Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:42])[CH2:15][C@H:16]([C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:43]O.[OH-].[Li+].Cl>C1COCC1.O>[O:39]1[CH:40]=[CH:41][C:37]([C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][C:14]([OH:42])=[O:43])=[N:38]1
Reactant: OO
Reactant: O=C(C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of the oxazolidinone 47.2 (58.0 mg, 0.1 mmol) dissolved in THF (5 mL), was added a 30% hydrogen peroxide solution (113 μL, 1 mmol) followed by a 2 M lithium hydroxide solution (250 μL, 0.5 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 47 (23.6 mg). MS ESI (pos.) m/e: 422.0 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.34 (1 H, s), 7.53 (2 H, d, J=8.6 Hz), 7.14 (2 H, d, J=8.6 Hz), 7.00 (2 H, d, J=8.6 Hz), 6.83 (2 H, d, J=8.6 Hz), 6.16 (1 H, d), 4.45 (1 H, t, J=7.8 Hz), 4.25-4.31 (2 H, m), 4.20-4.24 (2 H, m), 3.09 (1 H, dd, J=16.4, 8.2 Hz), 2.84 (1 H, dd, J=16.4, 7.4 Hz).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10]>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:10][CH2:9][C:8]([N:7]([CH3:12])[CH3:6])=[O:11])[CH3:2]
Reactant: CCNCC
Reactant: C=CC(=O)N(C)C
Product: CCN(CC)CCC(=O)N(C)C
Temperature: 58 °C
Yield: 86 %

Procedure:
In accordance with this example, anhydrous diethylamine (44 grams) and N,N-dimethylacrylamide (60 grams) were heated at reflux temperature (about 56-60° C.) for 48 hours. After this period of time, the reaction mixture was subjected to distillation to separate unreacted amine and amide followed by recovery of product in 86 percent yield at 70° C. and 2 mm. mercury pressure. The liquid product (purity = about 95 percent is designated herein as Amine Catalyst V, and has the formula, (C2H5)2N--CH2CH2C(O)N(CH3)2. The structure of this novel product was confirmed by infrared functional analysis and purity by gas-liquid chromatographic analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](CC2C=C3C(=C4C=CC=CC=24)N=CNC3=O)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][C:31]2[CH:32]=[C:33]3[C:38](=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=24)[N:37]=[CH:36][NH:35][C:34]3=[O:45])=[CH:28][CH:27]=1.IC1C=NC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)[C@@H]1CCCC[C@H]1N>C1COCC1.CS(C)=O.[Cu]I>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][C:31]2[CH:32]=[C:33]3[C:38](=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=24)[N:37]=[CH:36][NH:35][C:34]3=[O:45])=[CH:46][CH:47]=1.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][C:31]2[CH:32]=[C:33]3[C:38](=[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=24)[N:37]=[CH:36][N:35]([C:5]2[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=2)[C:34]3=[O:45])=[CH:46][CH:47]=1
Reactant: O=c1[nH]cnc2c1cc(Cc1ccc(Cl)nc1)c1ccccc12
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: COc1ccc(Cc2cc3c(=O)[nH]cnc3c3ccccc23)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(Cc2cc3c(=O)n(-c4cccnc4)cnc3c3ccccc23)cc1
Temperature: 120 °C

Procedure:
6-(4-methoxybenzyl)benzo[h]quinazolin-4(3H)-one was prepared by the same procedure as described for 6-[(6-chloropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one in Example 1. To a solution of 6-(4-methoxybenzyl)benzo[h]quinazolin-4(3H)-one (0.030 g, 0.095 mmol) and 3-iodopyridine (0.058 g, 0.28 mmol) in 2 mL of THF and 1 mL of DMSO under an atmosphere of nitrogen was added cesium carbonate (0.19 mL, 1 N aqueous, 0.19 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (1.3 mg, 0.0095 mmol), and copper(I) iodide (1.8 mg, 0.095 mmol). The reaction was heated at 120° C. for 15 h, cooled to rt, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 393.9 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.07 (d, J=8.0, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.14 (d, J=7.6 Hz, 1H), 8.07 (d, J=9.6 Hz, 2H), 7.95 (s, 1H), 7.74-7.54 (m, 5H), 4.57 (s, 2H), 4.21-4.09 (m, 1H), 3.92 (s, 3H), 2.20-2.18 (m, 1H), 2.03-1.96 (m, 1H), 1.95-1.83 (m, 2H), 1.58-1.39 (m, 3H), 1.29-1.18 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:42]4[CH2:43][CH2:44][CH:39]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:40][CH2:41]4)=[C:7]([O:32][CH3:33])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:19]=1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (112 mg), 4-(1-pyrrolidinyl)piperidine (111 mg), and potassium carbonate (166 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (47 mg, yield 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)c1
Yield: 72 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 72%). MS (ESI) m/z 442 (M+1).
Reaction SMILES: S([O:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[O:11][CH:12]1[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15]1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Temperature: 120 °C
Yield: 123.6 %

