Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH3:4][C:5]1([CH3:19])[CH2:11][CH2:10][CH2:9][NH:8][C:7]2[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:6]1=2>[Pd].C(O)C>[CH3:4][C:5]1([CH3:19])[CH2:11][CH2:10][CH2:9][NH:8][C:7]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:6]1=2
Reactant: CC1(C)CCCNc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1(C)CCCNc2ccc(N)cc21
Yield: 90.5 %

Procedure:
Added 6 mL of ethanol, 10% Palladium on activated carbon (50% wet with water for safety) (60 mg), and hydrazine monohydrate (89 ul) to 5,5-Dimethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (101 mg, 0.459 mmol). Heated reaction to 60° C. for 22 hours. Filtered reaction through Celite, and concentrated under reduced pressure. Purified with normal phase silica gel chromatography eluting with 5% methylene chloride in methanol to obtain a brown oil, 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (79 mg, 91%). LCMS: m/z=190.99 (M+H+), 1H NMR (400 MHz, CDCl3) δ 6.73 (d, 1H, J=2.0 Hz), 6.55 (d, 1H, J=8.1 Hz), 6.43 (dd, 1H, J=8.1, 1.5 Hz), 3.40 (br s, 3H), 2.97 (m, 2H), 1.86 (m, 2H), 1.59 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:70])([F:69])[C:25]1[CH:26]=[C:27]([C@H:35]2[O:39][C:38](=[O:40])[N:37]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:43]=3[C:52]3[C:57]([Cl:58])=[CH:56][CH:55]=[C:54]([C:59]4[CH:64]=[CH:63][C:62]([CH2:65][OH:66])=[CH:61][C:60]=4[CH3:67])[CH:53]=3)[C@H:36]2[CH3:68])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[F:70][C:24]([F:23])([F:69])[C:25]1[CH:26]=[C:27]([C@H:35]2[O:39][C:38](=[O:40])[N:37]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:45]=[CH:44][C:43]=3[C:52]3[CH:53]=[C:54]([C:59]4[CH:64]=[CH:63][C:62]([CH:65]=[O:66])=[CH:61][C:60]=4[CH3:67])[CH:55]=[CH:56][C:57]=3[Cl:58])[C@H:36]2[CH3:68])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1
Reactant: Cc1cc(CO)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin Periodinane (145 mg, 0.34 mmol) was added to a solution of alcohol from Example 49 (200 mg, 0.285 mmol) in methylene chloride (5 ml) at room temperature. The resulting slurry was stirred at room temperature for 1 h. No starting material was seen by TLC (EtOAc/hexane 2:8). The solid was filtered. The filtrate was concentrated. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (30:70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 6:4 atopoisomers 10.03 (s, 1H), 7.90 (s, ⅖H), 7.89 (s, ⅗H), 7.83 (s, 1H), 7.78 (d, J=8.0 Hz, ⅗H), 7.75 (d, J=8.0 Hz, ⅖H), 7.74 (s, 1.2H), 7.73 (s, 0.8H), 7.72 (s, ⅖H), 7.70 (s, ⅗H), 7.64 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, ⅗H), 7.47 (d, J=8.0 Hz, ⅖H), 7.46 (d, J=8.0 Hz, ⅗H), 7.43 (d, J=8.0 Hz, ⅖H), 7.40 (m, 1H), 7.28 (m, 1.5H), 7.23 (d, J=2.0 Hz, 0.5H), 5.64 (d, J=8.0 Hz, 1H), 5.04 (d, J=15.5 Hz, ⅗H), 4.83 (d, J=16 Hz, ⅖H), 4.09 (d, J=16 Hz, ⅖H), 4.01 (d, J=15.0 Hz, ⅗H), 4.00 (m, ⅖H), 3.91 (m, ⅗H), 2.43 (s, 1.8H), 2.41 (s, 1.2H), 0.65 (d, J=6.5 Hz, 1.8H), 0.61 (d, J=7.0 Hz, 1.2H).
Reaction SMILES: [C:1]([O:10][C:11]1[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:19](O)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].P(Cl)(Cl)(Cl)=O.Cl.[OH-].[Na+]>CN(C)C=O>[CH3:18][O:17][C:12]1[C:11]([O:10][C:1]([C:2]2[C:3]([O:4][C:19]([C:20]3[C:21]([OH:22])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:27])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:9])=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1O
Reactant: COc1ccccc1OC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccccc1OC(=O)c1ccccc1OC(=O)c1ccccc1O
Yield: 60 %

