Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([CH3:36])[C:26]=1[N:27]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[N:28]1)[O:5][C@H:6]([C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].CC1C=C(C=C(C)C=1N1C=C(C(F)(F)F)C=N1)O[C@@H](C1C=CC(C(NCCC(O)=O)=O)=CC=1)CCC.C1(C(NC2C=NC(N3C=C(C(F)(F)F)N=C3)=CC=2)C2C=CC(C(NCCC(O)=O)=O)=CC=2)CCCC1.C1([C@@H](NC2C=NC(N3C=C(C(F)(F)F)N=C3)=CC=2)C2C=CC(C(NCCC(O)=O)=O)=CC=2)CCCC1.C1([C@H](NC2C=NC(N3C=C(C(F)(F)F)N=C3)=CC=2)C2C=CC(C(NCCC(O)=O)=O)=CC=2)CCCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([CH3:36])[C:26]=1[N:27]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[N:28]1)[O:5][CH:6]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:22][CH:23]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC[C@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Agent: CCC[C@@H](Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Agent: O=C(O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CCCC2)cc1
Agent: O=C(O)CCNC(=O)c1ccc([C@@H](Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CCCC2)cc1
Product: CCCC(Oc1cc(C)c(-n2cc(C(F)(F)F)cn2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
(S)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid; (R)-3-(4-(1-(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)propanoic acid; (+/−)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid; (R)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid; and (S)-3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid; or a pharmaceutically acceptable salt thereof.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:19]=[N:20][CH:21]=[C:22]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[N:23]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cncc(N2CCOCC2)n1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Product: c1cc2c(cc1Oc1cncc(N3CCOCC3)n1)CCN(C1CCC1)CC2

Procedure:
Example (E288) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 4-(6-chloro-2-pyrazinyl)morpholine [Zagulyaeva, O. A., J. Org. Chem. USSR, EN, 14; 1978; 377-380] using an analogous method to that described for Example 242 (E242); MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[C:20](=[O:26])[NH:21][CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[C:20](=[O:26])[N:21]([C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:22]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(=O)NC2
Product: CC(C)(C)OC(=O)N1C2CCC1C(=O)N(c1ccc([N+](=O)[O-])nc1)C2
Yield: 153.6 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine (110 mg, 0.542), was combined with 2-Oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (135 mg, 0.596 mg), which after purification silica gel chromatography gave 3-(6-Nitro-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (290 mg, 81%). MS m/z 349.0 (MH+), and was used directly as is without further characterization.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[O:20][CH3:21].CC(O)=O.[Cl:26]N1C(=O)CCC1=O>O.CCOCC>[Cl:26][C:7]1[CH:8]=[C:3]([Cl:2])[C:4]([O:20][CH3:21])=[CH:5][C:6]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(c2cc(OC)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A 25-mL round bottom flask containing a magnetic stir bar and fitted with an inert gas inlet was charged with ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate, hydrochloride salt (367 mg, 1.23 mmol), AcOH (6 mL) and water (3.0 mL). The mixture was treated with N-chlorosuccinimide (206 mg, 1.54 mmol) in one portion. The mixture was stirred under argon at RT overnight and then diluted with water (20 mL) and Et2O (60 mL). The pH of the mixture was adjusted to a pH=10. The phases were separated and the aqueous phase was extracted with Et2O. The combined Et2O extracts were washed with brine, dried (MgSO4) and concentrated on a rotary evaporator. The resultant residue was purified by flash chromatography using a 12 g silica gel cartridge and gradient elution from 50:1 Hex/EtOAc to 20:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give ethyl 1-(2,4-dichloro-5-methoxyphenyl)piperidine-4-carboxylate (255 mg, 0.77 mmol, 70% yield) as a clear oil, which solidified on standing at room temperature. 1H-NMR (400 MHz, CDCl3) δ ppm 7.33 (1 H, s), 6.58 (1 H, s), 4.15 (2 H, qd, J=7.04, 6.87 Hz), 3.87 (3 H, s), 3.33 (2 H, d, J=11.70 Hz), 2.70 (2 H, t, J=9.66 Hz), 2.43 (1 H, dq, J=10.17, 5.09 Hz), 1.94-2.05 (4 H, m), 1.22-1.30 (3 H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][OH:20])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][O:20][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: COc1ccc(OCCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: MS (ESI) m/z 421 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:24][CH2:23][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]=3[CH2:13]2)=[N:10][CH:11]=1.[H][H]>C1COCC1.[Pd]>[C:28]([O:27][C:25]([N:15]1[C:14]2[CH2:13][N:12]([C:9]3[N:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:32])=[CH:11][N:10]=3)[CH2:24][CH2:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1cnc(N2CCc3c(n(C(=O)OC(C)(C)C)c4ccccc34)C2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1cnc(N2CCc3c(n(C(=O)OC(C)(C)C)c4ccccc34)C2)nc1
Yield: 73.3 %