Procedure:
To a solution of tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (1.0 g, 3.05 mmol) and 2,4-dichlorophenol (0.490 g, 3.05 mmol) in DMF (10 mL) was added potassium carbonate (0.630 g, 4.67 mmol) and the reaction mixture was heated to 120° C. for 2 h. Then reaction was quenched with water and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided tert-butyl 3-(2,4-dichlorophenoxy)azetidine-1-carboxylate (1.2 g, 63%) as a solid.
Reaction SMILES: [BH4-].[Li+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]([CH3:17])[C:13](OC)=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1COCC1>[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]([CH3:17])[CH2:13][OH:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: COC(=O)C(C)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 100.6 %

Procedure:
A solution of lithium borohydride (2M, THF, 2.0 equiv. 3.4 ml) was added to a solution of methyl 2-(3-nitrophenyl)propanoate (0.7 g) in THF. The resulting mixture was stirred for 18 hours then concentrated and poured into hydrochloric acid (10%) at 0□C. The mixture was extracted with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated to afford the title compound as yellow oil (0.610 g, 100% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:27]([CH:33]=O)=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:33][C:27]2[C:26]([CH3:25])=[CH:31][C:30]([CH3:32])=[CH:29][N:28]=2)[CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCCc3cccnc32)CC1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(C2CCN(C(=O)OC(C)(C)C)CC2)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-piperidine-1-carboxylic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[OH:18].[H-].[Na+].Br[CH2:22][CH2:23][OH:24]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH2:22][CH2:23][OH:24]
Reactant: OCCBr
Reactant: CCc1ccc(Cc2cc(Br)c(O)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2cc(Br)c(OCCO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 2-bromo-5-chloro-4-(4-ethylbenzyl)phenol (AT) (3.26 g, 10 mmol) in anhydrous DMF (15 mL), NaH (0.72 g, 30 mmol) was added in portions. The reaction mixture was stirred for 2 h at room temperature, and then 2-bromoethanol (3.75 g, 30 mmol) was added dropwise, and the reaction mixture was heated to 45° C. overnight. TLC showed the reaction was complete. The reaction was quenched with the saturated NH4Cl, the mixture was extracted with EtOAc, and then washed with water and brine. After drying with anhydrous Na2SO4 the organic portion was filtered and concentrated. The residue was purified by flash chromatography to give AU as an oil (3.00 g, yield 81%). 1H-NMR (CDCl3, 300 MHz) δ 7.32 (s, 1H), 7.13 (m, 4H), 6.94 (s, 1H), 4.11 (m, 2H), 3.57-3.99 (m, 4H), 2.64 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]1([C:7](=[N:17][OH:18])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:24](=O)=[O:25]>C1COCC1.CCCCCC>[OH:25][C:24]1[O:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1
Reactant: O=C=O
Reactant: CSc1ccc(CC(=NO)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2c(-c3ccccc3)noc2O)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a stirred solution of 1-phenyl-2-(4-methylsulfanylphenyl) ethanone oxime (2.0 g) in dry THF (20 mL), was added a solution of n-butyl lithium (0.98 M. 25 mL) in hexane at −70° C. over a period of 30 minutes. The reaction mixture was warmed to 20° C. over a period of 2 h. To this was added solid CO2 (25 g) and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with cold 1N HCl (20 mL) and extracted with ethyl acetate (3×50 mL). The organic extract was washed with water (100 mL); brine (100 mL), dried over sodium sulphate and evaporated under reduced pressure. The crude product was chromatographed over silicagel using 10% ethyl acetate in petroleum ether as eluent, yielding 1.2 g of pure product as a thick liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>C(Cl)(Cl)Cl>[CH2:23]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=CCN1CCC2(CC1)OC(=O)c1ccccc12

