Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(N(CC)CC)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
300 m(of chloroform was added to 100 g of 4-chloro-3-nitrobenzenesulfonyl chloride and the mixture was cooled to 0° C. Then, a chloroform solution containing 84.3 g of methyloctadecylamine was added dropwise to the mixture. After 39.5 g of triethylamine was added dropwise thereto while the temperature was kept at 0° to 10° C.., the mixture was stirred for 1 hour at room temperature. The chloroform was distilled off under reduced pressure, then 500 ml of methanol was added to the residue, and it was heated to dissolve the residue. The mixture was cooled to precipitate crystals and the crystals were filtered and dried.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][O:15][C:16]2[C:25]3[C:24]([NH2:26])=[N:23][S:22](=[O:28])(=[O:27])[NH:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C.[ClH:29].CO>>[ClH:29].[NH2:26][C:24]1[C:25]2[C:16]([O:15][CH2:14][C@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:17][CH:18]=[CH:19][C:20]=2[NH:21][S:22](=[O:27])(=[O:28])[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Agent: Cl
Solvent: CO
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Yield: 63.2 %

Procedure:
A solution of (S)-tert-butyl-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carboxylate (Example 2b, 7.0 g, 17.1 mmol) in conc. HCl:MeOH (1:1, 170 mL) was stirred at room temperature for 4 hours. The precipitate was collected by vacuum filtration, and dried to provide the desired product (3.75 g, 63.2%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.29 (m, 1H), 1.65 (m, 1H), 1.82 (m, 2H), 2.37 (m, 1H), 2.75 (m, 2H), 3.20 (d, J=8.0 Hz, 1H), 3.27 (d, J=11.2 Hz, 1H), 4.10 (d, J=6.0 Hz, 3H), 6.27 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H), 7.68 (s, 1H), 8.35 (br s, 1H), 8.74 (m, 1H), 9.05 (m, 1H), 10.98 (s, 1H). MS 311 (MH+).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.CN1CCCC1=O.Br[CH2:47][CH2:48][O:49][CH3:50]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:17]3[CH2:23][CH2:22][N:21]([CH2:47][CH2:48][O:49][CH3:50])[CH2:20][C:18]=3[N:19]=2)=[CH:12][CH:13]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: COCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(CCOC)C3)cc1
Yield: 53.4 %

Procedure:
To a solution of 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea, hydrochloride salt (bf) (51 mg, 0.13 mmol) in N,N-Diisopropylethylamine (7.0E1 uL, 0.40 mmol) and N-Methylpyrrolidinone (0.80 mL, 8.3 mmol) was added 1-Bromo-2-methoxyethane (3.01 uL, 0.32 mmol) at room temperature. The reaction was microwaved at 80° C. for 30 minutes. After purification, 30.6 mg white powder pc (52% yield) was obtained: 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.16 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 6.15 (t, J=5.5 Hz, 1H), 3.72 (m, 4H), 3.62 (s, 2H), 3.54 (t, J=5.6 Hz, 2H), 3.47 (m, 4H), 3.28 (s, 3H), 3.18-3.05 (m, 2H), 2.73-2.62 (m, 6H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=441 (M+H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH2:13]([OH:18])[CH2:14][CH2:15][CH2:16][OH:17]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:18])=[O:3]
Reactant: COc1ccccc1OC(=O)Cl
Reactant: OCCCCO
Product: COc1ccccc1OC(=O)OCCCCO

Procedure:
The reaction of 2-methoxyphenyl chloroformate with 1,4-butanediol is conducted on a 0.01 scale employing the same conditions as described in Example IV. A 1.5 g yield of the pure product is obtained as an oil.
Reaction SMILES: [Li+].[I-].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].O>C(OCC)C>[CH3:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC=O
Reactant: CC(C)=O
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCC/C=C/C(C)=O

Procedure:
A solution of 7.73 g (58 mM) of anhydrous LiI and 1.47 ml (20 mM) of acetone in 35 ml of diethyl ether was heated to gentle reflux. To this solution was added dropwise a solution of 1.59 ml (15.0 mM) 1-pentanal in 5 ml diethyl ether over 10 minutes. The solution was then heated at reflux for 6 hours. After the solution was cooled to ambient temperature water was added and the layers separated. The ether phase was washed once with brine and dried over anhydrous MgSO4. The diethyl ether was removed by distillation at atmospheric pressure followed by distillation of the residue. There was obtained 0.52 g (27%) of a highly mobile colorless liquid. 1H NMR (CDCl3):6.80δ (dt,1H,JHH =7Hz, 16Hz), 6.01δ (d,1H,JHH =16Hz), 2.20δ (s,3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 10.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 10.0 g of 1-methylpiperazine and 10.4 g of potassium carbonate in 93 ml of DMSO is stirred at ambient temperature overnight. The mixture is diluted with 160 ml of water and extracted three times with 150 ml of ethyl acetate. The organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 200 g of silica, elution being carried out with dichloromethane/methanol (98/2 then 95/5), so as to obtain 13.6 g of 1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.N12CCN(CC1)CC2.O>ClCCl>[CH3:1][C:2]1[N:3]([CH:18]([CH:20]([O:22][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C)C(C)n2c(C)c(C(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a mixture of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (1.1 g, 3.6 mmol) in dichloromethane (4 mL) were added 4-methylbenzene-1-sulfonyl chloride (1.3 g, 7.2 mmol), and 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was added to water (30 mL). The aqueous layers was extracted with dichloromethane (10 mL×3), The combined organic layers was dried over sodium sulfate and concentrate to afford tert-butyl 2-methyl-1-(3-(tosyloxy)butan-2-yl)-1H-indole-3-carboxylate (1.6 g, yield: 96%) as a yellow oil. LRMS (M+H+) m/z: calcd 457.19. found 458.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].CO.ClC(Cl)C(O)=O>O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: O=C(O)C(Cl)Cl
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 136 %

