Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1.OS(O)(=O)=O.CCOC(C)=O>CN1C(=O)CCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:17][CH:18]4[CH2:20][CH2:19]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: Clc1nc(NC2CC2)c2c(n1)C(c1ccccc1)CC2
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc(NC3CC3)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 97 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (175 mg, 0.612 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (151 mg, 0.674 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.046 mL, 0.857 mmol). The mixture was stirred at 97° C. for 20 hours. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/water and water, dried over Na2SO4, and finally removed. The residue was purified via Biotage (12 g, hexanes-80% EtOAc) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (200 mg, 0.423 mmol, 69.1% yield). LC-MS (M+H)+=473.10. 1H NMR (500 MHz, CDCl3) δ ppm 7.81 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.5 Hz), 7.44 (1H, s), 7.27-7.35 (2H, m), 7.19-7.25 (3H, m), 6.99-7.06 (2H, m), 6.95 (1H, d, J=8.2 Hz), 4.89 (1H, br. s.), 4.20 (1H, t, J=8.2 Hz), 3.45 (3H, s), 2.92 (1H, td, J=6.7, 3.1 Hz), 2.76-2.86 (1H, m), 2.59-2.75 (2H, m), 2.07-2.14 (1H, m), 0.85-0.91 (2H, m), 0.63-0.70 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3cnn(C)c3)cc21
Product: CC1c2cc(-c3cnn(C)c3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15](C)[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][CH:7]=1)=O.[CH2:26](I)C.CC(C)=O>O>[CH2:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH:15][CH2:16][C:17]2([CH3:26])[CH:18]=[CH:19][N:20]=[CH:21][CH2:22]2)=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: CCI
Solvent: O
Solvent: CC(C)=O
Product: CCNc1ccc(NC(=O)NCC2(C)C=CN=CC2)cc1
Reaction time: 8 h

Procedure:
To 2.89 gms. (0.01 mole) of 1-(p-trifluoroacetamidophenyl)-3-methyl-3-(4-pyridylmethyl)urea [prepared by reacting 1-(p-aminophenyl)-3-methyl-3- (4-pyridylmethyl)urea (Example 6., supra.) with trifluoroacetic anhydride (method of Hickenbottom, Reactions of Organic Compounds, Longmans, London, 1963)] there is added 6.24 gms. (0.04 mole) of ethyl iodide in 50 ml. of dry acetone. The acetone is then stripped and the residue added to 50 ml. of water. The aqueous mixture is warmed to reflux for about 30 minutes and then allowed to stand overnight. The mixture is then stripped of water to give 1-(p-ethylaminophenyl)-4-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Mg].[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O)(=O)C>C1COCC1>[C:25]([O:24][C:22]([N:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Temperature: -75 °C
Yield: 81 %

Procedure:
2-Bromobenzotrifluoride (4.5 g, 20 mmol) and magnesium turnings (0.54 g, 22 mmol) were refluxed under a nitrogen atmosphere in 100 ml THF until the magnesium had dissolved. The resulting solution was cooled to -75° C. and added to 4.6 g (20 mmol) di-t-butyl azodicarboxylate in 100 ml THF at -75° C. The solution was warmed to -40° C., acetic acid (1.5 ml, 25 mmol) was added, and the mixture concentrated to 20 ml. Hexane and water were added, and the hexane solution was evaporated to leave a brown oil which was chromatographed on silica with 10% ether in CHCl3, providing 6.1 g (81% yield) of N,N'-bis(t-butoxycarbonyl)-2-(trifluoromethyl)phenylhydrazine as a brown gum. This material was dissolved in 200 ml isopropanol, and hydrogen chloride gas was passed into the solution resulting in a weight gain of 8 g. The solution was stirred at 50° C. for 30 minutes, then evaporated to dryness. The residue was treated with ether, and the solids collected by filtration and dried in vacuo, providing 2.7 g (79% yield) 2-(trifluoromethyl)phenylhydrazine hydrochloride as a white powder, mp 241°-242° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[CH3:20][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CNCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(CCc1ccccn1)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 55.9 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), 2-(2-methylaminoethyl)pyridine (0.078 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided N2-methyl-N2-(2-pyridin-2-ylethyl)-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (0.095 g) as its trifluroacetic acid salt after reverse-phase HPLC purification.MS (ESI) m/z 378 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH2:13][F:14])/[C:8]([Cl:18])=[O:9])[N:3]=1
Reactant: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1nc(/C(=N/OCF)C(=O)Cl)ns1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 11.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 80 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 400 ml of ice water to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water, and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 6.70 g (56.3%). Purity: 91.5%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=1.O1CCOCC1>C(Cl)Cl>[NH2:13][C:14]1[N:15]=[C:16]([NH:20][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=2[F:12])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: Nc1cccc(N)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(F)cc(F)cc2F)n1
Temperature: 40 °C
Yield: 73.9 %

