Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([O:21][C:22]([C:24]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:14]2>C(#N)C>[Br-:1].[C:31]1([C:24]2([C:22]([O:21][C@@H:15]3[CH:16]4[CH2:19][CH2:20][N+:13]([CH2:2][CH2:3][NH:4][C:5]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=5)=[O:6])([CH2:18][CH2:17]4)[CH2:14]3)=[O:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(NCCBr)c1ccccn1
Solvent: CC#N
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)c1ccccn1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
Pyridine-2-carboxylic acid (2-bromo-ethyl)-amide (Example 60a) (75 mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (98 mg) in acetonitrile (2 mL). The reaction mixture was allowed to stir at room temperature for 16 h. A further 10 mg of pyridine-2-carboxylic acid (2-bromo-ethyl) -amide was added and the reaction mixture was stirred for 8 h. The volatiles were evaporated and the residue was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the title compound (55 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(O)[CH2:9]1)(C)(C)C.COCCN(S(F)(F)[F:34])CCOC.CO>C(Cl)Cl>[F:34][C:10]1([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:11][CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)(Cc2ccccc2F)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NC1CCCC(F)(Cc2ccccc2F)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl-3-(2-fluorobenzyl)-3-hydroxycyclohexylcarbamate (1 mmol, 323 mg) in DCM was added Deoxo-Fluor® (2 mmol, 370 μL) at room temperature. The reaction mixture was stirred for overnight. Methanol was added dropwise. The desired product was obtained after the removal of solvent by rotary evaporation.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([C:16]#[N:17])[C:5](=[O:15])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:18][C:3]1[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:5](=[O:15])[C:4]=1[C:16]#[N:17]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccccc1-n1cc(Br)c(Cl)c(C#N)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-n1cc(-c2ccccc2)c(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 64.3 %

Procedure:
A mixture of 5-bromo-4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (400 mg), phenylboronic acid (211 mg), tetrakis(triphenylphosphine)palladium(0) (143 mg), aqueous sodium carbonate solution (2 M, 1.24 mL) and 1,2-dimethoxyethane (4.0 mL) was heated with microwave irradiation at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (255 mg).
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.C(OCC)(=O)C>[CH2:24]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=2)[CH:12]=[N:13]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A 12 L 3-necked round-bottomed flask was charged with DMF (2 L), 5-nitroindazole (200 g, 1.22 mol.) and potassium carbonate (186 g, 1.35 mol). Benzyl bromide (230 g, 1.35 mol) was then added to the stirred suspension at a rate as to maintain the temperature below 40° C. Once the addition was complete the mixture was heated to 75° C. for a further 8 hours, the reaction being monitored by TLC (SiO2, 1:1 ethyl acetate:hexanes). The reaction was then cooled to room temperature, water (2 L) added and the resulting slurry stirred at room temperature for 0.5 h. The resulting yellow solids were filtered off and dried at 45° C. and 5 mm Hg vacuum for 48 h. This afforded 424 g of a 1.25:1 mixture of 1- and 2-benzyl-5-nitroindazoles as determined by HPLC analysis (Rt 1-benzyl=14.9 min, Rt 2-benzyl=14.1 min). This material was then split into four approximately 100 g batches and each batch dissolved in acetone (470 mL). Water (156 mL) was then added slowly as a steady stream. After stirring for an additional 1 hour at room temperature the resulting solids were filtered off and vacuum dried. This process afforded a combined total of 126 g (41%) of 1-benzyl-5-nitroindazole, which was 92.1% pure by HPLC analysis, the major contaminant being the 2-benzyl derivative.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:8]([CH3:19])([CH3:18])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=1.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([N:15]([CH2:16][CH3:17])[C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=3)[CH:11]=[CH:10][C:9]=2[C:8]([CH3:18])([CH3:19])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CCNc1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C)c1ccc(C(=O)O)cn1
Temperature: 125 °C
Yield: 8.6 %

Procedure:
To a mixture of 85 mg (0.37 mmol) of (8-t-butyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethyl-amine (Compound 169) and 0.11 g (0.78 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes to give the title compound as a white solid (12 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26][CH2:25]4)[C:20]3=[O:41])=[C:13](Cl)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C1COCC1.[OH-].[Li+].[ClH:50]>O.CO>[Cl:50][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:32]([CH3:33])[CH3:34])[CH:35]([CH3:36])[CH3:37])[CH2:26][CH2:25]4)[C:20]3=[O:41])=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Reactant: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)[Si](O[C@H]1CC[C@@H](N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)O)c(Cl)c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 1 °C