Procedure:
15.4 g. of Acetonine was dissolved in a mixed solvent comprising 169.8 g. of acetone and 56.6 g. of methanol. The solution was ice-cooled, added with 12.9 g. of dichloroacetic acid and 1.8 g. of water under stirring. The mixture was stirred at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, added with 40% aqueous potassium carbonate solution and extracted with ether. The extract was dried over anhydrous potassium carbonate, then ether was distilled off and the resulting residue was purified by distillation under reduced pressure to obtain triacetonamine in a yield of 136%.
Reaction SMILES: O[N:2]=[CH:3][C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1.C([O-])(=O)C.[NH4+].C([BH3-])#N.[Na+]>C(O)C.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:2][CH2:3][C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=NO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 102.5 %

Procedure:
To the solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((hydroxyimino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (800 mg, 1.399 mmol), in ethanol (40 ml) was added excess of ammonium acetate (1078 mg, 13.99 mmol) and sodium cyanoborohydride (879 mg, 13.99 mmol). The mixture was stirred in an ice bath until cold. To this suspension was added an aqueous solution of titanium(III) chloride (Aldrich Chemicals, 20% solution used as supplied, 10 ml, 1.963 mmol). The resulting mixture was blanketed with nitrogen, ice bath was removed and stirring continued at rt for an hour. LCMS showed the reaction was complete. At this point, the mixture was dark greenish-blue. A solution of sodium hydroxide, (3 ml, 10N) in 25 ml water was added into the reaction mixture, along with 30 ml of methylene chloride. The mixture was stirred vigorously until the dark blue phase was floating on top of the organic phase. The mixture was filtered through a plug of paper cellulose, the filtrate was clear. The organic layer was collected and the aqueous layer was extracted with CH2Cl2 (2×20 ml). The combined organic phase was dried over Na2SO4. The solvent was removed in vacuo to afford methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as an off-white solid (˜800 mg). The crude material was used in the next step without further purification. LCMS: m/e 558.5 (MH+), 2.53 min (method 2).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][N:9]([C@@H:16]2[CH2:18][C@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C(=O)C(F)(F)F)[CH2:4][CH2:3]1.[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]1([C@@H:17]2[CH2:18][C@H:16]2[NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:25][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[CH2:7][CH2:6]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN[C@H]2CC[C@H](CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-((trans-4-aminocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (100 mg, 0.294 mmol) in 1,2-dichloroethane (3 mL) was added 4-formylbenzoic acid (48.5 mg, 0.323 mmol). The reaction mixture was refluxed for 2 minutes, then cooled down to room temperature. Sodium triacetoxyborohydride (187 mg, 0.881 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. The reaction mixture was evaporated, and dissolved in 1 mL of water and 2 mL of methanol. The reaction mixture was injected on preperatory HPLC (5 to 40% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected and evaporated. The resulting oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 minutes then it was evaporated. The resulting product was injected on preperatory HPLC (2 to 20% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected and evaporated. 1 mL of 1 M HCl was added to each fraction and product was evaporated. 4-(((trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)amino)methyl)benzoic acid (60 mg, 0.151 mmol, 51.3% yield) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.68-13.69 (m, 1H), 9.23-9.66 (m, 4H), 7.99 (d, J=8.34 Hz, 2H), 7.72 (d, J=8.34 Hz, 2H), 7.28-7.35 (m, 2H), 7.11-7.26 (m, 3H), 4.24 (br. s., 2H), 2.79-3.09 (m, 4H), 2.58 (ddd, J=3.54, 6.38, 10.04 Hz, 1H), 2.20 (d, J=10.36 Hz, 2H), 1.96 (d, J=11.12 Hz, 2H), 1.65-1.85 (m, 1H), 1.54-1.66 (m, 1H), 1.46 (q, J=12.38 Hz, 2H), 1.18-1.34 (m, 1H), 1.03 (q, J=12.04 Hz, 2H); LC-MS Rt=0.56 min; MS (ESI): 379.4 [M+H]+.
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:31])([CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1>CS(C)=O>[CH3:30][C:18]([N:31]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: CCCCOc1ccccc1C(=O)C=O
Reactant: COc1ccc(CC(C)(C)N)cc1OC
