O:16]>O1CCOCC1>[CH3:23][N:21]([CH3:22])[C:19]1[CH:20]=[C:13]([CH3:12])[C:14]([CH:15]2[O:16][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[C:17]([CH3:24])[CH:18]=1
Reactant: Cc1cc(N(C)C)cc(C)c1C=O
Reactant: CC1(C)N=C1c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(N(C)C)cc(C)c1C1OC(C)(C)N=C1c1ccccc1

Procedure:
2.25 g of 2,2-dimethyl-3-phenyl-2H-azirine and 2 g of 2,6-dimethyl-4-(dimethylamino)benzaldehyde were exposed to light for 3 hours in 350 ml of 1,4-dioxane (with the light source described in Example 2). After purification as described in Example 11 and crystallization from n-pentane, there was obtained 5-[4-(dimethylamino)-2,6-xylyl]-2,2-dimethyl-4-phenyl-3-oxazoline which melted at 105° C. after drying for 4 hours at 60° C. and 13 Torr.
Reaction SMILES: Cl.F[C:3]1C=CC=CC=1C1C2C=C(Cl)C=CC=2N2N=C(C(N3CCN(C)CC3)=O)N=C2CN=1.[F:33][C:34]1[CH:66]=[CH:65][CH:64]=[CH:63][C:35]=1[C:36]([C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=1[N:45]1[C:49]([CH2:50][N:51]([CH3:53])[CH3:52])=[N:48][C:47]([C:54]([N:56]2CCN(C)[CH2:58][CH2:57]2)=[O:55])=[N:46]1)=[O:37].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH:57]([NH:56][C:54]([C:47]1[N:48]=[C:49]([CH2:50][N:51]([CH3:52])[CH3:53])[N:45]([C:39]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:38]=2[C:36](=[O:37])[C:35]2[CH:63]=[CH:64][CH:65]=[CH:66][C:34]=2[F:33])[N:46]=1)=[O:55])([CH3:58])[CH3:3]
Reactant: CN1CCN(C(=O)c2nc3n(n2)-c2ccc(Cl)cc2C(c2ccccc2F)=NC3)CC1
Reactant: CN(C)Cc1nc(C(=O)N2CCN(C)CC2)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(C)NC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2F)n1

Procedure:
from the base liberated from 23.8 g (0.050 mole) of 1-[[6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepin-2-yl]-carbonyl]-4-methylpiperazine hydrochloride: -1-[[1-[2-(o-fluorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazol-3-yl]-carbonyl]-4-methylpiperazine and the dihydrochloride thereof.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.Br[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18]C.[Mg].[Cl-].[NH4+]>C1COCC1>[Cl:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[C:11]([OH:18])[CH:12]=1
Reactant: O=Cc1cccnc1
Reactant: COc1cc(Cl)c(C)cc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cccnc2)c(O)cc1Cl
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of 3-pyridinecarbaldehyde (2.2 g) in THF (50 ml) was treated dropwise with a solution (50 ml) of Grignard reagent prepared from 1-bromo-4-chloro-2-methoxy-5-methylbenzene (5.0 g) and magnesium (0.8 g) in THF at 0° C., and stirred for 1 hour. The reaction solution was combined with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resultant residue was used in the next step without purification, combined with toluene (150 ml) and manganese dioxide (15 g), and heated under reflux with dehydrating using Deen Stark for 1 hour. After the reaction was completed, the reaction solution was filtered using celite, the filtrate was concentrated under reduced pressure. The resultant residue was combined with methylene chloride (50 ml) and a 1 N solution of BBr3/methylene chloride (60 ml), and stirred at room temperature overnight. After the reaction was completed, water was added, and the solvent was distilled off under reduced pressure. The resultant residue was neutralized with the addition of a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The extract was washed with water, and then dried over magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by a silica gel column (eluent: ethyl acetate) to obtain the title compound as an oil (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]([CH2:30][CH2:31][NH:32][CH3:33])=[CH:24][C:23]=1[Br:34]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:32]([CH3:33])[CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[C:22]([NH2:21])=[C:23]([Br:34])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCc1cc(Br)c(N)c(C#N)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Br)c(N)c(C#N)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloro-propane and 2-(4-amino-3-bromo-5-cyano-phenyl)-N-methyl-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][OH:20])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2CCC1(CO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.99 g of the title compound of Step C and 0.6 ml of methanesulfonyl chloride in 20 ml of THF at 0° C. was added 1.05 ml of triethylamine. The reaction was stirred overnight at room temperature, partitioned between 5% aqueous sodium bicarbonate and chloroform, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane to afford 1.1 g of the title compound as a viscous yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:4]([S:25][CH2:26][CH2:27]I)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:27][CH2:26][S:25][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c([N+](=O)[O-])cc32)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 4-(4-fluoro-2-(2-iodoethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (394 mg, 0.750 mmol) in DMF (5 mL) was added potassium carbonate (207 mg, 1.500 mmol), and the resulting mixture was stirred at 60° C. for 2 hours and then at 90° C. overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium carbonate (3×), water, and brine. The organic phase was dried, filtered, concentrated, and then chromatographed using 1:9 ethyl acetate:hexanes giving the desired product (193 mg, 64.7%) as a red foam. 1H NMR (DMSO-d6) δ 7.42 (d, J=6.6 Hz, 1H), 7.30 (d, J=11.7 Hz, 1H), 4.10-3.95 (m, 2H), 3.91-3.79 (m, 1H), 3.41-3.36 (m, 2H), 3.13-3.09 (m, 2H), 2.99-2.78 (m, 2H), 1.73-1.63 (m, 2H), 1.63-1.51 (m, 2H), 1.41 (s, 9H); ESI-MS (m/z, %): 420 (MNa+, 52), 398 (MH+, 35), 342 (100), 298 (64).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccccc1Cl
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 5.26 mL (40 mMol) 2-(2-chlorophenyl)ethanol and 8.36 mL (60 mMol) triethylamine in 100 mL tetrahydrofuran were added dropwise 3.25 mL (42 mMol) methanesulfonyl chloride with cooling. The reaction mixture was stirred 4 hours at ambient and was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed sequentially with water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 9.22 gm (98.3%) of the title compound as a yellow oil. The product was used without further purification.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].CCCCCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8](/[N:10]=[CH:13]/[N:14]([CH3:16])[CH3:15])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)c1nnc(N)s1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CN(C)/C=N/c1nnc(C(C)(C)C)s1
Temperature: 100 °C

Procedure:
A mixture of 5-tert-butyl-1,3,4-thiadiazol-2-amine (Aldrich) (10.0 g, 63.6 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (26.3 mL, 197 mmol) in 200 mL of toluene was heated at 100° C. for 12 hours. The mixture was cooled to room temperature and hexane was added. The solid was collected by filtration (hexane wash) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]([OH:18])=O)[C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH:10]3[C:11]([C:12]=2[CH:13]=1)=[N:26][N:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](=[O:18])[CH2:15]3)([O-:3])=[O:2]
Reactant: NNc1ccccc1
Reactant: O=C(O)CC1CCc2ccc([N+](=O)[O-])cc2C1=O
Solvent: CCO
Product: O=C1CC2CCc3ccc([N+](=O)[O-])cc3C2=NN1c1ccccc1

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid and phenylhydrazine in ethanol is refluxed under heating for 10 hours. The ethanol is distilled off and to the residue is added acetic acid and then the resulting mixture is refluxed under heating for 8 hours. After the acetic acid is distilled off, the mixture is extracted with chloroform and the extract is washed with water. After drying over magnesium sulfate anhydride, the chloroform is distilled off to give 9-nitro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:22]([O:24][C:25](=[O:37])[CH:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)[CH3:23].[NH4+].[Cl-]>C1COCC1>[CH2:22]([O:24][C:25](=[O:37])[CH2:26][C@@H:27]([C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[CH3:23]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc2ccoc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](c1ccc2ccoc2c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-α-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF (25 mL) at 0° C. was treated with n-BuLi (2.52 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of acrylate 3-4 (0.681 g, 3.15 mmol) in THF (5 mL) was added. After stirring for 15 min at −78° C., satd. aq. NH4Cl soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the β-aminoester 3-5 as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([OH:29])=[CH:5][C:6]([C:8]1[C:9](=[O:28])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:11]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)=[O:7].[OH-].