Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.C(O)(=O)C.C(O)(=O)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:29])[CH:23]([CH3:28])[C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1>CS(C)=O>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:22]([CH3:29])=[C:23]([CH3:28])[C:24](=[O:27])[NH:25][N:26]=2)=[CH:19][CH:20]=1
Reactant: CC1C(=O)NN=C(c2ccc(CCCCN)cc2)C1C
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1c(-c2ccc(CCCCN)cc2)n[nH]c(=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
44 ml of a 25% hydrogen bromide-acetic acid solution was added to 44 ml of an acetic acid solution containing 2.20 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dihydro-4,5-dimethylpyridazin-3(2H)-one, and the mixture was stirred at room temperature for 5 minutes. Then, 0.75 ml of dimethylsulfoxide was added to the mixture, and the resulting mixture was stirred for 6 hours. The solvent was removed, and the residue was dissolved in 150 ml of water. The solution was made alkaline with ammonia and extracted with chloroform. After the chloroform layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-28% aqueous ammonia (10:1:0.1)) to obtain 1.52 g of 6-[4-(4-aminobutyl)phenyl]-4,5-dimethylpyridazin-3(2H)-one.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COC(=O)C1(C2CCCC2)CC(=O)N(c2c(C)cccc2C)C1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C2CCCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 456 μL, 1.14 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (177 μL, 0.1.14 mmol) in THF (3 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 120 mg, 0.38 mmol) in THF (2 mL) was added and stirred for 2 h at 70° C. The reaction mixture was then purified by automated flash chromatography. Pure fractions were combined and concentrated under reduced pressure. The material was recrystallized from MeOH to obtain the desired product 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (60 mg, 31% yield) as white crystals. LC-MS: Rt (retention time): 3.32 min, MS: (ES) m/z 513.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.4 (s, 1H), 8.05 (s, 2H), 7.6 (s, 1H), 7.08-7.13 (m, 2H), 7.02-7.06 (m, 2H), 4.14 (d, 1H, J=11.5 Hz), 3.56 (d, 1H, J=11.5 Hz) 3.17 (d, 1H, J=16.9 Hz), 2.74 (d, 1H, J=16.9 Hz), 2.42-2.52 (m, 1H), 2.2 (s, 3H), 2.14 (s, 3H), 1.75-1.88 (m, 2H), 1.6-1.68 (m, 4H), 1.25-1.48 (m, 2H).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH2:13][O:12][C:11]1([CH3:22])[CH3:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][O:12][C:11]1([CH3:22])[CH3:21])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CCC(=O)O)COC1(C)C
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
Sodium hydroxide (27 mL of a 4.0 M solution in H2O, 108 mmol, 3.0 equiv.) was added to a solution of (4S)-4-(2-methoxycarbonylethyl)-2.2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (prepared as described in Chida et al., J. Chem. Soc., Chem. Commun. 1992, 1064) (10.5 g, 36.5 mmol, 1 equiv.) in CH3OH (150 mL), and the resulting cloudy reaction mixture was stirred at 23° C. for 3.5 h. The mixture was concentrated under reduced pressure to ˜30 mL volume, and then was partitioned between 0.5 M HCl (150 mL) and EtOAc (2×150 mL). The combined organic layers were dried over MgSO4 and were gravity filtered. The filtrate was concentrated under reduced pressure and the residue dried under vacuum, to afford (4S)-4-(2′-carboxyethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (10.0 g, 100% crude yield). This material was used without further purification: 1H NMR (CDCl3, mixture of rotamers) δ 1.49 (s), 1.57 (s), 1.60 (s), 1.84-2.05 (m), 2.39-2.41 (m), 3.71-3.74 (m), 3.91-4.05 (m).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([O-])C=C(C)C=C(C)C=1.[K+].[C:18](=[O:20])=[O:19]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:18]([OH:20])=[O:19])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C=O
Agent: Cc1cc(C)cc([O-])c1
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 83.8 %

