Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[N:20][CH:21]=1)#[CH:15].ClC1N=CC(C2N=NN(C3C=C(C=CC=3C)C(O)=O)C=2)=CC=1>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:14]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])[CH:15]=2)[CH:21]=[N:20][CH:19]=1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: C#Cc1cncc(OC)c1
Agent: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Product: COc1cncc(-c2cn(-c3cc(C(=O)O)ccc3C)nn2)c1

Procedure:
3-[4-(5-Methoxy-pyridin-3-yl)-[1,2,3]triazol-1-yl]-4-methyl-benzoic acid was prepared from 3-azido-4-methyl benzoic acid and 5-ethynyl-3-methoxy pyridine in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([NH:17][CH:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]1(Br)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C.C(N(CC)CC)C>[C:9]([NH:17][C:18]1[CH:27]=[C:26](/[CH:1]=[CH:2]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccccc1
Reactant: COC(=O)C1(Br)C=CC=CC1NC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(/C=C/c2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
0.83 mL of triethylamine, 34 mg of palladium acetate and 0.69 mL of styrene were added to 10 mL of N,N-dimethylacetamide solution containing 1.0 g of methyl 2-(benzamido)-1-bromobenzoate and 91 mg of tri(o-tolyl)phosphine, and stirred under nitrogen atmosphere at 120° C. for 1 hour and 30 minutes. After the reaction mixture was cooled to room temperature, 0.35 mL of styrene and 5 mg of palladium acetate were added and stirred at 120° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 0.18 g of methyl 2-(benzamido)-4-((E)-2-phenylvinyl)benzoate as white solid.
Reaction SMILES: Br[CH2:2][C:3]([CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH2:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)[CH3:35]>CN(C=O)C>[CH2:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][CH2:2]/[C:3](/[CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:4]/[C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:38][CH2:37]1)[CH3:35]
Reactant: CCN1CCC(N)CC1
Reactant: COC(=O)c1ccc(C=C(CBr)COc2cccc3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCC(NC/C(=C/c2ccc(C(=O)OC)cc2)COc2cccc3ccccc23)CC1
Yield: 46 %

Procedure:
Methyl 4-[2-bromomethyl-3-(naphthalen-1-yloxy)-propenyl]-benzoate (412 mg, 1 mmol) was dissolved in N,N′-dimethylformamide (2.5 ml) in a 100 ml flask at 0° C., and to the resulting solution, triethylamine (0.17 ml, 1.2 mmol, 1.2 eq.) and 1-ethylpiperidin-4-ylamine (128 ml, 1.0 mmol, 1.0 eq.) were added while stirring. The resulting mixture was heated from 0° C. to room temperature, and then reacted for 4 hours. After the completion of reaction, the mixture was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 211 mg of the title compound as pale yellow oil (yield 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:10])[CH2:4][CH2:3][CH:2]=[CH2:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCOCC
Product: C=CCCC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 156.1 %

Procedure:
To a suspension of 14.6 g (80 mmol) of CdCl2 in 200 niL of ether cooled to 0° C. was added 115 mL of 1.3 M solution of 3-butene-1-magnesium bromide dropwise. The mixture was refluxed for 1 h and ether was then removed by distillation. Benzene (500 mL) was introduced, followed by a solution of 17.5 g (100 mmol) 4-fluorophenylacetyl chloride. After refluxing for 1 h, the reaction mixture was quenched with 200 mL of saturated aqueous NH4Cl, 50 mL of 1 N HCl, and extracted with 200 mL of 1:1 hexane/EtOAC. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluted with 4:1 hexane/EtOAc to give 15 g of the title product. 1H NMR (CDCl3) d 2.40 (2H, t), 2.53 (2H, t), 3.63 (2H, s), 4.90-4.98 (2H, m), 5.67-5.78 (1H, m), 6.98 (2H, t), 7.13 (2H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[CH3:18][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Yield: 99.7 %