Procedure:
244 g of guaiacol salicylate (1.0 mole) and 138 g of salicylic acid (1.0 mole) are suspended in 1 liter of dimethylformamide. 80 g of phosphorus oxychloride are added over a period of about one hour to the solution, which is kept heated under agitation to 60°-70° C., and the mixture is maintained at this temperature until hydrochloric acid ceases to be evolved. The homogeneous dense mass, of straw colour, is poured under energetic agitation into 5 liters of a water-ice mixture and the suspension is neutralised slowly with dilute sodium hydroxide. The crystalline white solid which precipitates is filtered off, washed abundantly with water and then crystallised from isopropanol to obtain an overall yield of 60%. The product has a melting point of 85°-86° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[C:8]([CH:13]3[CH2:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:23](O)(=[O:27])[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:23]([C:16]1[C:17](=[O:19])[CH2:18][CH:13]([C:8]2[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH2:6][C:5]=3[C:7]=2[CH3:21])[CH2:14][C:15]=1[OH:20])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1c(C)c(C2CC(=O)CC(=O)C2)c(C)c2c1OC(C)(C)C2
Reactant: CCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c3c(c2C)CC(C)(C)O3)CC1=O
Temperature: 25 °C

Procedure:
To a solution of 3.18 g of the 5-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)cyclohexane-1,3-dione in 50 ml of absolute toluene was added 6.93 ml of anhydrous butyric acid and refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford an oily residue. To the solution of the residue in 50 ml of absolute toluene was added 0.26 g of 4-dimethylaminopyridine. After refluxing 8 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 3.8 g of 2-butyryl-5-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)-3-hydroxycyclohex-2-en-1-one as a yellow solid.
Reaction SMILES: [NH3:1].C([O:6][C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8])(C)(C)C>CO>[C:7]([C:9]1[CH:10]=[C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH2:19][NH2:1])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([OH:6])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: N
Solvent: CO
Product: NCc1ccc(-c2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonia gas was passed through a cooled solution of 4-(3-tert-butoxycarbonylphenyl) benzyl bromide (65 g, 0.18 mol) in methanol (2 L) for 6 h. Then the reaction mixture was stirred at RT overnight. Methanol was removed under vacuum. To the residue 6N aqueous solution of HCl (200 mL) was added and stirred overnight. Concentrated completely to get 4-(3-carboxyphenyl)benzylamine as a hydrochloride salt (20 g, 41%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:21]([O:23]C)=O)=[N:4][N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:7](=[O:20])[C:6]=12.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH2:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH:30][C:21]([C:3]1[C:2]([OH:1])=[C:6]2[C:7](=[O:20])[N:8]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[CH2:9][CH2:10][N:5]2[N:4]=1)=[O:23]
Reactant: COC(=O)c1nn2c(c1O)C(=O)N(CC(=O)N1CCOCC1)CC2
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1nn2c(c1O)C(=O)N(CC(=O)N1CCOCC1)CC2
Temperature: 90 °C

Procedure:
Methyl 3-hydroxy-5-[(2-morpholin-4-yl)-2-oxoethyl]-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (15 mg, 0.044 mmol) was dissolved in 3,4-dichlorobenzylamine (1.5 mL) and heated to 90° C. for 30 minutes. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, d6-DMSO) δ 8.89-8.86 (t, 1H), 7.55-7.51 (m, 2H), 7.27-7.25 (d, 1H), 4.40-4.38 (d, 2H), 4.33-4.29 (m, 4H), 3.84 (br s, 1H), 3.74-3.71 (t, 2H), 3.58-3.52 (m, 4H), 3.42-3.39 (m, 4H); ES MS (M+1)=482.
Reaction SMILES: [CH:1]1[C:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3](Cl)[CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([C:6]2[CH:5]=[CH:4][C:3]([O:26][C:21]3[CH:22]=[CH:23][C:24]([NH2:25])=[C:19]([CH3:18])[CH:20]=3)=[CH:2][CH:1]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Cc1cc(O)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)ccc1N
Temperature: 25 °C
Reaction time: 28 h
Yield: 42.9 %