Procedure:
A pressure vessel was charged with 4.72 g of phenol, 24.10 g of potassium 3,5-xylenolate being in a dry powder form and 50 ml of NeoSK 1400. With stirring, reaction was carried out at a carbon dioxide pressure of 7 kg/cm2 (G) and at 300° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 83.8% on the basis of phenol.
Reaction SMILES: C[C@@H]1N(S(O)(=O)=O)C(=[O:5])[C@H]1NC(/C(/C1N=C(N)SC=1)=N\OC(C(O)=O)(C)C)=O.C(N(CCCC)CCCC)CCC.OC1C2N=NNC=2C=CC=1.CN(C1C=CC=CN=1)C.[CH:61]1([N:67]=[C:68]=[N:69][CH:70]2[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]2)[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C)C=O>[C:68]([NH:67][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1)([NH:69][CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1)=[O:5]
Reactant: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of aztreonam (2.29 g, 5.27 mmol) in 35 ml dimethylformamide were added tributylamine (0.97 g, 5.27 mmol), hydroxybenzotriazole (0.78 g, 5.79 mmol), dimethylaminopyridine (0.064 g, 0.53 mmol) and dicyclohexylcarbodiimide (1.19 g, 5.79 mmol). After stirring for 30 minutes, the resulting dicyclohexylurea (0.47 g, 40.1%) was filtered off and solution (a) was added to the filtrate. After stirring overnight at room temperature, the mixture was filtered (yielding 0.53 g, 45% of dicyclohexylurea) and evaporated. The residue was taken up in acetone, filtered, and 9.0 ml of 10% potassium perfluorobutane sulfonic acid in acetone were added. The resulting precipitate was filtered off (1.70 g), dissolved in water and chromatographed on XAD under MPLC conditions with a water - acetonitrile gradient. The sample-containing fractions were collected and freeze-dried to give 250 mg (6.9%) of Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23]>>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:20][C:21]1[C:22]([NH2:23])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[N:4][CH:3]=2
Reactant: COc1cccc(OC)c1CCC#N
Reactant: Nc1cnccc1C=O
Product: COc1cccc(OC)c1Cc1cc2ccncc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 3-amino-4-pyridine carboxaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[F:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([NH2:43])[CH:38]=1>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][C:39]3=[N:43][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(F)ccn1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(C(=O)Nc2c(F)cccc2F)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (0.6 g, 1.49 mmol) in DCM (15 mL) at rt under N2 was added NBS (0.278 g, 1.56 mmol). The reaction was stirred approximately 60 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (15 mL) and 4-fluoro-2-pyridinamine (0.5 g, 4.46 mmol) was added. The reaction was stirred under N2, heated to 75° C., and stirred for approximately 18 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound of step B (0.391 g, 0.81 mmol, 55%) as a light yellow solid. MS (ESI): 480 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1>O.C1COCC1>[Cl:3][C:4]1[N:13]=[C:12]([OH:1])[C:11]2[C:6](=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=1
Reactant: [OH-]
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(O)nc(Cl)nc2c1C
Temperature: 40 °C
Yield: 99.3 %

Procedure:
A solution of NaOH (1.58 g, 39.6 mmol) in water (40 mL) was added to 2,4-dichloro-7-methoxy-8-methylquinazoline (139) (3.2 g, 13.05 mmol) in THF (20 mL). The resulting mixture was heated at 40° C. for 24 h. Then, the reaction mixture was cooled to room temperature, THF was evaporated and additional water (30 mL) was added. The precipitate was filtered off. Then, the pH of the filtrate was adjusted to 5 with AcOH to give a solid which was subsequently filtered off and successively washed with water and isopropylether to give the title compound (2.91 g, 99%) as a yellowish powder: m/z=225 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[F:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=1[N:54]=[C:55]=[O:56]>CN(C)C=O>[F:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=1[NH:54][C:55]([NH:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:37][CH:38]=1)=[O:56]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)Nc4ccc(F)cc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.3 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (65 mg) and anhydrous N,N-dimethylformamide (5 ml) was added 2,4-difluorophenyl isocyanate (81 mg) and the mixture was stirred at room temperature for 4.5 hours and then allowed to stand for 2 days. The reaction mixture was concentrated and diluted with water and tetrahydrofuran and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added ethyl acetate and the precipitate was isolated by filtration and washed with ethyl acetate to afford the title compound (0.2 g, mp 161-164° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH2:14])[O:9][C:8]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=4[CH:30]=3)[O:9][C:8]=2[CH:15]=1
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)O[C@@H](CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 90 °C
Yield: 30.8 %

Procedure:
(S)-2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine hydrochloride (11.5 g, 49.8 mmole), 7-(3-bromopropoxy)coumarin (14.2 g, 50.0 mmole), and diisopropylethylamine (12 ml, 68.9 mmole) were combined in 350 ml of DMF and heated at 90° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. Upon addition of an equal volume of saturated aqueous sodium bicarbonate, a white solid precipitated. This was filtered and redissolved in 550 ml of warm methanol and 35 ml of 4N isopropanolic HCl was added. The solution was boiled on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 0.54 g of the title compound precipitated as a white solid, monohydrochloride, quarter hydrate, m.p. 225°-227° C. Subsequent crops yielded as additional 6.1 g of product.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11].CC(C)([O-])C.[K+]>COCCOCCOC>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Yield: 82.2 %