Procedure:
A solution of 3′-methyl-[1.1′-biphenyl]-4-carboxylic acid ethyl ester of Step A (3.3 g, 13.7 mmol) in tetrahydrofuran (40 mL) and 1 N sodium hydroxide (27.5 mL, 27.5 mmol) was heated at reflux overnight. After cooling, the reaction was concentrated in vacuo. The residue was acidified with 2N hydrochloric acid to yield a white solid which was collected by filtration and dried under vacuum to provide the title compound (2.9 g, 99.7%) as a white solid, m.p. 198–200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([CH3:12])[CH:6]=[CH:5][N:4]=1.CO[C:15](OC)(N(C)C)[CH3:16]>>[CH3:15][C:16]1[NH:9][C:8]2[C:7]([CH:12]=1)=[CH:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1]
Reactant: COc1nccc(C)c1[N+](=O)[O-]
Reactant: COC(C)(OC)N(C)C
Product: COc1nccc2cc(C)[nH]c12
Reaction time: 18 h
Yield: 57 %

Procedure:
2-Methoxy-3-nitro-4-methyl pyridine (200 mg, 1.2 mmol) and dimethylacetamide dimethylacetal (0.5 mL) were heated at 130° C. for 18 h. The reaction mixture was cooled and concentrated in vacuo to a deep purple-red oil. Benzene (4 mL) and 10% Pd/C (25 mg) were added and the solution hydrogenated at 45 psi for 18 h (Parr apparatus). The red coloration disappeared. The crude reaction mixture was purified directly by silica gel chromatography (20% EtOAc/hex) to furnish 2-methyl-7-methoxy-6-azaindole (112 mg, 57% yield). LC-MS 163.1, M+H.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][C:9]([OH:11])=O)[C:3]=1[Br:12].[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:9](=[O:11])[CH2:8][O:7][C:4]1[C:3]([Br:12])=[C:2]([CH3:1])[O:6][N:5]=1)[N+:18]([O-:20])=[O:19]
Reactant: Cc1onc(OCC(=O)O)c1Br
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: Cc1onc(OCC(=O)NCCO[N+](=O)[O-])c1Br
Yield: 40.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 472 mg of 5-methyl-4-bromo-3-isoxazolyloxyacetic acid and 338 mg of nitroxyethylamine nitrate, 265 mg of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]([CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]([CH2:15][S:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)=[O:32])=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Fc1cccc(SCc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: O=S(Cc1nnc(-c2ccc3c(c2)CCO3)o1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-[[(3-fluorophenyl)thio]methyl]-1,3,4-oxadiazole (0.25 g, 0.76 mmol) in acetonitrile (5 mL) was added m-chloroperbenzoic acid (70%, 0.18 g, 0.76 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-2/1) and recrystallized from hexane/ethyl acetate to give the title compound (0.12 g, yield 46%) as colorless crystals.
Reaction SMILES: C(Cl)Cl.[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[CH:27]=[C:26]([CH2:28][NH:29][CH3:30])[CH:25]=[CH:24][C:14]=2[O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5].CCN(CC)CC.[F:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>O>[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[CH:27]=[C:26]([CH2:28][N:29]([CH3:30])[S:45]([C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH:25]=[CH:24][C:14]=2[O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2cc(F)cc(C#N)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2cc(F)cc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
To an anhydrous DCM (50 mL) solution of t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-((methylamino)methyl)phenoxy)acetate (22) (28 g, 72 mmol), was added Et3N (8.6 g, 85 mmol) followed by portionwise addition of 4-fluoro-benzenesulfonyl chloride (16.6 g, 85 mmol). The mixture was stirred at room temperature for 20 min and water (20 mL) was added. The organic layer was separated, dried and concentrated in vacuo. The crude was purified by column chromatography to give t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (23) (24 g, 63%).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]2[N:14]3[CH2:15][CH2:16][C@@H:11]([C@@H:12]([C:17](O)=[O:18])[CH2:13]3)[C:10]2=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:29](CC)[CH2:30]C)C.ClC(OCC)=O.N>C1COCC1.O>[CH3:27][N:29]([CH3:30])[C:17]([C@@H:12]1[C@@H:11]2[CH2:16][CH2:15][N:14]([CH:9]([CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]2=[O:20])[CH2:13]1)=[O:18]
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A suspension of 46 (1.1 g, 3.3 mmol) in THF (10 ml) was treated with triethylamine (0.66 g, 6.6 mmol) at room temperature. To this suspension was added ethyl chloroformate (0.36 g, 3.3 mmol) at 0° C. After 30 minutes, NH3 aq (0.67 g, 6.7 mmol) was added at 0° C. The mixture was stirred at room temperature for 1 hour, poured into H2O and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated to give 48 (1.2 g, 3.0 mmol, 90%; 4:1 mixture of isomers at 3-position). This was used without further purification.
Reaction SMILES: O=[C:2]([CH3:20])[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=O.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:27][CH:28]=1)[N:26]=[C:2]([CH3:20])[C:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[C:4]2[OH:6]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A round-bottomed flask equipped with a Dean-Stark apparatus was charged with ethyl 3-oxo-2-(4-(trifluoromethyl)benzyl)butanoate (7.00 g, 24.3 mmol, Intermediate 26: step a), 4-bromoaniline (4.20 g, 24.2 mmol), para-toluenesulfonic acid (0.418 g, 2.4 mmol), and toluene (121 mL). The mixture was heated to 125° C. After 16 hours, the flask was cooled to room temperature. The toluene was removed by rotary evaporation to provide an orange colored solid. A mixture of the solid and diphenyl ether (48.4 mL) was heated to 220° C. After 60 minutes, the mixture was cooled to room temperature at which point a yellow solid crashed out of solution. Hexanes (150 mL) were added. The mixture was filtered through filter paper, rinsing with hexanes. The yellow solids were collected, dried, and then used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][CH3:15])[CH2:9][C@H:10]([OH:13])[CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][CH3:15])[CH2:9][C@H:10]([O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](O)C[C@@H](CC)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C[C@H](C[C@@H](CC)NC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 86.1 %