Procedure:
To a 250 mL flask equipped with stirrer, condenser, under nitrogen atmosphere, was added 20 g (0.070 mol) of 4,4'-dichlorodiphenylsulfone, 12.8 g (0.104 mol) of 3-methyl-4-aminophenol, 15.5 g (0.112 mol) of potassium carbonate, and 130 mL of dimethylformamide. The resulting mixture was stirred at room temperature for 24 hours and at 125° for 28 hours. It was cooled and concentrated. The concentrated material was dissolved in 400 mL of toluene and washed with 4% sodium hydroxide, followed by water and brine washes. The organic layer was dried over sodium sulfate, concentrated, and chromatographed through 350 g of florisil column. Elution with hexane/ethylacetate (8/2) afforded 11.2 g (0.030 mol) of a yellow solid; mp 200° D.
Reaction SMILES: C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C1(O)C=CC=CC=1.C1(O)C=CC=CC=1.C(NC1C=CC=CC=1)=O>>[C:20]1([N:19]=[C:17]=[O:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CNc1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: Oc1ccccc1
Product: O=C=Nc1ccccc1
Yield: 90.3 %

Procedure:
Diphenyl carbonate (33.2 grams, 0.155 mole) is charged to a 50 ml three-neck flask equipped with a magnetic stirbar, a six inch Vigreaux column topped with a short path distillation head and an electrically heated addition funnel charged with a solution of formanilide (4.69 grams, 0.039 mole) in molten phenol (16.56 grams, 0.176 mole). The diphenyl carbonate is heated to 213° C. at 100 mmHg vacuum and the phenol/formanilide mixture added dropwise over a 50 minute period. When the addition is complete, the vacuum is slowly lowered to 5 mmHg over the next 10 minutes to remove the remaining phenol and phenyl isocyanate from the remaining diphenyl carbonate. Internal standard gas chromatographic (IS/GC) analysis of the overhead (29.72 grams) and pot material (22.94 grams) shows production of 4.17 grams of phenyl isocyanate and 0.02 grams of phenyl isocyanate as phenol carbamate, as a solution in phenyl formate and phenol, a recovery of 0.0352 moles of phenyl isocyanate (91.0% yield, based on formanilide fed). In calculating the yield of isocyanate, the easily thermolyzed carbamate is considered as isocyanate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=O.C([O-])(O)=O.[Na+]>CCO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=4)[N:1]=[C:2]3[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)sc1nc(-c3ccc(Br)cc3)cn12
Yield: 54 %

Procedure:
In the minimum volume of EtOH was dissolved the commercially available 2-amino-6-methoxybenzothiazole (2 mmol), then 2,4′-dibromoacetophenone (2 mmol) was added and the resulting mixture was refluxed for 5 h before addition of NaHCO3 (3 mmol). After 2 h more of reflux, the precipitate was filtered off, washed with a mixture 1/1 AcOEt/hexane and dried in vacuum and then used in the next step, optionally, without further purification. The result was a white solid as a 54% yield.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[CH2:14]([CH:17]([C:20]#[N:21])[C:18]#[N:19])[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([C:17]([CH2:8][N:6]1[CH:7]=[C:3]([Br:2])[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5]1)([C:20]#[N:21])[C:18]#[N:19])[CH:15]=[CH2:16]
Reactant: C=CCC(C#N)C#N
Reactant: CC(C)(C)c1nn(CCl)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cc(Br)c(C(C)(C)C)n1
Yield: 40.9 %

Procedure:
1.84 g of 4-bromo-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.77 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.02 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.84 g of allyl [(4-bromo-3-t-butyl-1H-pyrazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (14), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].[CH:13](=O)[CH3:14]>O.CO>[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:13]([CH3:14])[N:9]=1
Reactant: CN(C)C(=N)N=C(N)N
Reactant: CC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 84 %

