Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11].Br[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]>CN(C)C=O>[CH2:17]([N:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11])[CH2:16][CH2:15][CH:14]=[CH2:13]
Reactant: O=C1CCCCCCN1
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCN1CCCCCCC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a stirred suspension of sodium hydride (0.9 g, 37.5 mmole) in dimethylformamide (50 mL) was added azocan-2-one (3.83 g, 30 mmole). The mixture was stirred at room temperature for 15 minutes, and then 5-bromo-1-pentene (5.03 g, 33.7 mmole) was added slowly. The reaction mixture was stirred at room temperature for 30 minutes, and then at 80° C. for 16 hours. The solvent was removed under reduced pressure and water was added to the residue. The mixture was extracted with ethyl ether, the organic phase was washed with water, dried (magnesium sulfate) and concentrated to give 1-pent-4-enyl-azocan-2-one (5.53 g,) as an oil.
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=[C:19]([Cl:39])[N:18]=2)[CH2:6][C:5]1([CH3:41])[CH3:40].S([O-])([O-])=O.[Na+].[Na+].[C:48]([OH:52])([CH3:51])([CH3:50])[CH3:49]>O.C(OCC)(=O)C>[OH:52][C:48]([CH3:51])([CH3:50])[CH2:49][O:36][N:31]1[C:32]([CH3:35])([CH3:34])[CH2:33][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:21]2[N:22]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]3[CH2:6][C:5]([CH3:41])([CH3:40])[N:4]([O:3][CH2:49][C:48]([CH3:51])([OH:52])[CH3:50])[C:9]([CH3:11])([CH3:10])[CH2:8]3)[N:18]=[C:19]([Cl:39])[N:20]=2)[CH2:29][C:30]1([CH3:38])[CH3:37]
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Temperature: 42.5 °C
Yield: 99.9 %

Procedure:
A total of 40 g (0.59 mol) of 50% aqueous hydrogen peroxide is added in two portions over five hours to a mixture of 43.2 g (0.076 mol) of 2,4-bis[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-6-chloro-s-triazine and 7.0 g (0.035 mol) of ferrous chloride tetrahydrate in 150 g of tert-butyl alcohol and 15 g of water. Another portion of 50% aqueous hydrogen peroxide (3 g, 0.044 mol) is added to the reaction mixture while the temperature is maintained at 40-45° C. for 2.25 hours. The reaction mixture is diluted with 100 g of ethyl acetate. A solution of 100 g of 20% aqueous sodium sulfite is added and the reaction mixture is heated at 60° C. for one hour to decompose residual peroxide. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are concentrated. The crude product is purified by flash chromatography on silica gel with 1:1 (v/v) hexane/ethyl acetate to afford 54.1 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(Cl)CCl.Cl.C1C=NC2N(O)N=NC=2C=1.[NH2:40][C:41]1[C:46]([C:47](O)=[O:48])=[CH:45][N:44]=[CH:43][N:42]=1>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:47]([C:46]2[C:41]([NH2:40])=[N:42][CH:43]=[N:44][CH:45]=2)=[O:48])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: Nc1ncncc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2cncnc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 10.9 %

Procedure:
The mixture of N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine methylester (1.0 g), EDC/HCl (783 mg), HOAt (555 mg), triethylamine (747 μL), 4-aminopyrimidine-5-carboxylic acid (417 mg) and dichloromethane (15 mL) was stirred overnight. After diluting the mixture with dichloromethane and washing with saturated sodium bicarbonate water, the organic layer thereof was dried over sodium sulfate and concentrated. The residue was washed with dichloromethane to obtain 145 mg of a crude material of the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1C.ClC1CCCCC1=O>O>[CH2:1]([N:3]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: Cc1ccccc1C
Reactant: CCNc1ccccc1
Agent: O=C1CCCCC1Cl
Solvent: O
Product: CCn1c2c(c3ccccc31)CCCC2
Temperature: 100 °C