Procedure:
To a stirred solution of tert-butyl 2-{5-[(1E)-3-methoxy-3-oxoprop-1-enyl]pyrimidin-2-yl}-1,2,3,4-tetrahydro-9H-b-carboline-9-carboxylate (0.25 g, 0.0005 moles) (See Example 20) in 10 mL of dry THF was added 1:1 mixture of Pd (OH)2 (50 mg) & Pd/C (50 mg) and stirred in the hydrogen atmosphere using balloon. After stirring for >12 hours, the reaction was filtered through a celite pad. The filtrate was concentrated and the crude residue was purified through silica column using 30% EtOAc in hexane to give methyl 3-{2-[9-(tert-butyloxycarbonyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidin-5-yl}propanoate (0.16 g, 63% yield). 1H NMR (DMSO-d6, 400 MHz) ppm: 8.33 (s, 2H, 2Ar—H), 8.06 (d, 1H, J=8 Hz, 1Ar—H), 7.49 (d, 1H, J=8 Hz, 1Ar—H), 7.31-7.22 (m, 2H, 2Ar—H), 5.12 (s, 2H, CH2), 4.09 (t, 2H, J=8 Hz, CH2), 3.57 (s, 3H, OMe), 2.74 (brs, 2H, CH2), 2.7 (t, 2H, CH2), 2.67 (t, 2H, CH2), 1.68 (s, 9H, 3CH3). M/e=437 (M+1) (M, 436.504 Calcd. for C24H28N4O4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8]>[OH-].[Na+].CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1COc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)ccc1COc1ccc(Br)cc1

Procedure:
Methyl 5-bromo-2-(4 -bromophenoxymethyl)benzoate (90 g, 0.23 mole) was refluxed in a mixture of 100 mL of 10% sodium hydroxide and 200 mL of methanol for three hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with concentrated hydrochloric acid. A solid was precipitated and collected as the acid product (80 g). mp 214°-215° C. pmr (DMSO-d6) δ: 6.76-8.01 (m, 7H, aromatic H), 5.38 (s, 2H, ArCH2O).
Reaction SMILES: Br[CH:2]([CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=O.[C:17]([NH2:20])(=[S:19])[CH3:18]>ClC(Cl)C>[CH3:18][C:17]1[S:19][C:2]([CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][N:20]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(CC(Br)C=O)C(=O)OCC
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(Cc1cnc(C)s1)C(=O)OCC
Temperature: 25 °C
Yield: 112.8 %

Procedure:
A mixture of 108 g of α-bromo-γ,γ-dicarbethoxy-butyraldehyde 300 ml of anhydrous dichloroethane and 27 g of thioacetamide was refluxed for 6 hours during which 200 ml of dichloroethane were slowly distilled and the same quantity of dichloroethane was added again to the mixture. The mixture was cooled to room temperature and 500 ml of ice water were added thereto. Concentrated ammonium hydroxide solution was added to the mixture to adjust the pH to 10-12 and the mixture was decanted. The aqueous phase was extracted with methylene chloride and the organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness to obtain 110 g of diethyl 2-(2-methyl-5-thiazolyl-methyl)-propanedioate. A sample of the product was rectified to obtain the product with a boiling point of 102°C at 0.02 mm Hg.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[F:13][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1F
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC1
Product: CC(=O)c1ccc(-c2ccccc2S(=O)(=O)N2CCCC2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those described in Example 1 using (4-acetyl-3-fluorophenyl)boronic acid and 1-(2-bromo-phenylsulfonyl)pyrrolidine. MS (ESI): mass calcd. for C18H18FNO3S, 347.10; m/z found, 348.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J=7.9, 1.3, 1H), 7.95-7.89 (m, 1H), 7.63-7.58 (m, 1H), 7.58-7.51 (m, 1H), 7.30-7.27 (m, 2H), 7.26-7.25 (m, 1H), 2.98-2.90 (m, 4H), 2.69 (d, J=4.9, 3H), 1.76-1.67 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][C:10](OCC)=[O:11])([CH3:4])[CH3:3].O.[NH2:24][NH2:25].O>C(O)C>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][C:10]([NH:24][NH2:25])=[O:11])([CH3:4])[CH3:3]
Reactant: NN
Reactant: CCOC(=O)COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(OCC(=O)NN)cc(C(C)(C)C)c1O
Yield: 88.1 %