Procedure:
A 4 L two neck flask charged with 662 g (4 mol) metformin HCl and 1600 mL MeOH was stirred with a magnetic bar at 750 rpm at room temperature with a water bath. To this suspension was added sodium hydroxide 160 g (4 mol) in 200 mL water through one dropping funnel. At the same time acetaldehyde 226 mL (4 mol) in 400 mL of MeOH in another funnel was added to the mixture. The addition of NaOH solution finished in 70 minutes whereas the addition of acetaldehyde finished in 100 minutes. Then, the reaction mixture was filtered through celite to remove the sodium chloride. The solution was concentrated to give a white solid that was extracted with 1.2 L of hot ethanol to give a suspension. After filtration, the ethanol solution was concentrated to give a pale yellow solid, 520 g, yield is 84%.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)(C)(C)C.Cl.[NH2:14][CH2:15][CH2:16][NH:17][C:18]1[C:19]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=3)[C:26](=[O:36])[O:25][N:24]=2)=[N:20][O:21][N:22]=1.C(N(CC)CC)C>ClCCl.Cl>[Cl:35][C:30]1[CH:29]=[C:28]([N:27]2[C:26](=[O:36])[O:25][N:24]=[C:23]2[C:19]2[C:18]([NH:17][CH2:16][CH2:15][NH:14][S:2]([NH2:5])(=[O:4])=[O:3])=[N:22][O:21][N:20]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of chlorosulfonyl isocyanate (2.0 mL, 23 mmol) in dichloromethane (70 mL) was treated with t-butyl alcohol (2.2 mL, 23 mmol) at 0° C. and stirred at 25° C. for 1 h. This mixture was added to a suspension of 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (4.3 g, 11 mmol) in dichloromethane (70 mL). The reaction mixture was treated with a solution of triethylamine (6.3 mL, 45 mmol) in dichloromethane (20 mL) at 0° C. and stirred at 25° C. for 3 h. The reaction mixture was diluted with 0.1 N HCl and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a white solid. The white solid was diluted with dichloromethane (100 mL), treated with trifluoroacetic acid (20 mL), and stirred at 25° C. for 3 h. The reaction mixture was concentrated to a crude residue that was purified by silica gel chromatography to give the desired product (3.7 g, 78%) as a white solid. LCMS for C12H12ClFN7O5S (M+H)+: m/z=420.0. 1H NMR (300 MHz, DMSO-d6): δ 7.98 (dd, J=6.4, 2.1 Hz, 1H), 7.70-7.60 (m, 2H), 6.66 (t, J=5.9 Hz, 1H), 6.57 (s, 2H), 6.52 (t, J=5.9 Hz, 1H), 3.42-3.35 (m, 2H), 3.13-3.06 (m, 2H).
Reaction SMILES: NC1C=CC=CN=1.BrC(C=O)C=O.[N:14]1[CH:15]=[C:16]([CH:23]=O)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12.C(N(CC)CC)C.Cl.[NH2:33][CH2:34][CH:35]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:36][C:37](OC)=[O:38]>O1CCOCC1.C(O)C>[N:14]1[CH:15]=[C:16]([CH2:23][N:33]2[CH2:34][CH:35]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:36][C:37]2=[O:38])[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: O=Cc1cnc2ccccn12
Reactant: COC(=O)CC(CN)c1ccccc1
Agent: Cl
Agent: Nc1ccccn1
Agent: O=CC(Br)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CC(c2ccccc2)CN1Cc1cnc2ccccn12
Temperature: 25 °C

Procedure:
A solution of 2-aminopyridine x8 (1 g, 1 eq, 10.6 mmol) and bromomalonaldehyde x9 (1.6 g, 1 eq, 10.6 mmol) in 1.4-dioxane (20 ml) is refluxed for 3 days (Imidazo[1,2-a]pyridine-3-carbaldehyde x10 is formed in situ and not isolated). After cooling to room temperature, triethylamine (2.96 ml, 2 eq, 21.25 mmol), methyl 4-amino-3-phenylbutanoate hydrochloride x1 (2.44 g, 1 eq, 10.6 mmol) and ethanol (10 ml) are successively added. The mixture is then allowed to react during 3 days at room temperature. The reaction mixture is poured on ice, and organic solvents are removed under reduced pressure. The resulting aqueous layer is extracted by CH2Cl2 and the cumulated organic layers are dried over MgSO4, filtered, and condensed under reduced pressure. The crude product is purified by preparative chromatography on silicagel (CH2Cl2/iPrOH: 97/3 (v/v)), then recristallized in ethyl acetate leading to 1-(imidazol-[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one 7 as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:17])[C@H:4]([CH2:12][C:13]([O:15]C)=[O:14])[NH:5][CH2:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[ClH:18]>>[ClH:18].[CH2:6]([NH:5][C@H:4]([C:3]([OH:17])=[O:2])[CH2:12][C:13]([OH:15])=[O:14])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)C[C@H](NCCC(C)(C)C)C(=O)OC
Agent: Cl
Product: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Yield: 91 %