Procedure:
266.2 g N-ethyl aniline was charged in a reactor along with 200 ml o-xylene. To this 132.5 g of 2-chloro-cyclohexanone was added over a period of 2 hours to obtain a clear solution which was then heated to 100° C. and stirred for 2 hours with water removal. The contents were further heated to 150-160° C. with simultaneous water removal by applying mild vacuum. The reaction mass was worked up as above to get 136 g crude 9-ethyl tetrahydrocarbazole with 96.8% GC purity.
Reaction SMILES: N([O-])=O.[Na+].N[C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[C:13]([CH2:19][CH3:20])[CH:12]=1)[C:7]([OH:9])=[O:8].C([O:23]CC)C>O.OS(O)(=O)=O>[CH2:19]([C:13]1[CH:12]=[C:11]([CH2:10][C@@H:6]([OH:23])[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][C:14]=1[CH2:17][CH3:18])[CH3:20]
Reactant: CCOCC
Reactant: CCc1ccc(C[C@@H](N)C(=O)O)cc1CC
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1ccc(C[C@@H](O)C(=O)O)cc1CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.2 g (47 mmol) sodium nitrite in 20 mL water was slowly added dropwise with stirring to an ice-cooled mixture of 2.0 g (7.8 mmol) (R)-2-amino-3-(3,4-diethyl-phenyl)-propionic acid in 60 mL 0.5 M H2SO4. The reaction mixture was stirred for 3 h while cooling with ice and for 3 days at RT, combined with 80 mL diethyl ether, vigorously stirred and the organic phase is separated off. The aqueous phase was again extracted with 80 mL diethyl ether, the combined organic phases were dried and evaporated down under reduced pressure. The residue was purified by chromatography on silica gel and the product fractions were evaporated down under reduced pressure.
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:6])C.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O.[OH-].[Na+]>CN(C=O)C.CCO>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:10]2[N:9]=[N:8][C:7]([C:5]([OH:4])=[O:6])=[N:11]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nnn[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1H-tetrazole-5-carboxylic acid ethyl ester sodium salt (500 mg, 3.05 mmol) in DMF (5 ml) at room temperature is added 4-methoxybenzyl chloride (747 μl, 5.48 mmol) and TEA (1500 μl, 10.76 mmol). The reaction mixture is stirred at room temperature overnight. The reaction is added water and extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (10% to 30% EtOAc/Heptane). To a solution of the purified residue in EtOH (2 ml) at room temperature is added NaOH (2 ml, 2.000 mmol) and the mixture is stirred at room temperature. After stirring for 1 hour, the mixture is concentrated under reduced pressure to remove EtOH and extracted with EtOAC after being acidified to pH<5. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=O)[CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])=[O:10])C.O>C1COCC1>[NH:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9](=[O:10])[CH2:8][CH2:7][C:6]1=[O:5]
Reactant: CCOC(=O)CCC(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(=O)c2ccccc2N1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a suspension of sodium hydride (10 mg, 0.43 mmol) in dry THF (1 mL) was added 4-(2-amino-phenyl)-4-oxo-butyric acid ethyl ester (80 mg, 0.36 mmol) under Argon at −40° C. The reaction mixture was then allowed to warm up to rt over 3 h, and then added to water (20 mL). The mixture was then extracted with DCM (3×15 mL) and the combined extracts were then dried (sodium sulfate), and evaporated to leave an off-white solid. Recrystallization from EtOAc afforded a white solid (51 mg, 81%), m/z 175 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[CH:25](OCC)(OCC)OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:25]=[N:13][N:12]=[C:10]3[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: CC(C)CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2cnnc21