Procedure:
Stir a mixture of 3′,5′-dichloro-4′-[(R)-2-oxo-cis-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (35.6 g, 56.26 mmol), 150 mL THF and 100 mL methanol under nitrogen in an ice/water bath. Add a solution of lithium hydroxide (4.04 g, 168.79 mmol) in 100 mL water. Stir the mixture 4 hr at RT. Cool the solution to about 1° C. in an ice/acetone bath, dilute with 500 mL water, then adjust the pH to about 2-3 with 0.5 M aqueous hydrochloric acid. Extract with ethyl acetate (3×150 mL), wash with 100 mL each, water and brine then dry over magnesium sulfate. Filter, and concentrate to 34.6 g (99%) of a foam.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[CH:10][C:3]=12.[N:30]1[CH:34]=[CH:33][CH2:32][N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.O.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>[NH:30]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:9]=[CH:10][C:3]=23)[CH:32]=[N:31]1
Reactant: C1=CN=NC1
Reactant: Ic1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ncc3c(-c4cn[nH]c4)ccnc32)cc1
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A mixture of 4-iodo-1-trityl-pyrazolo[5,4-b]pyridine (1.404 g, 2.880 mmol), 444,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-pyrazole (950 mg, 4.896 mmol) and tetrakis(triphenylphosphine)palladium(0) (166.4 mg, 0.1440 mmol) in DME (20 mL) was treated with Na2CO3 (5.559 g, 5.040 mL of 2 M, 10.08 mmol) and heated in the microwave for 60 minutes at 150° C. The reaction mixture was diluted with EtOAc and water and the layers separated. The organics were dried (MgSO4), filtered and concentrated and purified by column chromatography (1:1 Petroleum ether/EtOAc moving to EtOAc to) give the pure compound as a white solid (597 mg, 49% Yield). 1H NMR (DMSO, 400 MHz) δ 6.25 (1H, m), 7.20-7.25 (15H, m), 7.33 (1H, m), 7.65 (2H, m), 8.19 (1H, m), 8.71 (1H, s), 8.60 (1H, br s); MS (ES+) 428.18
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24](O)=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].O.[NH2:34][NH2:35].O>C1COCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24]([NH:34][NH2:35])=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NN
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 127.1 %

Procedure:
[step 1] (E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (130 mg, 0.31 mmol) obtained in Example 2 was dissolved in THF (1.5 mL), N,N′-carbonyldiimidazole (80 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature for 10 min. Hydrazine monohydrate (60 μL, 1.24 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give (E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetohydrazide (172 mg) quantitatively.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H][H].[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:29])=[C:25]([CH:28]=1)[C:26]#[N:27]>CN(C=O)C.CCOCC>[Cl:20][C:21]1[CH:28]=[C:25]([C:26]#[N:27])[C:24]([F:29])=[CH:23][C:22]=1[CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: [H][H]
Reactant: N#Cc1cc(Cl)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c(C#N)cc1Cl