Procedure:
A mixture of N-neohexyl-L-aspartic acid dimethyl ester (15 g, 0.061 mol) in 1N hydrochloric acid (350 mL) was heated at reflux for 4 hours to form a clear solution. The mixture was freeze dried to give N-neohexyl-L-aspartic acid hydrochloride as a white solid (14 g, 91%), M.P. 133-138° C., [α]D +14.69 (c=1, water). Anal. Calc'd. for C10H19NO4 --HCl; C, 47.52; H, 7.92; N, 5.54; Cl, 14.05. Found: C, 47.84; H, 8.14; N, 5.31; Cl, 13.08.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]2[C:7]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]=3[CH:15]=[CH:16][CH:17]=2)(=[O:4])=[O:3].[H-].[Na+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([CH2:21][N:10]2[C:11]3[C:7]4[C:6](=[CH:17][CH:16]=[CH:15][C:8]=4[C:9]2=[O:14])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=3)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2CC1CC1
Reaction time: 17 h

Procedure:
A mixture of 2.5 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3) in 50 ml of N,N-dimethylformamide is treated with 0.35 g of sodium hydride and 1.5 ml of (bromomethyl)cyclopropane at 75° C. in a pressure bottle for 24 hours. An additional 1.5 ml of (bromomethyl)cyclopropane is added and heating continued at 75° C. for 17 hours in a pressure bottle. The reaction mixture is cooled then evaporated. The concentrate is chromatographed on silica gel using 1:1 ethyl acetate-hexane to afford 0.72 g of the desired product as yellow crystals, m.p. 148°-150° C.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:11]([Mg]Br)[CH3:12].B(F)(F)F.CCOCC.Cl>ClCCl.C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:7][C:6]1([C:5]2[CH:8]=[CH:9][C:2]([C:1]#[N:10])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccc(C2(N)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of terephthalonitrile (3.30 g, 25.8 mmol.) in dichloromethane (130 ml), Titanium (IV) isopropoxide (7.6 ml, 25.8 mmol) was added at room temperature followed by dropwise addition of ethyl magnesium bromide 1M in diethyl ether (47.0 ml). The mixture was stirred at room temperature for 45 min, then boron trifluoride etherate (5 ml) was added at once. After 2 hours, HCl aqueous solution (5%) was added to quench the reaction. The aqueous phase was separated, basified with aqueous 1M NaOH and extracted with ethylacetate. The organic phase was dried over Na2SO4 and concentrated under vacuo. The residue was purified by column chromatography eluting with a mixture petroleum ether/ethyl acetate (5:1). Collected fractions after solvent evaporation afforded the title compound (D14) (500 mg) as a white solid.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[C:9]1=[O:37])(=O)=O.[CH3:38]O>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([N:10]3[CH:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)[CH2:12][N:8]([CH2:7][CH2:6][O:5][CH3:38])[C:9]3=[O:37])=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: CO
Product: COCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O

Procedure:
A solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethyl methanesulfonate (10.0 mg, 0.0180 mmol) in MeOH (0.3 mL) is heated at 60° C. overnight. After removal of the solvent the residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.56-7.44 (m, 4H), 7.30 (d, 2H), 7.23 (d, 2H), 6.86 (m, 4H), 5.22 (dd, 1H), 4.07 (t, 1H), 3.57 (m, 3H), 3.49 (m, 1H), 3.36 (dd, 1H), 3.34 (s, 3H); HPLC-MS calculated for C25H22ClF3N2O3 (M+H+) 491.1, found 491.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1
Reactant: Cc1ccc(CO)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C)nc1

Procedure:
2-Methyl-5-hydroxymethylpyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.15 mole) at room temperature overnight. The mixture is concentrated to dryness, and the residue is dissolved in 70 ml. of water and extracted with 3×25 ml. of chloroform. After drying over magnesium sulfate, the chloroform is concentrated to dryness to give 2-methyl-5-acetoxymethylpyridine.