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=NC(C)(C)Cc1ccc(OC)c(OC)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of 2-n-butoxyphenylglyoxal hydrate are dissolved in 2.5 ml of dimethylsulfoxide, and a solution of 1.83 g of α,α-dimethyl-3,4-dimethoxyphenethylamine in one ml of dimethylsulfoxide is added thereto. The mixture is stirred at 25° C. for 30 minutes, whereby a solution of α-(α,α-dimethyl-3,4-dimethoxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].[C:25]([O:44][CH2:45][CH2:46][CH2:47]O)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl.CCCCCC>[CH3:1][C:2]1([CH3:24])[S:6][CH:5]2[N:4]([C:8](=[O:9])[CH:7]2[NH:10][C:11](=[O:12])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:3]1[C:21]([O:23][CH2:47][CH2:46][CH2:45][O:44][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:22]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)C2SC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of penicillin V (1 g, 2.9 mmol), 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (860 mg, 2.6 mmol), 1,3-dicyclohexylcarbodiimide (620 mg, 3 mmol) and 4-(N,N-dimethylamino)pyridine (catalytic amount) in dichloromethane (30 ml) was stirred overnight at room temperature. The reaction mixture was diluted with hexane (50 ml), filtered and concentrated to dryness. The residue was washed with hexane (3×50 ml) to remove unreacted 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane. The semisolid residue was disolved in diethyl ether (150 ml), washed with water (100 ml) and dried. The ether solution was diluted with hexane (125 ml) and the solution filtered through a bed of silica (4 cm×4 cm). The filtrate was concentrated, yielding 1-(3,3-dimethyl-7-oxo-6([phenoxy acetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptan-2-oyloxy)-3-(z,z,z-octadeca-6,9,12-trienoyloxy)propane as a viscous colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[OH:35][CH2:34][C@H:31]1[CH2:30][CH2:29][C@H:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:33][CH2:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)O)CC2)c2ncnn12
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](CO)CC2)c2ncnn12
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxylic acid (7 g), N-methylmorpholine (1.9 mL) and tetrahydrofuran (100 mL) was added ethyl chlorocarbonate (1.6 mL) at 0° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was cooled to −15° C., sodium borohydride (1.6 g) and methanol (25 mL) were added, and the mixture was allowed to gradually warm to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (5.3 g, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:27]1(C)C=CC=C[CH:28]=1>C(O)C>[CH2:27]([O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:28]
Reactant: Cc1ccccc1
Reactant: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
243 g of 2(S)-benzyloxycarbonylamino-3-cyclohexylpropionic acid (manufacture: Helvetica Chimica Acta 57. 2131(1974)) are placed in 600 ml of toluene and 900 ml of ethanol. The reaction mixture is cooled to 0° and 88.3 g of thionyl chloride are added dropwise within 30 minutes. The cooling is removed and the mixture is stirred for 18 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue is separated by means of flash chromatography (2 kg of silica gel 60, 40-63 μm, eluant F). The product-containing fractions are combined, concentrated by evaporation and dried under a high vacuum. The title compound is obtained in the form of a slightly yellowish oil. Rf (F)=0.2; Rf (B)=0.52.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][NH2:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:38]([NH:39][C:20](=[O:21])[CH2:19][N:3]1[CH2:4][CH2:5][C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]1=[O:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ccccc1
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.031 g, 0.105 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.044 g, 0.115 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.027 mL, 0.157 mmol) followed by phenylmethanamine (0.014 mL, 0.126 mmol). After stirring overnight, the reaction was loaded onto a silica gel column (Analogix® SF15-12, Burlington, Wis.), and the product was eluted with a gradient of 0.4% to 5.25% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. The product residue was dissolved in dichloromethane/diethyl ether followed by the addition of hexanes which upon concentration gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.34 (m, 15H), 6.23 (t, J=5.8 Hz, 1H), 4.32 (d, J=5.8 Hz, 2H), 4.06 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.80 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 383 (M−H)−.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH2:20]([C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[N:32][CH:33]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].O>C(O)CCC.C(Cl)(Cl)Cl>[CH2:20]([C:28]1[CH:33]=[N:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:36][CH:35]=2)=[N:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: CCCCCCCCc1cnc(-c2ccc(OCC(F)CCCCC)cc2)nc1
Reaction time: 5.5 h

Procedure:
0.43 g (1.5 mmol) of the thus obtained (+)-2-fluoroheptyl p-toluenesulfonate and 0.28 g (1.0 mmol) of 5-octyl-2-(4-hydroxyphenyl)pyrimidine were mixed with 0.2 ml of 1-butanol, followed by sufficient stirring. To the solution was quickly added a previously obtained alkaline solution of 0.048 g (1.2 mmol) of sodium hydroxide in 1.0 ml of 1-butanol, followed by 5.5 hours of heat-refluxing. After the reaction, 10 ml of distilled water was added, and the mixture was extracted respectively once with 10 ml of benzene and 5 ml of benzene, followed by drying with an appropriate amount of anhydrous sodium sulfate, distilling-off of the solvent and purification by silica gel column chromatography (eluent: chloroform to obtain 0.17 g (0.43 mmol) of objective (+)-5-octyl-2-[4-(2-fluoroheptyloxy)phenyl]pyrimidine.