[Na+].Cl>CO>[CH2:21]([N:10]1[CH:11]=[C:12]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[C:8]([C:6](=[O:7])[CH:5]=[C:4]([OH:29])[C:3]([OH:30])=[O:2])[C:9]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(O)=CC(=O)c1cc(Cc2ccccc2)cn(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(O)=CC(=O)c1cc(Cc2ccccc2)cn(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl-4-(1,5-dibenzyl-1,2-dihydro-2-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoate 7 (0.069 g, 0.17 mmol) in MeOH (5 mL) at 0° C. was added a solution of 1N NaOH (0.5 mL) and reaction mixture allowed to stir at 0° C. for 30 min. Reaction was then allowed to stir at ambient temperature for 1 h. The reaction mixture was neutralized with 1 N HCl, the solid separated was filtered and dried under vacuum. Recrystallization with EtOAc/Hexane gave yellow solid. Yield 0.034 g (52%), yellow solid, mp 158-159° C. 1H NMR (CDCl3, 500 MHz): δ 3.82 (s, 2H, CH2), 5.26 (s, 2H, CH2), 7.16-7.39 (m, 10H, Ar—H), 7.45 (d, 1H, CH, J=2 Hz), 7.98 (s, 1H, olefenic CH), 8.26 (d, 1H, CH, J=2 Hz), 13C NMR (CDCl3, 125 MHz): δ 37.5, 53.3, 100.8, 119.8, 123.1, 127.0, 128.2, 128.5, 128.5, 128.6, 128.6, 128.9, 128.9, 129.0, 129.1, 129.1, 135.2, 138.4, 141.3, 145.1, 159.5, 162.3, 173.7; HRMS (M+H)+ calcd for C23H20NO5 390.1341, found 390.1342.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:19]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
From 4-nitrobenzyl alcohol (5.0 g; 33 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 15 min at 135° C. The yield was 0.95 g (52%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:41])[C@H:22]([CH2:38][CH2:39]O)[CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:25]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Al]>C(Cl)Cl.C1(C)C=CC=CC=1.O.CCOC(C)=O.CC(OC)(C)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:41])[C@H:22]2[CH2:23][N:24]3[C:32]4[C:27]([C:26]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:25]3[CH:39]=[CH:38]2)=[CH:28][CH:29]=[CH:30][CH:31]=4)(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1cn(C[C@@H](CCO)N(C)S(=O)(=O)c2ccc(F)cc2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c2n(c3ccccc13)C[C@H](N(C)S(=O)(=O)c1ccc(F)cc1)C=C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of CH2Cl2, oxalyl chloride (0.54 M, 1.2 equiv.) was cooled to −76° C. DMSO (2.5 equiv.) was then added dropwise such that T<−60 ° C. The mixture was stirred for 30 min, upon which methyl (1-{(2R)-2-[[(4-fluorophenyl)sulfonyl](methyl)amino]-4-hydroxy-butyl}-1H-indol-3-yl)acetate from Step 6 was added as a solution in CH2Cl2 (0.3 M). The reaction was stirred an additional 30 min. Triethylamine (4 equiv.) was then added dropwise, and the reaction warmed to rt and stirred for 2 h. The reaction was quenched by the addition of saturated NaHCO3. The layers were separated, and the aqueous back-extracted with CH2Cl2 (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered through a plug of SiO2 and concentrated to give a yellow foam. This crude aldehyde was dissolved in toluene (0.25 M) and charged in a three necked round bottom flask fitted with a temperature probe, nitrogen inlet, reflux condenser, and mechanical stirrer. Pyridinium p-toluenesulfonate (0.2 equiv.) was added, and the reaction heated to 60° C. for 16 h (protected from light with aluminum foil). The reaction was diluted with water and extracted with EtOAc. The layers were separated, and the aqueous back extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (20:80 to 40:60) to give a light yellow foam. This light yellow foam was then swished by dissolving in EtOAc (2 mL/g), slow addition of MTBE (5 mL/g), then slow addition of Heptanes (7 mL/g) to give the title compound (73%) as an off white solid . The mother liquor was concentrated and purified by flash again to more (7%) of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[CH:7][N+:8]([O-:10])=[O:9].[Br:11]Br>O>[Br:11][C:7]([N+:8]([O-:10])=[O:9])=[C:3]1[NH:4][CH2:5][CH2:6][N:2]1[CH3:1]
Reactant: BrBr
Reactant: CN1CCNC1=C[N+](=O)[O-]
Solvent: O
Product: CN1CCNC1=C(Br)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A stirred solution of 3.57 grams of 1-methyl-2(nitromethylene)imidazolidine (Compound 1) in 25 milliliters of water was treated dropwise with 3.99 grams of bromine at room temperature. After 30 minutes, the reaction mixture was extracted with methylene chloride. The extract was dried (MgSO4) and the solvent was evaporated to give 3.0 grams of crude product, melting point 100° (with vigorous decomposition). Recrystallization of the crude product from methylene chloride gave 15, melting point: 97° (explodes).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[CH3:26].[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:14][CH:15]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Commercially available ethyl 2-(4-formylphenoxy)acetate (20.0 g, 0.1 mol) and commercially available 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 200 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (22.0 g, 0.392 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water and brine (200 mL each), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained yellow oil was dried under high-vacuum, 10 g (33%) of yellowish solid was obtained. MS (EI): 313 (MH+).