Procedure:
A solution of ethyl [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]acetate (2.5 g, 8.1 mmol) and hydrazine monohydrate (1.2 mL, 24.3 mmol) in ethanol (40 mL) is heated at 65°-75° C. for 8 hours. The reaction mixture is cooled and poured into 500 mL of water. The solids are filtered and washed twice with water. The white solid is dried overnight at 50° C. in vacuo to give 2.1 g (87%) of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]-acetic acid hydrazide; mp 141.0°-142.5° C.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].C[O+](C)C.[CH3:10][N:11]([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)[CH3:12].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:10][N+:11]([CH2:13][C-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)([CH3:19])[CH3:12].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: CN(C)C[c-]1cccc1
Agent: [Fe+2]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[N+](C)(C)C[c-]1cccc1
Reaction time: 16 h

Procedure:
(Trimethylammoniomethyl)ferricinium bis(tetrafluoroborate) was prepared by the following procedure. A slurry of 7.47 g of trimethyloxonium tetrafluoroborate (50.6 mmol) in 125 mL of CH2Cl2 was added to 10 mL of dimethylaminomethylferrocene in 100 mL of the same solvent. The resulting mixture was stirred for 16 hours and the solvent was removed under reduced pressure. The resulting residue was recrystallized from hot water to give 13.62 g of (trimethylammoniomethyl)ferrocene tetrafluoroborate as golden-yellow platelets. 1.32 g of the (trimethylammoniomethyl)ferrocene tetrafluoroborate (8 mmol) were added to a mixture of 0.864 g of p-benzoquinone (8 mmol) and 2.16 mL of 48% aqueous tetrafluoroboric acid (16 mmol) in 60 mL of diethyl ether. The resulting mixture was stirred for 15 minutes and filtered to give a dark blue-black residue which was washed with ether until the washings were colorless to remove quinhydrone and dried under reduced pressure to give 1.69 g of (trimethyl-ammoniomethyl)ferricinium bis(tetrafluoroborate) (3.9 mmol) as a navy-blue solid, which decomposed at high temperature without a characteristic melting point.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:20]([CH:16]3[CH2:19][CH2:18][CH2:17]3)=[O:21])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Reactant: O=C(Cl)C1CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2csc(NC(=O)C3CCC3)n2)cc1
Yield: 77.1 %

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-yl amine (90 mg, 0.41 mmol) was acylated in CH2Cl2 using cyclobutane carbonyl chloride (60 μL, 0.52 mmol, 1.25 eq.) in the presence of excess pyridine. The reaction was quenched with sat. NH4Cl, extracted with EtOAc and dried over MgSO4. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded 95 mg (80%) of cyclobutanecarboxylic acid [4-(4-isopropyl-phenyl)-thiazol-2-yl]-amide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O.[Cl-].[NH4+]>[Cl-].[Na+].O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:10]([O:14][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C

Procedure:
A toluene (70 mL) solution of (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 3.50 g, 18.1 mmol) was slowly added to a toluene (100 mL) suspension of sodium hydride (oily, 60%, 5.80 g, 145 mmol) while being stirred. A toluene (30 mL) solution of (9Z,12Z)-octadec-9,12-dienyl methanesulfonate (Nu-Chek Prep., Inc.; 15.6 g, 45.3 mmol) was then dropped on the mixture. The resulting mixture was stirred overnight under heat and reflux. After cooling the mixture to room temperature, the reaction was stopped with a saturated ammonium chloride aqueous solution. After adding saturated brine, the mixture was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform=0/100 to 2/98) to give compound VI-1 (6.96 g, 55.7%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:18]=[CH:19]OCC)[S:16][CH:17]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[NH:24][NH2:25]>C(O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([N:18]=[CH:19][NH:25][NH:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])[S:16][CH:17]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)NN
Reactant: CCOC=Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Solvent: CCO
Product: CCOC(=O)NNC=Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Reaction time: 18 h
Yield: 87 %