Procedure:
To a solution of ((1R,3S)-1-ethyl-3-hydroxy-pent-4-enyl)-carbamic acid tert-butyl ester (0.541 mmol; 124 mg) and imidazole (2.164 mmol; 147 mg) in DMF (1.8 mL) is added tert-butyldimethylsilyl chloride (1.623 mmol; 245 mg) at room temperature under N2. After 12 hours, the reaction mixture is quenched with water, extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give [(1R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-1-ethyl-pent-4-enyl]-carbamic acid tert-butyl ester (160 mg, 86%); ESI-MS m/z: 288 [M+−tBu+2], Retention time 5.77 min (condition B).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(azetidin-1-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol/ammonia=9:1:0.5) C27H25N3O3
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:21][CH:20]2[C:8]([CH3:33])([CH:9]3[CH:17]([CH:18]([OH:22])[CH2:19]2)[CH:16]2[C:12]([CH3:31])([CH:13]([CH:23]([CH3:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:15]2)[CH:11]([OH:32])[CH2:10]3)[CH2:7][CH2:6]1.[Br:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].C(N1CCOCC1)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:21][CH:20]2[C:8]([CH3:33])([CH:9]3[CH:17]([CH:18]([OH:22])[CH2:19]2)[CH:16]2[C:12]([CH3:31])([CH:13]([CH:23]([CH3:30])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:15]2)[CH:11]([OH:32])[CH2:10]3)[CH2:7][CH2:6]1)=[O:39]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN)CCC4(C)C3CC(O)C12C
Agent: CCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCNC(=O)c5cccc(Br)c5)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 47 %

