Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]>CCOCC>[C:9]([N:13]=[N:14][C:15]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)N=NC1(c2ccccc2)CCCCC1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a clean, dry 250 ml. round bottom 4 neck flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel, which was being purged with nitrogen, was added an ether solution containing 0.06 moles of phenyl-magnesium bromide. The solution was cooled to 5° C. and a solution of 8.7 g. (0.043 moles) of 1-t-butylazo-1-chlorocyclohexane in 50 ml. of ether was added dropwise over 1/2 hour. After the addition was complete, the reaction was stirred for 15 minutes at room temperature and the excess phenylmagnesium bromide destroyed by the addition of wet ether. The reaction mixture was poured into 200 ml. of cold water and the ether layer separated, washed with 5% HCl, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the ether removed on a rotating evaporator leaving 9.75 g. (93%) of a yellow liquid. The infrared spectrum of the product was in agreement with the structure of the title compound.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].[OH2:14].C[N:16]([CH:18]=O)[CH3:17]>>[C:5]([O:4][CH2:2][O:12][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:2](=[O:3])[CH3:1])(=[O:14])[C:10]1[CH:9]=[CH:8][CH:17]=[N:16][CH:18]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CN(C)C=O
Reactant: O
Product: CC(=O)Oc1ccccc1C(=O)OCOC(=O)c1cccnc1
Temperature: 45 °C
Yield: 50 %

Procedure:
TEA (0.08 ml, 0.68 mmol, 1.2 eq) and methyl formyl reagent [259] (0.1 g, 0.56 mmol, 1.0 eq) was added to a solution of aspirin [4154] and 2-acetoxybenzoic acid, (0.1 g, 0.56 mmol, 1.0 eq) in DMF (2 ml). The reaction mixture was heated at 45° C. for 16 h, followed by cooling to room temperature and dilution with water. The organic material was extracted with ethyl acetate, was washed with water dried over Na2SO4 and evaporated under vacuum to get crude product. The crude product was purified by silica gel column chromatography (ethyl acetate in cyclohexane 100-200 mesh) to yield a dark colored sticky product [318], ((2-acetoxybenzoyl)oxy)methyl nicotinate, (0.09 g, 50%).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[NH:16][C:15](=[O:17])[C:14]3([CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18]3)[N:13]([C:24]([O-:26])=[O:25])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1>CO>[C:7]([O:25][C:24]([N:13]1[C:14]2([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23]2)[C:15](=[O:17])[N:16]([CH2:10][C:5]([OH:4])=[O:1])[CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:12]1)=[O:26])([CH3:11])([CH3:8])[CH3:6]
Reactant: [OH-]
Reactant: COc1cccc(C2CN(C(=O)[O-])C3(COCCOC3)C(=O)N2)c1
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C2CN(C(=O)OC(C)(C)C)C3(COCCOC3)C(=O)N2CC(=O)O)c1

Procedure:
2.5 ml (2.5 mmol) of a 1N aqueous sodium hydroxide solution were added to 0.38 g (0.82 mmol) tert-butyl (3-(3-methoxyphenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 5 ml MeOH. After 1 h MeOH was distilled off and the aqueous solution was acidified with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[H-].[Na+].Br[CH2:33][CH3:34].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[N:19]([CH2:33][CH3:34])[C:18]3=[O:23])=[CH:14][N:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCBr
Reactant: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)NC2=O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nn(-c3ccccc3)cc2C=C2SC(=O)N(CC)C2=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