Procedure:
A mixture consisting of 4-(4-cyclohexylphenyl)-2-ethoxymethyleneaminothiazole (500 mg), ethyl carbazate (170 mg) and ethanol (10 ml) was stirred under ice-cooling for 1 hour and then at room temperature (about 15° C.) for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crystals were collected by filtration with hexane to give ethyl 3-[4-(4-cyclohexylphenyl)-2-thiazolyliminomethyl]carbazate (515 mg, yield of 87 %). Recrystallization from dimethylforamide-water produced colorless prisms, mp of 188 to 189° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:56]([C:57](O)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[C:56]([C:57]([N:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:3]3)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:50][CH:51]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: CCC(O)(CC)C1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(O)(CC)C1CCCN(C(=O)c2conc2-c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A solution of 3-piperidin-3-ylpentan-3-ol hydrochloride (8 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H28N2O3: 356.2100, found 356.2098.
Reaction SMILES: [CH3:1][C:2](=[CH2:32])[CH2:3][N:4]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:16]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1>CO.[Pd]>[CH2:3]([N:4]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[N:16]=1)[C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH:2]([CH3:32])[CH3:1]
Reactant: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Yield: 92.1 %

Procedure:
A solution of (2-methyl-allyl)-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-trifluoromethyl-phenyl)-amine (270 mg, 0.6 mmol), Pd/C (10%, 30 mg) in methanol (30 mL) was hydrogenated for 4 h. The mixture was filtered through Celite, washed with methanol, and evaporated. The residue was dissolved in CH2Cl2, filtered and evaporated to give the product as a white solid (250 mg, 92%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=7.91 Hz, 2H), 7.70 (d, J=8.29 Hz, 2H), 7.58-7.66 (m, 2H), 7.38 (d, J=8.29 Hz, 2H), 7.06 (s, 1H), 6.45 (s, 1H), 3.95 (d, J=7.16 Hz, 2H), 2.25 (s, 3H), 2.10-2.22 (m, 1H), 0.98 (d, J=6.78 Hz, 6H). MS m/e 453.3 (M+H).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:7]=2[C:8](=[O:11])[C:9]=1[CH3:10])(=[O:3])C.CC1C(=O)C2C=CC=C(C=CC)C=2OC=1[C:34](=O)[NH:35]C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[C:16]([C:15]1[C:6]2[O:5][C:4]([C:1]([NH:35][CH3:34])=[O:3])=[C:9]([CH3:10])[C:8](=[O:11])[C:7]=2[CH:12]=[CH:13][CH:14]=1)([OH:18])=[O:17]
Reactant: CC=Cc1cccc2c(=O)c(C)c(C(=O)NC)oc12
Reactant: CC(=O)c1oc2c(C(=O)O)cccc2c(=O)c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CNC(=O)c1oc2c(C(=O)O)cccc2c(=O)c1C
Yield: 60 %

Procedure:
The title compound was prepared following the method described for Compound 2C but using Compound 5A instead of Compound 2B. The reaction mixture was poured into an 1% aqueous solution of sodium dithionite and filtered after overnight resting to give Compound 5B (60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]>C(#N)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COC(=O)CC[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
1.3 g of N-tert.-butyloxycarbonyl-L-glutamic acid 5-methyl ester 1-tert.-butyl ester (1.2., 4.12 mmol) are dissolved in 15 ml of acetonitrile and mixed with 100 mg of N,N-dimethyl-4-aminopyridine (DMAP). A solution of 1.79 g of di-tert.-butyl-bicarbonate (8.2 mmol) in 7 ml of acetonitrile is added under nitrogen atmosphere. After stirring overnight, the solvent is removed under vacuum and the crude product obtained is purified by means of chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:15])[CH2:13][OH:14])[CH:8]=[CH:7]2.CO[C:18](OC)([CH3:20])[CH3:19].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]1[CH2:13][O:14][C:18]([CH3:20])([CH3:19])[O:15]1)[CH:8]=[CH:7]2
Reactant: COC(C)(C)OC
Reactant: OCC(O)c1ccc2cccc(Br)c2n1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc3cccc(Br)c3n2)O1
Reaction time: 2 h

Procedure:
To 1-(8-bromoquinolin-2-yl)ethane-1,2-diol (505 mg, 1.88 mmol) in acetone (5 mL) and 2,2-dimethoxypropane (5 mL, 1.88 mmol) was added Montmorillonite K 10 (1 g). The reaction mixture was stirred for 2 hours, then filtered and concentrated to give crude product.