Procedure:
To sodium hydride (60% in mineral oil, 3.75 g, 94 mmol) under nitrogen was added dry DMF (150 mL) and the suspension was cooled in an ice bath. Di-t-butyl malonate (8.1 g, 37.5 mmol) was added dropwise over 15 minutes via syringe with hydrogen evolution. The suspension was stirred for 30 minutes after which time 5-chloro-2,4-difluorobenzonitrile (5.0 g, 28.8 mmol) in DMF (10 mL) was added dropwise over 15 minutes and the reaction was heated to 80° C. for 12 hours when TLC (15% ethyl acetate/hexanes) indicated mostly product. The reaction was diluted with ether and quenched into water containing aq. ammonium chloride. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (2-10% ethyl acetate/hexanes) to give the title product. NMR indicated about a 6:1 mixture of product and the isomeric di-t-butyl, 2-(4-chloro-2-cyano-5-fluorophenyl)malonate. 1H-NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 18H), 5.05 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.71 (d, J=6.0, 1H) (major isomer) and 1.46 (s, 18H), 4.95 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.78 (d, J=6.0, 1H) (minor isomer).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26].NCCC(O)=O>C(O)(=O)C.O>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:21])[CH3:20])[N:8]=[C:7]([CH:22]=[C:30]2[S:24][C:25](=[S:26])[NH:27][C:28]2=[O:29])[N:6]=1)([CH3:4])[CH3:1]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Reactant: O=C1CSC(=S)N1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1nc(C=C2SC(=S)NC2=O)nc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A mixture of 4,6-bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles), rhodanine (0.25 g, 1.8 mmoles), and β-alanine (0.27 g, 3.1 mmoles) in acetic acid is heated at reflux for 1.5 hours. This solution is cooled to room temperature and diluted with 100 mL of water. The precipitate is collected by filtration and recrystallized from isopropyl ether/hexane. Yield of 5-[[4,6-bis-(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]methylene]-2-thioxo-4-thiazolidinone=0.26 g (48%). MP=257°-261° C. dec.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:41])[N:27]3[C:30]([O:32][CH:33](Cl)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:42]([OH:47])(=[O:46])[CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:41])[N:27]3[C:30]([O:32][CH:33]([O:47][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: CCCC(=O)O
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OC(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(=O)OC(OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of chloro(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (4.11 g, 6.66 mmol) in dimethyl formamide (40 mL) was added butyric acid (0.91 mL, 9.99 mmol) and cesium carbonate (1.63 g, 4.99 mmol). The reaction was stirred at room temperature for 20 hours then diluted with ethyl acetate (40 mL) and washed with 1:1 water/brine (3×50 mL). The organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give butyryloxy(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-91 (1.12 g). The material was determined to be 67% pure by LCMS.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[S:10][CH:11]=[C:12]([C:14]#[N:15])[N:13]=2)[CH2:3]1.CN(C=O)C.[Br:21]N1C(=O)CCC1=O.[OH-].[Na+]>O>[Br:21][C:11]1[S:10][C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[N:13][C:12]=1[C:14]#[N:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1CN(c2nc(C#N)cs2)C[C@H](C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2nc(C#N)c(Br)s2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A flask charged with Intermediate 2 (25.61 g, 114.69 mmol) and DMF (250 mL) was cooled in an ice/water bath. N-bromosuccinimide (24.49 g, 137.63 mmol) was added portionwise (slightly exothermic reaction). The reaction mixture was stirred at room temperature for 10 min. Water (400 mL) was then added dropwise leading to a yellow precipitate, followed by sodium hydroxide 1 M (115 mL). The precipitate was filtered, washed with water (50 mL) and DIPE (10 mL). This solid was recrystallised from acetonitrile. Filtration and overnight drying in a vacuum oven at 50° C. yielded 25.5 g (73%) of Intermediate 3 as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:15](=[O:17])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)CCC1NC(=O)OCc1ccccc1

Procedure:
WO 93/09120 describes a process for the preparation of dimiracetam (2,5-dioxohexa-hydro-1H-pyrrolo[1,2-a]imidazole) 1 and related compounds. 5-Ethoxy-2-pyrrolidone is reacted with benzyl carbamate with a catalytic amount of p-toluenesulfonic acid to give 5-benzyloxycarbonylamino-2-pyrrolidone. This compound is then deprotonated at the pyrrolidine nitrogen with sodium hydride in acetonitrile, and reacted with ethyl bromoacetate to give ethyl 5-benzyloxycarbonylamino-2-oxo-1-pyrrolidine-acetate 2. Cyclization can then be performed after cleavage of the ethyl ester and/or the benzyloxycarbonyl protecting group in the presence of a variety of cyclizing agents.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=1.N1C(C)=CC=CC=1C>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][CH2:36][CH2:37][OH:38])[N:31]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1ccn(CCCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCO)n2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
In a round bottom flask was placed (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 114, 65 mg, 0.20 mmol), methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 110 μL, 0.22 mmol). Upon addition there was gas evolution. This was stirred for 30 min at 25° C. after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 29 mg, 0.20 mmol), 2,6-lutidine (46 μL, 0.40 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol, diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (60 mg, 68%) as a white foam: [α]25589=−6.2° (c=0.21, methanol); ES-HRMS m/e calcd for C22H28N4O4S (M+H)+ 445.1904, observed 445.1903; 1H NMR (300 MHz, DMSO-d6) δ 1.11 (m, 2H, CH2), 1.38-1.90 (m, 10H, 5×CH2), 2.12 (m, 1H, CH), 3.33 (brm, 2H, OCH2), 3.36 (s, 3H, SO2CH3), 3.98 (m, 1H, ArCHCO), 4.02 (t, J=7.1 Hz, 2H, NCH2), 4.56 (t, J=5.0 Hz, 1H, OH), 6.40 (d, J=2.2 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.94 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 8.10 (d, Jm=1.6 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)(=[O:3])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCOCC1.CO>[Br:23][CH2:2][C:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)CBr)N1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
12.00 kg (40.36 mol) 8-acetyl-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one 3a are dissolved in 108 l 1,4-dioxane. Then a solution of 24.33 kg (50.45 mol) tetrabutylammonium tribromide in 48 l of 1,4-dioxane and 12 l methanol is metered into the suspension at 20° C. The reactor contents are stirred for 2 hours at 20° C. Then 72 l water are added at 20° C. within 15 minutes. After cooling to 3° C. the mixture is stirred for 1 hour, centrifuged and washed with a mixture of 9 l of 1,4-dioxane and 4.5 l water. Then it is washed with 60 l water and dried in vacuo at 50° C.