5-[3-(3-Bromo-4-ethoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl-methylene]-thiazolidine-2,4-dione (Compound No. 77, 0.10 mg, 0.21 mmol) was dissolved in 1.00 mL of anhydrous dimethylformamide. Sodium hydride (12.74 mg, 0.32 mmol) was added under nitrogen atmosphere and bromoethane (23.72 μL, 0.32 mmol) was added 5 minutes later. The mixture was stirred at room temperature for 2 hours. When the reaction was completed, 10 mL of water was added and the solution was extracted with dichloromethane (10 mL×2 times). The organic layer was washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The product was purified with silica gel chromatography (n-hexane/ethyl acetate=4:1) to obtain 52 mg (49.2%) of the target product in yellow solid form.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=[N:10][C:11]#N)[N:3]=1.[CH2:13](N)[CH2:14]C>O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=[N:10][CH2:11][CH2:13][CH3:14])[N:3]=1
Reactant: N#CN=CNc1cccc(O)n1
Reactant: CCCN
Solvent: O
Product: CCCN=CNc1cccc(O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g (14 mmol) of N-(2-hydroxy-6-pyridyl)-N'-cyanoformamidine are added in portions at room temperature over a period of 20 minutes to a stirred solution of 8.3 ml (99 mmol) of n-propylamine in 8 ml of water The reaction mixture is stirred for 2 hours at room temperature It is then extracted three times with chloroform The combined organic phases are dried over MgSO4 and concentrated by evaporation. The resulting crude product is chromatographed on silica gel with methylene chloride and then crystallised from ether/n-hexane. N-(2-pyridon-6-yl)-N'-propylformamidine and N-(2-hydroxy-6-pyridyl)-N'-propylformamidine having a melting point of 178°-179° are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1)=[O:5])[CH3:2].C[Si]([C:23]#[N:24])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N>[C:23]([CH2:12][C:10]1[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1)#[N:24]
Reactant: C[Si](C)(C)C#N
Reactant: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl-5-(bromomethyl)benzene-1,3-dioate (1.9 g, 6.0 mmol) in 69 mL MeCN was added trimethylsilyl cyanide (1.2 mL, 9.0 mmol) and tetrabutylammonium fluoride (1M in THF, 9.0 mL, 9.0 mmol). The reaction was stirred for 0.5 h and concentrated. Flash chromatography (silica gel, 0-30% EtOAc/hexanes) gave diethyl 5-(cyanomethyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.20 (app t, J=0.7 Hz, 2H), 4.43 (q, J=7.1 Hz, 4H), 3.86 (s, 2H), 1.43 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](Cl)=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][CH3:25])[CH3:15]>ClCCl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([C:21]1[CH:20]=[CH:19][C:18]([O:23][CH2:24][CH3:25])=[C:17]([O:16][CH2:14][CH3:15])[CH:22]=1)=[O:7]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CCOc1ccccc1OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)CCC(=O)OC)cc1OCC
Reaction time: 14 h

Procedure:
1.1 A solution of 70 ml 3-chlorocarbonyl-propionic acid methyl ester in 100 ml dichloromethane is added to a suspension of 80.0 g of AlCl3 in 300 ml dichloromethane at 20-25°. At 0° a solution of 85.0 g 1,2-diethoxybenzene in 100 ml dichloromethane is added. The solution is tirred for 14 hours at room temperature. Work-up is as usual, yielding 122.2 g of 4-(3,4-diethoxy-phenyl)-4-oxo-butyric acid methyl ester (“AA”), m.p. 84-85°.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[N:17]#N.CCOCC.[C:24]([C@:31](N)([CH2:34][CH3:35])[CH:32]=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:24]([C@@H:31]([CH2:34][CH3:35])[C:32]([NH2:17])([C:5]1[O:1][C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:3][N:4]=1)[OH:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: N#N
Reactant: c1cncc(-c2nnco2)c1
Reactant: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC[C@H](C(=O)OC(C)(C)C)C(N)(O)c1nnc(-c2cccnc2)o1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 3-[1.3.4]oxadiazol-2-yl-pyridine (5 g, 34 mmol) in THF (100 mL) was added HMPA (5 mL) and n-BuLi (1.6 M solution in hexane, 21.25 mL) drop wise under N2 at −78° C. After 1 h, MgBr.Et2O (8.77 g, 34 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 h before being treated with 2(S)-Boc-aminobutyraldehyde (4.22 g, 22.1 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 2(S)-Boc-amino-1-(5-pyridin-3-yl-[1.3.4]oxadiazol-2-yl)-butan-1-ol (1.5 g).
Reaction SMILES: N1N(C2C=CC(C(F)(F)F)=CC=2C(O)=O)N=CC=1.N1(C2C=CC(C(F)(F)F)=CC=2C(O)=O)C=CN=N1.[N:37]1[NH:38][N:39]=[CH:40][CH:41]=1.Br[C:43]1[C:51]([F:52])=[CH:50][C:49]([F:53])=[CH:48][C:44]=1[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[F:52][C:51]1[C:43]([N:38]2[N:39]=[CH:40][CH:41]=[N:37]2)=[C:44]([CH:48]=[C:49]([F:53])[CH:50]=1)[C:45]([OH:47])=[O:46]
Reactant: O=C(O)c1cc(F)cc(F)c1Br
Reactant: c1cn[nH]n1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(F)cc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 1.0 g, 10.86 mmol) and 2-bromo-3,5-difluorobenzoic acid (CAS number 651027-01-9; 1.27 g, 5.43 mmol) in 1,4-dioxane (5 ml) and water (1 ml). The crude solid was purified by using column chromatography (silica, 0-3% methanol/DCM) to afford 3,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 40a). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 3,5-difluoro-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 40b).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1ccccc1
Product: O=C(Nc1nc2cccc(-c3ccco3)n2n1)c1ccccc1
Yield: 26 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B1), 75 mg; 0.24 mmol; 1.0 eq.) and 2-furanboronic acid (53 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, 45:55) gave the title compound as an off-white powder (19 mg, 26%). HPLC, Rt: 3.24 min. (purity 97.9%). LC/MS, M+(ESI): 305.3, M−(ESI): 303.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:30][CH2:31][CH3:32])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:33](Cl)([Cl:35])=[O:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:33]([Cl:35])=[O:34])[C:10]([C:20]3[C:21]([O:30][CH2:31][CH3:32])=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Product: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C27H24N6O3F3Cl2 [(M+H)+] 607.1234, observed 607.1231.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[CH2:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:17])[CH2:4][CH2:3]2)[CH2:24][CH2:23]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.5 g of 1,3-dihydro-1-(4-oxocyclohexyl)-2H-benzimidazol-2-one, 1.12 g of ethyl 4-amino-1-piperidinecarboxylate, 20 mL of 1,2-dichloroethane, 0.40 mL of glacial acetic acid and 1.79 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 50 mL chloroform and 50 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 10% methanol in ethyl acetate gave 1.3 g of 1,3-dihydro-1-{trans-4-[1-ethoxycarbonyl-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.8-9.9 (br m, 1H), 7.30 (m, 1H), 7.11-7.02 (m, 4H), 4.37 (m, 1H), 4.17-4.06 (m, 4H), 3.15 (m, 1H), 2.88 (t, 2H), 2.7 (m, 1H), 2.55 (m, 2H), 1.97 (d, 2H), 1.86 (d, 2H), 1.65 (q, 4H), 1.25 (m, 5H). Analysis calculated for C21H30N4O3C: 65.26, H: 7.82, N: 14.46 found C: 65.20, H: 7.57, N: 14.15.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(C)(C)C)(=O)C.Cl(O)(=O)(=O)=O>[C:2]([O:19][C:18](=[O:20])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:7])([CH3:3])[CH3:1]
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Nα -(Benzyloxycarbonyl)-L-lysine (5.0 gm, 17.84 mmol) was dissolved in 268 ml of tert-butyl acetate containing 2.80 ml of perchloric acid (69-72% aqueous solution). The solution was stirred for 2 days at room temperature and then was extracted with water (3×200 ml). The combined aqueous layers were adjusted to pH 10 with 50% sodium hydroxide. The aqueous solution was then extracted with ethyl acetate (3×200 ml) and the organic layers dried over MgSO4. After filtration to remove MgSO4, the solvent was removed by evaporation at reduced pressure to provide Nα -(benzyloxycarbonyl)-L-lysine tert-butyl ester as a clear oil (2.16 gm, 36%). 1H NMR (CDCl3) 1.35 (s,9H), 1.40-2.0 (m,6H), 2.60 (t,2H), 4.10 (m, 1H), 4.98 (s,2H), 5.29 (bs,1H), 7.35 (s,5H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[C:21]1([CH:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:28]2[CH2:31][C:30](=O)[CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.COC(OC)OC>CO>[CH:27]([N:28]1[CH2:31][C:30](=[N:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:8][CH:7]=2)[CH2:29]1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: COC(OC)OC