Procedure:
932 mg of methyl 4-[3-(2-aminoethoxy)-7,12-dihydroxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl]pentanoate (Example 1d) and 402 mg of 3-bromobenzoic acid are dissolved in 20 ml of anhydrous DMF and first 656 mg of O[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) (Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991) and then 760 μL of N-ethylmorpholine are added at 0° C. The reaction mixture is stirred at RT for 20.5 hours and then poured into 100 ml of a 10% aqueous NaHCO3 solution. It is extracted 3 times using 150 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA yields 610 mg of a viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:41])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:33]4[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=4[Cl:40])[O:27][C:28]=3[C:29]([F:32])([F:31])[F:30])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[C:26]1[O:27][C:28]([C:29]([F:32])([F:30])[F:31])=[C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:4][C:3]([OH:42])=[O:2])[CH2:10][CH2:9]3)=[CH:12][CH:13]=2)=[O:41])=[O:23])[N:25]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4c(Cl)cccc4Cl)oc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[2-(2,6-dichloro-phenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (459 mg, 0.733 mmol) was put into THF/water (50 mL, 3:1) solvent, and NaOH (146.54 mg, 3.663 mmol) was added thereto. The mixture was stirred for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain the desired compound (434 mg, 97%) as a white solid.
Reaction SMILES: CN(C)C=O.Cl.[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([OH:20])[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9].[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[ClH:29].[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(N)NCCCC[C@H](O)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)NCCCC[C@@H](CC(N)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 2.5 ml of dimethylformamide, was dissolved 2.09 of (S)-7-guanidino-3-hydroxyheptanamide hydrochloride followed by 1.7 ml of pyridine. To the solution, while being cooled in ice, was added slowly and dropwise 2.6 ml of benzoyl chloride. The mixture was stirred for 30 minutes while cooling in ice and for further two hours at room temperature. The reaction mixture was diluted with 20 ml of ice water, the separated oily layer was separated, and the aqueous layer was admixed with 600 mg of sodium chloride. The aqueous layer was passed through a column of Diaion® HP-20 which had been equilibrated with 0.5 M aqueous sodium chloride solution, and the column was washed successively with 0.5 M, 0.2 M and 0.1 M aqueous sodium chloride solutions, and with water. The fractions eluted with 20 to 40% (v/v) aqueous methanol were collected and concentrated under reduced pressure to yield 820 mg of (S)-7-guanidino-3-benzoyloxyheptanamide hydrochloride in oily form. NMR: 1.4-2.0 (CH2 x3), 2.65 (CH2), 3.17 (CH2), 5.50 (CH), 7.2-8.1 (COC6H5).
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[N:43][CH:44]=1>CN1C(=O)CCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:45][C:42]1[CH:41]=[CH:40][C:39]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:44][N:43]=1
Reactant: Cc1ccc([Sn](C)(C)C)cn1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CCC2=O)cn1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 21.4 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)-phenyl)-2-cyclopenten-1-one (0.315 g, 1.0 mmol), Pd2 (dba)3 (0.018 g, 0.02 mmol), and AsPh3 (0.049 g, 0.16 mmol) in NMP (2.5 mL) was added a degassed NMP solution (2.5 mL) of 5-trimethylstannanyl-2-methylpyridine (~2.0 mmol). The resulting mixture was heated to 60° C. for 16 hours, then to 100° C. for a further 3.5 h. The mixture was then cooled to r.t., diluted with EtOAc, washed 2 times with 10% NH4OH and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (100% EtOAc/hexanes) to provide 0.070 g of the title compound as a rigid foam.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.O.[CH:11](=[O:14])[CH2:12][CH3:13]>CO>[OH:14][CH:11]([C:7]1[O:8][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[OH:9])[CH2:12][CH3:13]
Reactant: CCC=O
Reactant: Cc1cc(=O)c(O)co1
Solvent: CO
Solvent: O
Product: CCC(O)c1oc(C)cc(=O)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxides. