Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:40][CH2:39][CH2:38][C@H:12]1[C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)=[O:14])=O)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH:11]1[CH2:40][CH2:39][CH2:38][C@H:12]1[C:13]([NH:15][C@H:16]([C:23]([NH:25][C@H:26]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)=[O:14]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(=O)OC(C)(C)C
Yield: 116.4 %

Procedure:
A mixture of the protected tripeptide of formula III, Z-Pro-His-Leu-OBut (5.9 g, 10.6 mmol, described in Example 2), and 5% palladium on carbon (600 mg) in glacial acetic acid is subjected to hydrogenation. The mixture is filtered and the filtrate evaporated under reduced pressure to give 5.2 g of H-Pro-His-Leu-OBut in the form of its acetate salt. This product is suspended in toluene and the toluene then is removed by distillation so the excess acetic acid is removed azeotropically.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([CH:8]3[CH2:11][CH2:10][CH2:9]3)[CH2:13][CH2:14]2)=[CH:25][CH:24]=1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Triethylamine (66.5 g, 0.658 moles) was added to a solution of 4-[(1-Cyclobutyl-4-piperidinyl)oxy]aniline (81 g, 0.329 moles, obtained in preparation 1) in dichloromethane (1 L), at 0° C. under nitrogen atmosphere. Then the resulting mass was treated with a solution of chloro acetyl chloride (44.6 g, 0.395 moles) in dichloromethane (1 L) drop wise at 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum and the crude compound thus obtained was purified by flash chromatography (methanol:chloroform, 2:8) to obtain the title compound 76.1 g (Yield: 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:30][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a stirred solution of 2-fluoro-1-methyl-4-nitrobenzene (1 g, 6.446 mmol) in carbon tetrachloride was added benzoyl peroxide (497 mg, 1.2847 mmol) and N-bromosuccinimide (1.377 g, 7.736 mmol). The reaction mixture was refluxed for 18 h, then cooled to room temperature. The mixture was dissolved in ethyl acetate, then washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo to obtain 1-(bromomethyl)-2-fluoro-4-nitrobenzene (1.335 g) as a crude.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br-].[CH2:12]1COC[CH2:13]1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:13]=[CH:12][NH:8][C:7]=12
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Br-]
Product: Clc1nccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of 2-chloro-3-nitropyridine (31.5 mmol) in dry THF (200 mL) was cooled to −78° C. Vinylmagnisium bromide (1.0 M in THF, 100 mL) was added dropwise under N2. The mixture was stirred at −78° C. for 1 hr, followed by −20° C. for further 8 hrs. The mixture was quenched with 150 mL NH4Cl (20% in H2O) and extracted with EtOAc (3×150 mL). The organic layers were combined, washed with brine, dried on MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to elute 7-chloro-1H-pyrrolo[2,3-c]pyridine as white solid (1.77 g, yield 37%). 1H-NMR (DMSO-d6) δ: 6.63 (d, 1H, J=3.2 Hz, Ar—H), 7.58 (d, 1H, J=5.6 Hz, Ar—H), 7.66 (d, 1H, J=2.8 Hz, Ar—H), 7.90 (d, 1H, J=5.2 Hz, Ar—H). MS (ESI+) m/z 153.0260 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH2:7][CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:10](O)=[O:11])#[N:6].[BH4-].[Na+]>O1CCCC1.C(O)C>[OH:11][CH2:10][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22])[CH2:8][CH2:7][C:5]#[N:6]
Reactant: N#CCCC(C(=O)O)c1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: N#CCCC(CO)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Thionyl chloride (8.25 mL) was added to 4-cyano-2-(2-trifluoromethylphenyl)butanoic acid (2.9 g), and the mixture was heated under reflux. After one hour, concentration under reduced pressure gave an oil. The oil was dissolved in tetrahydrofuran (50 mL) and ethanol (20 mL), and sodium borohydride (855 mg) was added at 0° C. After stirring at room temperature for one hour, the reaction was terminated with water, followed by dilution with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a pale yellow oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%) to obtain the title compound (2.14 g).
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:19]=3[CH:18]=2)[C:14]([Cl:29])=[CH:13][N:12]=1.N.CO.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)C>[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([NH2:4])=[O:27])[C:19]=3[CH:18]=2)[C:14]([Cl:29])=[CH:13][N:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: NC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Diisopropylethylamine (0.574 mL) is added to a stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (1.02 g, 3.14 mmol) in anhydrous dichloromethane (20 mL) at 0° C. under nitrogen to form a clear solution. The solution is treated dropwise with 7M NH3/MeOH (0.493 mL, 3.45 mmol) to form a suspension. Powdered 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.46 g, 3.30 mmol) is added to the mixture and the resultant mixture is allowed to stir at 0° C. for 2 hours and at room temperature for 5 hours. Diethyl ether (15 mL) is added in small portions to the mixture. The mixture is stirred for another 20 minutes before filtration. After drying, the title compound is obtained as a tan solid and is used without further purification (0.994 g).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]3)=[N:8]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH:12][C:28](=[O:29])[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:10][C:9]([C:13]3([C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]3)=[N:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.6 %

Procedure:
To a solution of 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (574 mg, 2.0 mmol) in DCM (20 mL) was added K2CO3 (423 mg, 3.06 mmol) and phenyl chloroformate (386 μL, 3.06 mmol). The solution was stirred at rt overnight. The reaction mixture was filtered and the solids washed with DCM, the filtrate concentrated and purified using silica gel chromatography eluting with an EtOAC/Hexane gradient (5-20%) to give phenyl 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-ylcarbamate (1.04 g, quantitative yield). 1H NMR (300 MHz, DMSO d6) δ 1.33 (m, 4H), 2.34 (s, 3H), 6.51 (s, 1H), 7.12 (m, 2H), 7.23 (m, 1H), 7.37 (m, 6H), 10.13 (s, 1H); LC-MS (ESI) m/z 402 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][CH2:2][OH:1])[NH:8][C:7]2=[O:13])=[CH:17][CH:16]=1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccc(Br)cc1
Temperature: 90 °C
Yield: 41 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (3.0 g, 17 mmol), 4-bromobenzaldehyde (3.1 g, 17 mmol) and piperidine (8.4 mL, 85 mmol) in ethanol (113 mL) was heated at 90° C. for overnight. The reaction mixture was concentrated and the residue was chromatographed on a column of silica gel to give 2.4 g (41%) of 3-(4-bromo-benzylidene)-4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one as a yellow orange solid.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O>>[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Product: Fc1c(OCCNCc2ccccn2)ccc2ccccc12
Yield: 46 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and pyridine-2-carbaldehyde in 46% yield as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH2:10][Cl:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.B.C1(C2(C3C=CC=CC=3)OBN3CCC[C@H]23)C=CC=CC=1.CO>O1CCCC1>[Cl:11][CH2:10][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[OH:9]
Reactant: O=C(CCl)c1cccc(Cl)n1
Agent: B
Agent: B1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CO
Product: OC(CCl)c1cccc(Cl)n1
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
A solution of chloromethyl 6-chloro-2-pyridyl ketone (8.126 g) in tetrahydrofuran (32 ml) and a solution of borane in tetrahydrofuran (1.0M, 25.7 ml) were added simultaneously to a mixture of a solution (R)-tetrahydro-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborole in tetrahydrofuran (ca. 0.335M, 8.9 ml) and a solution of borane in tetrahydrofuran (1.0M, 4.3 ml) at -5° C. under nitrogen atmosphere over 0.5 hour and the whole was stirred for 3.5 hours. Methanol (10.4 ml) was added dropwise to the mixture at 0° C. and the whole was stirred at ambient temperature overnight. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform as an eluent to give (-)-2-chloro-1-(6-chloro-2-pyridyl)ethanol (7.98 g) as an oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=1)=[O:3].[NH3:20]>O1CCCC1>[O:17]=[C:8]1[C:7]2[CH:18]=[CH:19][C:4]([C:2]([NH2:20])=[O:3])=[CH:5][C:6]=2[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[NH:9]1
Reactant: N
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1NC2=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O

Procedure:
Dissolve the acid chloride from Step A in 20 ml. of dry tetrahydrofuran and add this solution dropwise with stirring to a cooled (ice-bath) saturated solution of ammonia in 60 ml of tetrahydrofuran. Pass ammonia through the reaction mixture simultaneously for 15 minutes. Stir at room temperature for an additional 15 minutes and evaporate the reaction mixture to dryness. Add a mixture of 12 ml of ethanol and 60 ml of water to the residue and stir at room temperature for an additional 30 minutes. Separate the solid by filtration and wash with water, then with ethanol and then with ether. Dry in vacuo to obtain the title product.
Reaction SMILES: C(OC([N:8]([CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[OH:34])[CH2:9][CH2:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>O1CCCC1.O1CCOCC1>[Cl:41][C:37]1[CH:36]=[C:35]([C@@H:33]([OH:34])[CH2:32][NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:30][CH:31]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)COc1cccc(COc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(COc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of ethyl [3-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]phenoxy]methyl]phenoxy]acetate (1.0 g) in tetrahydrofuran (5.0 ml) was added 4N hydrochloride in dioxane (4.3 ml). The mixture was stirred at room temperature for 8 hours and evaporated under reduced pressure. The residue was diluted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/chloroform=1/20) to give ethyl [3-[[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]-methyl]phenoxy]acetate (632 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[O:9]1[CH2:13][CH2:12][C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:11]2[CH2:12][CH2:13][O:9][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(Br)ccn1[C@H]1CCOC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.50 g), (R)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester (0.40 g), potassium carbonate (0.80 g), and dimethylsulfoxide (5 mL) was stirred at 80° C. overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound [besides, 4-bromo-2-[(S)-tetrahydro-furan-3-yloxy]-pyridine was isolated in 0.36 g (56% of theory)]. Yield: 0.11 g (16% of theory); LC (method 3): tR=2.18 min; Mass spectrum (ESI+): m/z=244/246 (Br) [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:11][CH2:10]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31]CC)=[CH:27][CH:26]=3)[CH:18]=2)[C@@H:6]1[O:34][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2].B(Br)(Br)Br>ClCCl.C(OCC)C.O>[C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:10][CH2:11]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[CH:18]=2)[C@@H:6]1[O:34][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)cc2)c1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (300 mg, 0.56 mmol) in dry dichloromethane (5 mL) was added BBr3 (0.54 mL, 5.6 mmol) at −78° C. After stirring for 1 h, reaction mixture was diluted with diethyl ether (5.0 mL), stirred for 30 min. and further diluted with water and extracted with DCM to furnish 280 mg of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([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][CH2:25][CH3:26])[C:8]([OH:10])=[O:9].O=O.[C:30]([OH:33])(=[O:32])C>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:30]([C:7]([C:2]1[CH:1]=[CH:6][CH:5]=[CH:4][CH:3]=1)([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][CH2:25][CH3:26])[C:8]([OH:10])=[O:9])([OH:33])=[O:32]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1C
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Product: CCCCCCCCCCCCCCCCC(C(=O)O)(C(=O)O)c1ccccc1
Temperature: 105 °C

Procedure:
One-hundred and eight grams of the distilled tolylstearic acid was charged to a one-liter stirred Parr autoclave with 400 mls acetic acid and 50 gms cobalt (II) acetate. The reactor was sealed, heated to 105° C. and pressured with oxygen to 350 psig.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[O:15][CH2:2][C:3](=[O:4])[NH:16][C:10]=12)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cccc(O)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1NC(=O)CO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At RT chloro-acetyl chloride (8.06 mmol) is added dropwise to a solution of 2-amino-3-hydroxy-benzoic acid methyl ester (7.33 mmol) in DMF (50 mL). After 20 min K2CO3 (34.9 mmol) is added portionwise, the mixture is stirred for 16 h at RT and the solvents are removed in vacuo. Water and DCM are added, the layers are separated and the organic layer is washed with brine and dried over Na2SO4. The solvents are removed in vacuo to give a crude product which is purified by FC (heptane to heptane/EtOAc 6/4). LC-MS: tR=0.82 min; [M+CH3CN+H]+=249.0.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][C:17]2[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][C:17]2[CH:27]=[CH:26][C:20]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(CC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc(CC2SCC(=O)N2CCC2(O)CCCCC2)cc1

Procedure:
p-{3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinylmethyl}cinnamic Acid (7.8 g., 0.02 mole) in ethanol (125 ml.) is hydrogenated over 2.5 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and 27° C. When the theoretical amount (0.02 mole) of hydrogen has been absorbed, the catalyst is filtered off, the solvent evaporated, and the residue chromatographed on silica gel with 4% methanol in chloroform as the eluant. The title compound is obtained as a colorless, viscous oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:23][N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: CNc1ccccc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Solvent: Cc1ccccc1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)c1ccccc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution of methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (100 mg, 0.31 mmol) and N-methylaniline (328 mg, 3.1 mmol) in toluene (5 mL) was heated at 110° C. in a sealed tube for 36 hrs. The solution was concentrated to an oily residue which was dissolved in MeOH (5 mL). To this solution was added 10 N NaOH solution (1 g). The mixture was stirred and refluxed for 1 hr and then cooled to RT. The pH was carefully adjusted to 7 whereupon a precipitate formed. The solid was filtered and dried to give the title compound (41 mg) as an off white solid: 1HNMR (400 MHz, CD3OD): δ 2.79 (3H, s), 3.64 (2H, t, J=4.4 Hz), 4.21 (2H, t, J=4.4 Hz), 6.62 (1H, m), 6.68 (2H, m), 7.18 (2H, m), 7.57 (1H, m), 7.66 (1H, s), 7.84 (1H, s), 8.23 (1H, s), 8.63 (1H, m). [M+H] Calc'd for C18H18N4O2, 323. Found, 323.
Reaction SMILES: [C:1](Br)(=[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].[O:19]=[C:20]([CH2:22][N:23]([C:25](=[NH:27])[NH2:26])[CH3:24])[OH:21].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[CH3:24][N:23]([CH2:22][C:20]([OH:21])=[O:19])[C:25]([NH:27][C:1](=[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])=[NH:26]
Reactant: CCCCCCCCCCCCCCCC(=O)Br
Reactant: CN(CC(=O)O)C(=N)N
Agent: O=C=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the palmitoyl bromide solution, 10.99 g (60 mmol) of creatine is suspended, with stirring, in 100 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between to about −10° C. and 0° C. When the target temperature is reached the drop wise addition of palmitoyl bromide is commenced. Addition of palmitoyl bromide continues, with cooling and stirring, until all of the palmitoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(1-methyl-3-palmitoylguanidino)acetic acid.