Product: O[C@@H](CN=C1CN(C(c2ccccc2)c2ccccc2)C1)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.6 %

Procedure:
A mixture of (2S)1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (1.64 g, 6 mmol) and 1-(diphenylmethyl)-3-azetidinone (1.19 g, 5 mmol) in methanol (20 ml) was treated with trimethylorthoformate (1.59 g, 15 mmol), and stirred at room temperature for 2 days. The resulting suspension was filtered, and the precipitate washed with 3×5 ml of methanol, and dried in vacuo to give 1.96 g of a white solid. The methanol filtrate was evaporated, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was filtered through a pad of silica gel, and eluted with 2×30 ml of ethyl acetate. The combined filtrate was evaporated, and the residue triturated with a mixture of ether and hexanes to give an additional 0.30 g of product; m.p. 141-142° C.; MS (ES) m/z 748 (MH+); HRMS (EI) Calcd. for C32H32N2O3 (M+): 492.2413, Found: 492.2397.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:4][CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44].C(OCC)(=O)C>O1CCCC1>[C:43]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:21])[CH3:22])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:4][CH:3]=1)(=[O:45])[CH3:44]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)NC(C(C)C)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.83 g) and triethylamine (0.45 mL) in tetrahydrofuran (10 mL) at 0° C. was added acetyl chloride (0.17 mL) and the resulting solution was allowed to stir for 0.5 h. The mixture was poured into ethyl acetate and the solution was washed (1N hydrochloric acid, water), dried, and evaporated to give 2-(5-acetamido-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a foamy solid (0.86 g); TLC: Rf =0.4, methanol:dichloromethane (5:95).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:8]
Reactant: CC(C)CCCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccccn1
Product: CC(C)CCCCCCCCCCCCCCCOC(=O)c1ccccn1

Procedure:
Isooctadecyl picolinate was prepared using the method of Example 7 from picolinic acid and isooctadecyl alcohol, the commercial material obtained from Farbwerke Hoechst AG and described in Example 8. The light brown, oily product of the reaction had an estimated purity of 93.5%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1.[ClH:42].Cl.C(O)(C)C>>[ClH:42].[F:38][C:37]([F:39])([F:40])[C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CC(C)O
Product: O=C(N[C@H]1CCN(CCc2ccc(C(F)(F)F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(4-trifluoromethylphenyl)ethyl p-toluenesulfonate (0.69 g) were reacted under the same conditions as in Example 1. After the same post-treatment as in Example 1, the obtained compound was converted to hydrochloride with 30% hydrochloric acid-isopropanol to give (S)-N-(1-(2-(4-trifluoromethylphenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide hydrochloride 1/2 hydrate (0.51 g), melting point 214-215° C.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([CH2:14]C=C)[C:8]=1[OH:17].C(=O)(O)[O-].[Na+]>C(OO)(=O)C>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([CH2:14][CH:1]2[O:4][CH2:2]2)[C:8]=1[OH:17]
Reactant: C=CCc1ccc(Cl)c(Cl)c1O
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1c(CC2CO2)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred solution of sodium acetate (1 g.) in 40% peracetic acid (25 ml.) is cooled to 15° C. then treated dropwise with 2,3-dichloro-6-allylphenol. The reaction mixture is stirred at 25° C. for 48 hours, poured into excess aqueous sodium bicarbonate, extracted into ether, washed with aqueous sodium bicarbonate, water, aqueous ferrous sulfate, water, brine and dried over magnesium sulfate. Evaporation of the ether leaves 2,3-dichloro-6-(2,3-epoxypropyl)phenol which is rearranged by heating at 110° C. for ten minutes then distilled to give 10.4 g. of 6,7-dichloro-2,3dihydro-2-hydroxymethylbenzofuran which boils at 130°/0.1 mm.