Procedure:
A mixture of 1.02 g. of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 1.0 g. of sodium bicarbonate, 10 ml. of chloroform, and 0.60 g. of allyl bromide is stirred at room temperature for 24 hours and filtered. The filtrate is washed with water, dried over potassium caarbonate, and concentrated to an oily solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1.[CH3:40][O:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45].C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: COc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)NCC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HATU (293 mg, 0.77 mmol) was added to a DMF (3 mL) solution of the compound (150 mg, 0.7 mmol) synthesized in (2), 2-methoxybenzoic acid (117 mg, 0.77 mmol), and diisopropylethylamine (0.27 mL, 1.54 mmol), and the mixture was stirred at room temperature for 24 hours. After adding ethyl acetate, the reaction mixture was washed twice with distilled water, and once with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (244 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:5]2=[N:6][CH:7]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.C(N(CC)CC)C>CN(C)C=O.O.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]4[NH:17][C:32](=[O:33])[NH:18][C:14]4=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccc(-n3nc(Cc4ccccc4F)c4ncc(F)cc43)nc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
70 mg (0.20 mmol) of the compound from example 40A were initially charged in dimethylformamide (5 ml), then 161 mg (0.993 mmol) of N,N-carbonyldiimidazole and 0.33 ml (2.38 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. The reaction mixture was subsequently diluted with water and saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated by rotary evaporation. Preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) of the residue gave 38 mg (48% of theory) of the desired title compound in solid form.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:24])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([CH2:20][C:21](O)=[O:22])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])#[N:2].[CH:25]1[CH:30]=[N:29][C:28]2N(O)N=N[C:27]=2C=1.C(Cl)CCl.N1CCCC1>CC#N>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:8]1[N:7]2[CH:17]=[C:18]([CH2:20][C:21](=[O:22])[N:29]3[CH2:28][CH2:27][CH2:25][CH2:30]3)[N:19]=[C:6]2[N:5]=[C:4]([CH3:24])[C:3]=1[C:1]#[N:2]
Reactant: On1nnc2cccnc21
Reactant: Cc1nc2nc(CC(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1C#N
Solvent: CC#N
Solvent: C1CCNC1
Solvent: ClCCCl
Product: Cc1nc2nc(CC(=O)N3CCCC3)cn2c(-c2ccc(Cl)cc2Cl)c1C#N
Reaction time: 0.08 h
Yield: 55.5 %

Procedure:
To a solution of 2-(6-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetic acid (72 mg, 0.2 mmol) in CH3CN (0.7 mL) were added HOAT (41 mg, 0.3 mmol) and EDC (77 mg, 0.4 mmol). After one min all of the solids had dissolved to produce a clear tan to brown solution. At 5 min, pyrrolidine (14.5 mg, 0.2 mmol) was added. At 20 min from the addition of pyrrolidine, the reaction was quenched with EtOAc (3 mL) and then washed with satd aq NaHCO3 (2×3 mL), satd aq NH4Cl (2×3 mL), and water (3 mL). The organic layer was dried with MgSO4, filtered, and concentrated to yield 5-(2,4-dichlorophenyl)-7-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)imidazo[1,2-a]pyrimidine-6-carbonitrile (46 mg, 56%) as a yellow-brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:27]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:11]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (82 mg) in methanol (2 mL) were added benzaldehyde (25 μL) and sodium hydrogen carbonate (31.5 mg). The reaction mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (14.2 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.4 mg).
Reaction SMILES: C(N(CC)CC)C.CS([Cl:12])(=O)=O.O[CH2:14][CH2:15][C@@H:16]([O:38][CH2:39][O:40][CH3:41])[C@H:17]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=1)[C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:12][CH2:14][CH2:15][C@@H:16]([O:38][CH2:39][O:40][CH3:41])[C@H:17]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=1)[C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COCO[C@H](CCO)[C@@H](C(=O)NNC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCO[C@H](CCCl)[C@@H](C(=O)NNC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.209 mL) and methanesulfonyl chloride (58 uL) were added to a solution of tert-butyl N′-[(2S*,3R*)-5-hydroxy-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (264 mg) in methylene chloride (10 mL) at 0° C. The reaction solution was stirred at 0° C. for 30 minutes. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Subsequently, lithium chloride (265 mg) was added to a solution of the residue in DMF (5 mL), and the reaction solution was stirred at 80° C. for three hours. The reaction solution was left to cool to room temperature. Then, water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 87.5 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].[CH2:16](I)[CH3:17].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH2:16][CH3:17])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CCI
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(C#N)CC2CN(C(=O)N(C)C)CC2C1
Yield: 48.1 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (3.0 g, 14.5 mmol) was dissolved in 60 mL of tetrahydrofuran with stirring followed by addition of ethyl iodide (4.52 g, 29 mmol) and lithium hexamethyldisilazide (29 mL, 29 mmol) under nitrogen atmosphere. The reaction mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 20 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an oil. TLC showed that there are two adjacent spots, and then the oil was purified by silica gel column chromatography to obtain the title compound 5-cyano-5-ethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19a (1.64 g) as a light yellow solid.