Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:19])(=O)[CH2:2][CH2:3][CH3:4].[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22]>CO>[CH2:20]([O:23][NH:24][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][C:7]1=[O:19])[CH2:2][CH2:3][CH3:4])[CH:21]=[CH2:22]
Reactant: C=CCON
Reactant: CCCC(=O)C1C(=O)CC(C2CCOCC2)CC1=O
Solvent: CO
Product: C=CCONC(CCC)=C1C(=O)CC(C2CCOCC2)CC1=O

Procedure:
14.0 parts by weight of 2-butyryl-5-(tetrahydropyran-4-yl)-cyclohexane-1,3-dione and 4.2 parts by weight of allyloxyamine in 100 parts by volume of methanol are stirred for 16 hours at room temperature. The solvent is distilled off under reduced pressure, the residue is dissolved in dichloromethane, the solution is then washed with 5% strength hydrochloric acid and water and dried over sodium sulfate, and the solvent is stripped off under reduced pressure to give 12.9 parts by weight of 2-(1-allyloxyamino-n-butylidene)-5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione in the form of a solid (active ingredient No. 2).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>CN(C=O)C>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:12][C:8]2[CH:7]=[C:6]([CH2:5][CH:4]([O:13][CH3:14])[C:3]([OH:2])=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(Cc1cccc(OCCCOc2ccc(-c3ccccc3)cc2)c1)C(=O)O
Reaction time: 8 h

Procedure:
A mixture of 3-(3-Hydroxyphenyl)-2-methoxy-propionic acid methyl ester (1 eq) from Step D, Cesium Carbonate (3 eq) and 4-(3-bromopropoxy)biphenyl (1 eq) in DMF and in a 10 mL tube was shaked in an orbital agitator over a weekend. The mixture was filtered through a hydrofobic syringer and evaporated in a speed-vac apparatus. Then diluted with NaOH 1N-Ethanol and stirred overnight. Then HCl 3N was added and the reaction mixture was concentrated to remove the ethanol in vacuo, reconstituted in dichloromethane and filtered through a hydrofobic syringe. The organic layer was evaporated to give the title compound. MS (ES) for C25H26O5 [M+NH4]+: 424.2, [M+Na]+: 429.2. 1H-NMR (CDCl3, 200.15 MHz): 7.57–7.17 (m, 9H), 6.98 (dd, 2H, J=6.7, 1.9), 6.84–6.81 (m, 3H), 4.19 (dd, 4H, J=14.0, 6.4), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.28 (qui, 2H, J=5.9)ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH:13](O)[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>C(#N)C.ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH:13]([Cl:40])[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1C=C2C(CC(O)CN2Cc2ccc(Cl)nc2)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: O=C1C=C2C(CC(Cl)CN2Cc2ccc(Cl)nc2)O1
Temperature: 25 °C

Procedure:
At 70° C., 146.0 mg (0.52 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-6-hydroxy-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one (cf. I-16) and 274.2 mg (1.05 mmol) of triphenylphosphine are stirred in a mixture of 2.5 ml of acetonitrile and 2.5 ml of carbon tetrachloride. After cooling to room temperature, the mixture is diluted with dichloromethane and washed successively with dilute aqueous ammonium hydroxide solution and saturated sodium chloride solution: the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 063 m) using the mobile phase ethyl acetate and subsequent preparative HPLC gives both possible diastereomers of 4-[(6-chloropyridin-3-yl)methyl]-6-chloro-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one: (a) 4 mg of diastereomer A (3% of theory) and (b) 15 mg of diastereomer B (9% of theory). In addition, (c) 10 mg (7% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-7,7a-dihydrofuro[3,2-b]pyridin-2(4H)-one are obtained.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8](=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:61]1[CH:62]=[C:63]2[C:68](=[O:69])[N:67]([CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][C:72]=3[O:79][CH3:80])[CH2:66][CH2:65][N:64]2[CH:81]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8]([N:7]=1)=[C:9]([C:61]1[CH:62]=[C:63]3[C:68](=[O:69])[N:67]([CH2:70][C:71]4[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][C:72]=4[O:79][CH3:80])[CH2:66][CH2:65][N:64]3[CH:81]=1)[CH:10]=[CH:11][CH:12]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2CCn3cc(Br)cc3C2=O)c(OC)c1
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN2CCn3cc(-c4cccc5nc(C)c(NC(C)(C)C)nc45)cc3C2=O)c(OC)c1
Temperature: 135 °C
Yield: 26.1 %