Procedure:
To a mixture of 1.7 parts of 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine prepared in Examples 8 and 11, 3.7 parts of triethyl orthoformate and 40 parts by volume of ethanol, is added 1 part of concentrated sulfuric acid with stirring and ice-cooling. The mixture is stirred for about 20 minutes at room temperature. After completion of reaction, the mixture is neutralized with sodium bicarbonate, followed by extraction with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with n-hexane, whereby 8-chloro-4-isobutyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine is yielded as pale yellow crystals. Recrystallization from a mixture of benzene and n-hexane yields colorless needles melting at 140.5° C to 141.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH:6]([CH3:14])[CH2:7][CH2:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1.Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[OH-].[Na+].C1COCC1>CN(C=O)C.O>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH:6]([CH3:14])[CH2:7][CH2:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1
Reactant: CC(CCc1nnn[nH]1)Oc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(CCc1nnn[nH]1)Oc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 2.34 g (0.01 mol) 5-[3-(3-hydroxyphenoxy)butyl]tetrazole, 2.13 g (0.01 mol) 2-chloromethylquinoline hydrochloride and 12 ml (2N, NaOH) in 20 ml DMF and 20 ml THF is heated over a steam bath for a period of 24 hours. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethyl acetate (3:1) as eluent. Evaporation of eluent gives 5-[3-(3-(2-quinolylmethyloxy)phenoxy)butyl]tetrazole. (M.P. 147°-149° C.).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]1[C:31]([O:32][CH3:33])=[CH:30][C:20]2[NH:21][C:22]([C:24]3[C:28]([NH2:29])=[CH:27][NH:26][N:25]=3)=[N:23][C:19]=2[CH:18]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39]([CH:43]=1)[C:40](O)=[O:41]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:17]([O:16][CH3:15])=[CH:18][C:19]2[NH:23][C:22]([C:24]3[C:28]([NH:29][C:40](=[O:41])[C:39]4[CH:43]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=4[O:44][CH3:45])=[CH:27][NH:26][N:25]=3)=[N:21][C:20]=2[CH:30]=1
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Reactant: COc1ccc(F)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)c3cc(F)ccc3OC)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of EDC (44 mg, 0.23 mmol) and HOBt (31 mg, 0.23 mmol) in DMF (5 ml) was added 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.19 mmol) and 5-fluoro-2-methoxy-benzoic acid (36 mg, 0.21 mmol) and the mixture stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between DCM (20 ml) and saturated aqueous sodium bicarbonate (20 ml). A precipitate was formed which was removed by filtration and oven dried to yield N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-5-fluoro-2-methoxy-benzamide (64 mg, 81%). (LC/MS: Rt 2.64, [M+H]+ 412).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[CH3:36][CH:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:38]=O.O>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]=[CH:36][CH:37]([CH3:38])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:29][CH:30]=1
Reactant: CCCCCCCCCC(C)C=O
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)C=CCc1ccc(OC)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
p-Methoxyphenethyltriphenylphosphonium bromide (3.40 g, 7.12 mmol, 1.0 equiv.) in THF (14 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 4.5 mL, 7.12 mmol, 1.0 equiv.) at 0° C., the red solution was stirred at 65° C. for 1 h. The mixture was re-cooled to 0° C., 2-methylundecanal (1.97 g, 10.7 mmol, 1.5 equiv.) in THF (6 mL) was added, and the mixture was stirred at 70° C. for 14 h. After addition of H2O, the aqueous layer was extracted with cyclohexane (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 98:2) to yield 1.36 g (63%) of the title compound as a light yellow oil.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[CH2:22][CH2:23][O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)=[CH:28][C:26]=4[CH:27]=3)=[O:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:4][C:5]1[C:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[CH2:22][CH2:23][O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]5[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=5)=[CH:28][C:26]=4[CH:27]=3)=[O:20])=[CH:16][CH:17]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccnc1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ncccc4O)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75.9 %

Procedure:
To a solution of N-[4-(3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (1.00 g) in ethanol(20 ml) was added concentrated hydrochloric acid (5.0 ml), and the mixture was stirred at room temperature for 4 days. To the mixture was added saturated sodium bicarbonate solution at 0° C. to make the solution pH 6-7, and precipitated crystal was collected by filtration to give N-[4-(3-hydroxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 174) (693 mg) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCc1cccc(B(O)O)c1
Product: CCc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 79.5 %

Procedure:
The title compound (89 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3-ethylphenylboronic acid (99 mg, 0.6 mmol) as a colourless liquid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[NH:5][C:6](=[O:18])[CH:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[K+]>CO>[CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[NH:5][C:6](=[O:18])[CH:7]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(=O)O)CC(C)C
Reaction time: 8 h