Procedure:
Combine 2,4,6-trifluorobenzoyl chloride (3.891 g, 20 mmol), 2,6-diaminopyridine (6.548 g, 60 mmol) and dioxane (25 mL) and stir for 1 hr. at room temperature followed by heating at 40° C. overnight. Dilute the reaction mixture with CH2Cl2 (100 mL), and wash with 0.1N NaOH solution. Extract the aqueous layer three times with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate to a residue. Chromatography on silica gel, eluting with a gradient of 40–50% ethylacetate in hexanes gives the title intermediate (3.95 g, 74%): mass spectrum (ion spray): m/z=267.9 (M+1); 1H NMR (CDCl3, ppm):8.28 (s, br, 1H), 7.66 (d, 1H), 7.52 (t, 1H), 6.78 (m, 2H), 6.31 (d, 1H), 4.36 (s, br, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[CH:15](/[CH:16]=[CH:17]/[C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]1=[O:25].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]([CH2:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]1=[O:25]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1C/C=C\CCCC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCC(=O)CCC1CCCC(=O)N1CCCCCCC(=O)OC
Reaction time: 19 h
Yield: 94 %

Procedure:
Palladium on carbon (10 wt. %, 5 mg) was added to a solution of (Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acid methyl ester (40 mg, 0.11 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 38 mg (94%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)=[N:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[CH:7][CH:8]=2)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]
Reactant: Nc1ccc(-c2cc[nH]n2)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-c4cc[nH]n4)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
4-(1H-Pyrazol-3-yl)aniline (0.159 g, 1.003 mmol), triethylamine (0.101 g, 1.003 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.170 g, 1.003 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.180 g, 0.350 mmol, 52%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)=O.[NH2:11]/[C:12](/[CH3:19])=[CH:13]\[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:19][C:12]1[N:11]=[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:3]2=[CH:1][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=CC1CCCCCC1=O
Product: CCOC(=O)c1cc2c(nc1C)CCCCC2
Yield: 47.8 %

Procedure:
2-Formylcycloheptanone (1.70 g, 12.1 mmol) and ethyl 3-aminocrotonate (1.58 g, 12.1 mmol) were stirred at 100° C. for 15 hours. After cooling, the reaction solution was purified by a silica gel column chromatography (ether/hexane=1:3) to obtain the title compound (1.35 g, 46.1%) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[B:28](OC)([O:31]C)[O:29]C>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]([B:28]([OH:31])[OH:29])=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(B(O)O)c2C1
Temperature: -78 °C
Reaction time: 0.02 h
Yield: 126.5 %

Procedure:
A 1.3M solution of isopropylmagnesium chloride lithium chloride complex solution (39 mL, 0.5 mmol) was added to a stirred solution of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.2 g, 0.42 mmol) in THF (4 mL) at −78° C. and under N2. The mixture was stirred at −78° C. for 1 minute and then trimethyl borate (0.093 mL, 0.84 mmol) was added. The mixture was stirred−78° C. for 30 minutes and at room temperature for 1 hour. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield {5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronic acid (0.21 g, 56% yield) as a yellow oil that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[C@@H](C)O>C(#N)C.ClCCl>[CH2:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(Cc2ccccc2)n1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(Cc2cncc(N3CCNCC3)n2)cc1
Temperature: 85 °C
Reaction time: 8.5 h
Yield: 57 %