Procedure:
A mixture of N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (Example 174b; 187 mg, 0.55 mmol), XPhos (Strem, Newburyport, Mass.; 13 mg, 0.027 mmol), Pd2(dba)3 (12 mg, 0.014 mmol), 7-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Example 165b; 167 mg, 0.46 mmol) and potassium phosphate (291 mg, 1.37 mmol) in 2 mL of dioxane and 0.5 mL of water was heated in a microwave at 135° C. for 45 min. The mixture was then treated with 2 mL of 1 N NaOH, and extracted with EtOAc (2×5 mL). The organic extracts were concentrated. Purification of the brown residue on a silica gel column (eluted with 25-75% EtOAc in hexanes) afforded 7-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-(2,4-dimethoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (60 mg) as a brown amorphous solid. m/z (ESI, +ve) 500.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][O:28][CH2:29][C@@H:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:32][C@@H:30]([CH3:31])[CH2:29][O:28][CH3:27])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: COC[C@H](C)N
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: COC[C@H](C)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-1-methoxy-2-propylamine via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-methoxypropan-2-yl)terephthalamide. MS (Q1) 459 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[C:11]([CH3:17])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH2:27][CH2:28][NH:29][CH3:30])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([N:29]([CH3:30])[CH2:28][CH2:27][N:19]([CH3:18])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:16])=[C:11]([CH3:17])[CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: Cc1cc(NC(=O)OC(C)(C)C)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(NC(=O)OC(C)(C)C)sc1C(=O)N(C)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
The compound (600 mg, 2.33 mmol) obtained in Example 89a and tert-butyl methyl[2-(methylamino)ethyl]carbamate (439 mg, 2.33 mmol) described in the literature (J. Med. Chem. 1990, 33, 97) were dissolved in methylene chloride (23 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (670 mg, 3.50 mmol) and 4-dimethylaminopyridine (14 mg, 0.117 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, 1 N hydrochloric acid was added to the resulting residue, the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, v/v) to give the title compound (757 mg; yield, 79%) as a light yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27]([CH:29]5[CH2:33][CH2:32][CH2:31][N:30]5C([O-])=O)=[O:28])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.O1CCOC[CH2:39]1>C(OCC)(=O)C.CO>[CH3:39][C@@:29]1([C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][CH:11]=4)[N:19]=3)=[CH:25][CH:24]=2)=[O:28])[CH2:33][CH2:32][CH2:31][NH:30]1
Reactant: C1COCCO1
Reactant: O=C(Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1)C1CCCN1C(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@]1(C(=O)Nc2ccc(-c3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)cc2)CCCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
1,1-Dimethylethyl (2R)-2-{([(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}-phenyl)amino]carbonyl}pyrrolidine-1-carboxylate (0.38 g, 0.698 mmoles), was dissolved in an ethyl acetate (10 ml) and methanol (2 ml) mixture. 4 M hydrogen chloride in 1,4-dioxane (1.75 ml, 6.98 mmoles, 10 equivalents, purchased from Sigma-Aldrich) was then added in a drop wise fashion over 5-10 minutes. Upon completion of addition, the reaction mixture was stirred at room temperature, and the progress of the reaction monitored by LC/MS. After 16 hours, additional 4M hydrogen chloride in 1,4-dioxane (0.87, 1.25 mmoles, 5 equivalents) was added. After a total of 48 hours the reaction was complete and the resulting slurry was filtered off. The reaction flask was rinsed with ethyl acetate to ensure complete transfer of product. The resulting solid was washed with ethyl acetate (3×10 ml), followed by diethyl ether (3×25 ml) and dried under reduced pressure to give of 0.264 mg 2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-pyrimidin-4-yl}phenyl)prolinamide (68% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].CCN(CC)CC>O=S(Cl)Cl.CN(C=O)C.CCOCC>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CCN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzoic acid (10.0 g, 40 mmol) in SOCl2 (100 mL) containing DMF (2 drops) was heated under reflux for 5 h, and then concentrated to dryness and azeotroped with benzene. A solution of the resulting crude acid chloride in Et2O was added to a vigorously-stirred suspension of methyl 3-aminopropanoate hydrochloride (6.22 g, 44 mmol) and Et3N (13.9 mL, 100 mmol) in Et2O (100 mL). after stirrign for 30 min, the resulting precipitate was filtered off, washed well with water, and recrystallized from EtOAc/petroleum ether to give 5-chloro-N-[2-(methoxycarbonyl)ethyl]-2,4-dinitrobenzamide (6.24 g, 47%), mp 139-141° C. 1H NMR [(CD3)2SO] δ8.98 (t, J=5.6 Hz, 1H, CONH), 8.83 (s, 1H, H-3), 8.09 (s, 1H, H-6), 3.63 (s, 3H, OCH3), 3.47 (dt, J=6.7, 5.6 Hz, 2H, CONCH2), 2.61 (t, J=6.7 Hz, 2H, CH2CO2CH3) Anal. Calcd for C11H10ClN3O7. C, 39.84;H, 3.04; N, 12.67, Cl, 10 69. Found: C, 40.07;H, 2.79; N, 12 55; Cl, 10.92%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CC=C(c2c[nH]c3ccccc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
(8.7 mg, 22%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4e, 24.8 mg, 0.12 mmol) and 4-fluorobenzoyl chloride (28 uL, 0.24 mmol); HRMS-FAB+ for C21H19N2O2F: calculated MH+ : 335.15598; found: 335.15560.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16](=[O:45])[NH:17][C:18]1[C:19]([CH3:44])=[C:20]2[N:25]([CH:26]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[C:30]([Cl:43])[CH:29]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16](=[O:45])[NH:17][C:18]1[C:19]([CH3:44])=[C:20]2[N:25]([CH:26]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[C:30]([Cl:43])[CH:29]=1
Reactant: Cc1c(NC(=O)OC[C@H]2COCCN2C(=O)OC(C)(C)C)cn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC(=O)OC[C@H]2COCCN2)cn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Yield: 53.3 %