Procedure:
N-[3-(Ethoxycarbonyl)-2-(2-methylpropyl)propanoyl]-O-methyl-L-tyrosine N-methylamide (4.7 g., 0.012 mol.) was suspended in methanol (25 mls.) containing potassium hydroxide solution (12 mls. of 1M). The mixture was stirred overnight and the solvent was removed by evaporation in vacuo to yield a gum. The gum was partitioned between diethyl ether (50 mls.) and sodium bicarbonate solution (50 mls.). The aqueous phase was separated, washed with ethyl ether (50 mls.) and adjusted to pH 2 by the addition of dilute hydrochloric acid. The aqueous mixture was extracted with dichloromethane (3×100 mls.) and the extracts combined and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation in vacuo to yield a gum (3.3 g.). The gum was recrystallized from a mixture of dichloromethane and hexane to yield N-[3-carboxy-2-(2-methylpropyl)propanoyl]-O-methyl-L-tyrosine N-methylamide as a white solid which was a mixture of two diastereomers. (m.p. 92°-96° C.
Reaction SMILES: [C:1]([O:18][CH:19]([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])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]>>[C:1]([O:18][CH:19]([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])[CH2:20][C:21]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: NCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Yield: 76.3 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (10.8 g) prepared by the method described in Preparation 2 and β-alanine (5.36 g), N-(3-hexadecanoyloxyoctadecanoyl)-β-alanine (9.33 g) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20](=[O:32])[C:21]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.O>C(O)C>[F:27][C:26]1[C:25]([F:28])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=1[C:20]([C:14](=[CH:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:32]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1ccc(F)cc1F
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 94.5 %

Procedure:
44.3 g of 2,4-difluoroaniline are added dropwise to a solution of 115 g of ethyl 3-ethoxy-2-(2,3,4,5,6-pentafluorobenzoyl)-acrylate in 380 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 380 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, washed with ethanol/H2O (1:1) and dried. 135.4 g of the title compound of melting point 97°-99° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[H-].[K+].[C:11](=[O:18])([O:15][CH2:16][CH3:17])OCC>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([C:11]([O:15][CH2:16][CH3:17])=[O:18])[C:11]([O:15][CH2:16][CH3:17])=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [K+]
Product: CCOC(=O)C(C(=O)OCC)c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 36 %

Procedure:
2-Chloro-4-picoline was added to a solution of potassium hydride (1.80 g, 15.8 mmol) in diethyl carbonate (10 ml) at 0° C. The reaction mixture was allowed to attain room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (15 ml) and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford the crude product. Purification by column chromatography over silica gel (60-120 mesh) using 8% ethyl acetate in petroleum ether as eluent afforded 750 mg (36%) of diethyl 2-(2-chloropyridin-4-yl)malonate as colorless liquid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:6][N:5]=1.I[CH2:15][CH3:16]>O1CCCC1.[Cl-].[Na+].O>[CH2:15]([N:6]1[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([I:3])=[N:5]1)[CH3:16]
Reactant: CCOC(=O)c1c[nH]nc1I
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CC)nc1I
Temperature: -45 °C
Reaction time: 4 h

Procedure:
A 500 mL flask was charged with the sodium hydride (0.584 g, 14.61 mmol) and tetrahydrofuran (100 mL). To the resulting suspension was added a solution of EXAMPLE 59A (3.11 g, 11.69 mmol) in tetrahydrofuran (50 mL) dropwise over about 20 minutes and the reaction was stirred for 4 hours under nitrogen. The reaction mixture was cooled to −45° C. and a solution of iodoethane (3.77 mL, 46.8 mmol) in tetrahydrofuran (20 ml) was added dropwise over 20 minutes. The reaction mixture was allowed to come to ambient temperature and stirring was continued for 42 hours. The reaction was diluted with brine (400 mL) and extracted with ether (400 ml, 2×200 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified on the ISCO chromatography system on a silica gel cartridge (150 g) eluting with a 0, 10, 25, and 50% ethyl acetate/hexane step gradient to give the title compound. MS DCI+) m/e 295 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14]C(C)(C)[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][CH2:9][CH:10]([CH2:15][OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(COCc2ccccc2)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: OCC(CO)COCc1ccccc1
Yield: 79.6 %

Procedure:
A mixture of 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxane (3.40 g, 14.4 mmol) and a few crystals of p-toluenesulfonic acid monohydrate in 100 mL of methanol was stirred at room temperature for 20 h. The methanol was removed in vacuo and the residual oil purified by column chromatography on silica gel (ethyl acetate) to give 2.25 g (80%) of 2-benzyloxymethyl-1,3-propanediol as a colorless, clear liquid.