Procedure:
A mixture of the product from step 1 above (0.83 g, 4.0 mmol), piperazine (1.1 g, 12.8 mmol) and K2CO3 (0.62 g, 4.49 mmol) in acetonitrile (7 mL) was stirred at 85° C. for 8.5 h. Thr reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (20×4 cm) using CHCl3/MeOH (9:1) as eluent. The resulting oil was redissolved in CHCl3 and filtered through a short (4 cm) plug of alumina using ether/MeOH (96:4) as eluent. Solvent removal in vacuo furnished 0.59 g (57%) of the title compound as an oil which became semi-solid upon refrigeration. HRMS m/z calcd for C15H18N4 (M)+ 254.1531, found 254.1527. Anal. (C15H18N4) C, H, N.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[C:1]([NH:26][CH2:25][C:24]([NH:23][CH:20]1[CH2:19][CH2:18][N:17]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:22][CH2:21]1)=[O:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A chloroform (0.4 mL) solution of benzoyl chloride (0.060 mmol) was added to a chloroform (1.0 mL) solution of 1-benzyl-4-(glycylamino)piperidine (0.050 mmol) and triethylamine (0.070 mmol). The resulting reaction mixture was shaken at room temperature for 12 hours, and an (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added to the mixture. The obtained mixture was shaken at room temperature for 12 hours. The resulting reaction mixture was filtered, and the resin was washed with dichloromethane (0.5 mL). The filtrate and washings were combined, and dichloromethane (4 mL) was added. The solution was washed with a 2 M aqueous solution of NaOH (0.5 mL) to provide 4-(N-benzoylglycyl)amino-1-benzylpiperidine (Compd. No. 386) (11.3 mg, 64%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 352.0 (M++H, C21H25N3O2).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([N:19]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:13]1([N:19]2[CH2:23][CH2:22][CH:21]([NH:24][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCN(c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(NC1CCN(c2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of 6.9 g (0.037 mole) of 4-nitrobenzoyl chloride in 30 ml. of chloroform was added dropwise at room temperature to a stirred mixture of 6 g. (0.037 mole) of 1-phenyl-3-aminopyrrolidine and 10 g. of potassium carbonate in 30 ml. of water and 30 ml. of chloroform. The mixture was stirred 30 minutes, the chloroform layer separated, dried over magnesium sulfate and evaporated. Recrystallization of the crude solid residue from alcohol-water gave 10.6 g. (92%) of an orange solid which melted at 153-155° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:11]=O>O.[Pd]>[CH3:11][N:5]1[CH2:6][CH2:7][C:2]([CH3:1])([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: C=O
Reactant: CC1(C(=O)O)CCNCC1
Agent: [Pd]
Solvent: O
Product: CN1CCC(C)(C(=O)O)CC1

Procedure:
4-Methyl isonipecotic acid (5.10 g, 35 mmol) was placed in a Parr flask and diluted with 400 mL H2O. 10 mL of a 30% formaldehyde solution was added followed by 5.0 g of 10% Pd/C. The reaction mixture was hydrogenated at 50 psi overnight, filtered through celite, washed with H2O, and evaporated. HPLC 1:1 methanol/dichloromethane containing 2% acetic acid afforded 1,4-dimethylpiperidine-4-carboxylic acid. (0.859 g, 15%). 1H NMR (200 MHz DMSO d6) δ3.0 (m, 2H), 2.5 (m, 2H), 2.4 (s, 3H), 2.1 (m, 2H), 1.5 (m, 2H), 1.1 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[Cl-].[C:22]([SiH:26]([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[Si:26]([O:15][CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: C[SiH](C)C(C)(C)C
Reactant: Nc1ccc(-c2cccc(CO)c2)cn1
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
4.99 g of [3-(6-aminopyridin-3-yl)phenyl]methanol are placed in a round-bottomed flask and dissolved in 240 ml of tetrahydrofuran. 2.2 g of 1H-imidazole are added thereto, followed by 4.51 g of tert-butyldimethylsilane chloride, and the mixture is left to stir at ambient temperature for 48 hours. The reaction mixture is then hydrolysed with water, and the organic phase, which has been extracted with ethyl acetate, is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 7.0 g of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:13]=1)=[O:11].[CH:23]([NH2:26])([CH3:25])[CH3:24].O>O1CCCC1>[CH:23]([NH:26][C:19](=[O:21])[CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:17][CH:16]=1)[CH3:22])([CH3:25])[CH3:24]
Reactant: CC(C(=O)O)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)NC(=O)C(C)c1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
3.38 g of 2-[4-(2,3-dichlorophenylcarbamoyl)phenyl]propionic acid was dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the solution with ice water, 2.43 g of N,N'-carbonyldiimidazole was added thereto, and the mixture was stirred for 30 minutes. Thereafter, 0.59 g of isopropylamine was added thereto. The mixture was returned to room temperature and stirred for 5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of water, and the resulting crystals were collected by filtration, washed with water and dried, and then recrystallized from toluene to obtain 3.30 g of desired N-isopropyl-2-[4-(2,3-dichlorophenylcarbamoyl)-phenyl]-propionamide. The yield was 87%, and the melting point of this compound was from 203° to 204° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:36])[C@@H:10]([NH:23][C:24](=[O:35])[CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:44]1([C:50](Cl)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][C:24]([NH:23][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:50]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:35])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate and triethylamine (0.50 g) in chloroform (30 ml) was added triphenylmethyl chloride (1.37 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (5S)-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-6-oxohexylcarbamate (1.62 g) as an oil.