Procedure:
A solution of 4D (100 mg, 0.156 mmol) in TFA (1.2 ml) was stirred at rt for 5 min. The solution was concentrated in vacuo and the residue was purified by a Shimadzu auto prep HPLC, employing 30% to 100% 10 min gradient, 6 min 100% holding elution with 0.1%TFA in MeOH-water solvent system, 220 nM detection, 20 mL/min elution with a YMC ODS S5 20×100 mm column to give 4E (45 mg, 53%). Analytical HPLC retention time=2.93 min. (YMC S5 ODS column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) and a LC/MS M++1=541.
Reaction SMILES: [C:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[H-].[Na+].C([Li])CCC.Br[CH2:18][CH:19]=[CH:20][CH:21]1[O:23][CH2:22]1.P(O)(O)([O-])=O.[Na+]>O1CCCC1.CCCCCC>[O:23]1[CH2:22][CH:21]1/[CH:20]=[CH:19]/[CH2:18][CH2:2][C:1](=[O:3])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrCC=CC1CO1
Reactant: CCOC(=O)CC(C)=O
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC/C=C/C1CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A solution of 1.742 g of ethyl acetylacetate in 5 ml of tetrahydrofuran was slowly added to a mixture of 672mg of sodium hydride in a 50% oil mixture in 10 ml of tetrahydrofuran cooled to 0° C and the mixture was held at 0° C for 30 minutes. 8.7 ml of 1.6N butyllithium in hexane was added dropwise at 0° C to the reaction mixture and after standing at 0° C for 30 minutes, the mixture was cooled to -60° C. A solution of 2.3 g of the product of Step B in 5 ml of anhydrous tetrahydrofuran was added to the mixture and the mixture was held at -60° C for 3 hours and then overnight at -20° C. The mixture was poured into an iced monosodium phosphate solution and was extracted with ethyl acetate. The extracts were washed, dried and evaporated to dryness to obtain a yellow oil residue. The latter was chromatographed over silica gel and was eluted with an 80-20-2 cyclohexane-ethyl acetate-triethylamine mixture to obtain 1.47 g of ethyl (6E) 8,9-epoxy-3-oxo-6-nonenoate in the form of an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:5].[C:16](OC(=NC(C)C)NC(C)C)([CH3:19])([CH3:18])[CH3:17]>ClCCl.COC(C)(C)C>[CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a slurry of 4-(3-methylbutanoyl)benzoic acid (499 mg, 2.42 mmol) in dichloromethane (6 mL) was added O-tert-butyl-N,N′-diisopropylisourea (1.82 g, 9.07 mmol). The mixture was stirred at room temperature for 50 hours then diluted with tert-butyl methyl ether (75 mL). The mixture was washed with sat. aq sodium bicarbonate (50 mL), dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave tert-butyl 4-(3-methylbutanoyl)benzoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.09-8.04 (m, 2 H), 8.00-7.94 (m, 2 H), 2.86 (d, J=6.8 Hz, 2 H), 2.37-2.23 (m, 1 H), 1.62 (s, 9 H), 1.01 (d, J=6.7 Hz, 6 H).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[CH3:14][O:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: CC(C)(C)NCCC1CCCCC1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Product: COC(=O)c1ccc(CN(CCC2CCCCC2)C(C)(C)C)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 1178G starting with N-t-butyl-N-(2-cyclohexylethyl)amine, prepared as in Example 1181A, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D. m/e (ESI) 422 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>>[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: Oc1cccnc1
Product: O=Cc1ccc(Oc2cccnc2)cc1