Procedure:
A mixture of 4-(hydroxymethyl)phenol (1.0 g, 8.1 mmol) and 2-nitropropane (4.0 g, 45 mmol) in diglyme (50 mL) was cooled in an ice bath. Potassium tert -butoxide (0.45 g, 4.0 mmol) was added in portions, then the reaction mixture was heated to reflux overnight. After cooling, the mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give 4-(2-methyl-2-nitropropyl)phenol (1.3 g, 83% yield) as a light yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:38]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH2:38])=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(N)=O)c4c3OCC4)nc2N1C1CCCC1
Yield: 90.6 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (187 mg, 0.43 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (138 mg, 0.43 mmol) were dissolved in 40 mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.2 mL, 0.95 mmol), stirred until the solution became clear, followed by the addition of 5 mL of a solution of (cis-exo)-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-amine 5k (60 mg, 0.43 mmol) in dichloromethane, and stirred for another 2 hours. The resulting solution was added with 30 mL of dichloromethane, washed with dilute aqueous ammonia (20 mL), water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (cis-exo)-N-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 5 (170 mg, yield: 71.0%) as a white solid.
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].O>C1(C)C(C)=CC=CC=1>[C:1]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:18]([OH:20])=[O:19])[NH2:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCC(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 81.9 %

Procedure:
Lysine octanoate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 26.9 g of Nε -octanoyl lysine (yield 81.9%). This is designated Derivative B.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]([OH:24])(=[O:23])[CH3:22].OO.C(OC(=O)C)(=O)C>O>[C:21]([O:24][CH:9]1[C:10]2[N:1]=[C:2]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2c(nc1C(=O)OCC)CCCC2
Agent: OO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C(=O)OCC)C(OC(C)=O)CCC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture comprising 2.8 g of diethyl 5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate, 10 ml of acetic acid and 1.1 ml of a 35% hydrogen peroxide aqueous solution, was stirred at 75° C. for 3 hours under heating. 1.0 ml of a 35% hydrogen peroxide aqueous solution was added thereto, and the mixture was further reacted at 75° C. for 9 hours. After cooling the mixture, water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried, and then the solvent was distilled off to obtain an oily substance. This oily substance was added to 50 ml of acetic anhydride under reflux, and refluxed for 15 minutes. The solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was dried, and then the solvent was distilled off. The residue was purified by column chromatography to obtain 2.3 g (yield: 69%) of diethyl 8-acetoxy-5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[N:16]2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH3:22][C:17]1[C:18]([CH3:21])=[C:19]([CH3:20])[N:15]([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[N:16]=1
Reactant: Cc1nn(C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c(C)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nn(C[C@H]2CC[C@H](N)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of trans-[4-(3,4,5-trimethyl-pyrazol-1-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (step 2) (215 mg, 0.669 mmol) in methanol (3 mL) at room temp is added a solution of 4M HCl in dioxane (3 mL). The mixture is stirred at room temp for 1 hour and then concentrated in vacuo. The resulting gum is dried under vacuum overnight to afford the title compound which is used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.16 (3H, br s), 4.10 (2H, d), 2.90 (1H, m), 2.29 (3H, s), 2.27 (3H, s), 2.01-1.90 (5H, m including 3H, s), 1.83 (1H, s), 1.54 (2H, m), 1.30 (2H, m), 1.12 (2H, m). (NMR shows contamination with side products and solvents.)
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[Na+].[Na+].[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[C:11]([N:14]1[CH2:19][CH2:18][N:17]([CH2:2][C:3]#[N:4])[CH2:16][CH2:15]1)(=[O:13])[CH3:12]
Reactant: N#CCCl
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(CC#N)CC1

Procedure:
Chloroacetonitrile (14.7 ml, 234 mmol) was added slowly to a well stirred suspension of sodium carbonate (32 g, 300 mmol) and acetylpiperazine (30 g, 230 mmol) in toluene (200 ml). The mixture was heated under reflux for 3 hours. The reaction was cooled, filtered and the filtrate evaporated under reduced pressure. The resulting solid was recrystallised from ethyl acetate to afford the title compound as a yellow solid, 18.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131)(50 mg, 0.19 mmol) was coupled to aniline (124)(40 mg, 0.21 mmol) using Method D to give the product, which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 89 %

Procedure:
224 mg Of octene-1, 329 mg of triethoxysilane and 400 mg of toluene were placed in a glass reaction tube and 0.004 ml of acetic acid was then added to the tube. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of the octene-1 was 96% and n-octyltriethoxysilane was produced at a yield of 89%.