Procedure:
By the similar procedure to that in Referential example 6, using 3-hydroxypyridine and 4-hydroxybenzaldehyde as starting materials, the title compound was obtained as a yellow oil.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH:6]#[C:7][CH2:8][NH:9][C@H:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1>C(OC(C)C)(C)C>[CH:6]#[C:7][CH2:8][NH:9][C@H:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1.[C:1]([O-:5])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)O
Agent: C#CCN[C@@H]1CCc2ccccc21
Solvent: CC(C)OC(C)C
Product: CCC(=O)[O-]
Reaction time: 1.5 h

Procedure:
To a solution of 43 mg (0.58 mmol, 1.0 eq) propionic acid in 0.5 ml diisopropyl ether a solution of 100 mg (0.58 mmol) rasagiline in 0.5 ml diisopropyl ether was added. After stirring for 90 min the solvent was removed in vacuo. The residue was dried in high vacuum for 5 h to yield a thick oil (143 mg, 0.58 mmol, quant.).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]2[CH:38]=[CH:37][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29]C(=O)OC(C)(C)C)=[O:21])=[CH:18][CH:17]=2)=[N:5][CH:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][NH:13][CH2:14][CH3:15])[CH:8]=1)#[N:2].Cl>O1CCOCC1>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:37]=[CH:38][C:16]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][O:10][CH2:11][CH2:12][NH:13][CH2:14][CH3:15])=[CH:6][N:5]=2)=[CH:17][CH:18]=1
Reactant: CCNCCOCc1cnc(-c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)c(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCNCCOCc1cnc(-c2ccc(C(=O)Nc3ccccc3N)cc2)c(C#N)c1

Procedure:
t-Butyl (2-{[4-(3-cyano-5-{[2-(ethylamino)ethoxy]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate (466 mg, 0.90 mmol, prepared as described in Method 28), 1,4-dioxane (3.4 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (3.4 ml) were stirred at ambient temperature for 4 hours.
Reaction SMILES: CCN(C(C)C)C(C)C.O[C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[C:14]([NH:16]CC(O)=O)=[O:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N1(C(C2C=CC=CC=2C(F)(F)F)=O)CCNCC1>CN(C=O)C.O>[C:14]([NH2:16])(=[O:15])[C:13]1[CH:21]=[CH:22][CH:23]=[CH:11][CH:12]=1
Reactant: O=C(O)CNC(=O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
DIPEA (0.7692 g, 3 mmol) was added dropwise to (3-hydroxy-benzoyl amino)-acetic acid (50 mg, 0.26 mmol) in DMF (4 mL). EDCI (122 mg, 0.64 mmol) and HOBT (41 mg, 0.31 mmol) were added consecutively and after 10 mins, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone (90 mg, 0.31 mmol) was added and was allowed to stir at room temperature overnight. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 90:10 EtOAc:hexane as eluent) afforded 3-hydroxy-N-[2-Oxo-2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl]-benzamide in 39% yield. LC-MS purity: 98%, H1—NMR (DMSO-D6): δ 9.6 (s, 1H), 8.4 (d, 1H), 7.8 (dd, 2H), 7.7 (d, 1H), 7.6 (t, 1H), 7.2 (d, 3H), 6.9 (d, 1H), 4.1 (dd, 2H), 3.6 (m, 4H), 3.4 (s, 2H), 3.2 (d, 2H).
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21](O)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:25][CH2:26][C:27]#[N:28].C(P(=O)([O-])OCC)#N>ClCCl.C(N(CC)CC)C>[C:26]([CH2:27][NH:28][C:21]([C:20]1[N:19]=[CH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9][C:10]=12)=[O:22])#[N:25]
Reactant: N#CCN
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Agent: CCOP(=O)([O-])C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCNC(=O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reaction time: 1.17 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 323, 0.203 g), 0.060 g of aminoacetonitrile hydrochloride, and 3 ml of dichloromethane are added 0.23 ml of triethylamine and 0.15 ml of ethyl cyanophosphonate. A slight exotherm ensued. After about 45 min a precipitate formed and an additional 5 ml of dichloromethane are added. When the reaction had stirred for a total of 70 min it is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel (125 ml) eluting with methanol/methylene chloride (2/98), the appropriate fractions are pooled and concentrated to give the title compound, mp 241°-242.5°; MS (m/z) at 350; IR (mineral oil) 1641, 1506, 1658, 1409, 1417, 2237 (weak) cm-1 ; NMR (CDCl3) 1.83, 3.31, 4.36, 5.06, 7.12-7.30, 7.40, 7.49, 7.94 δ.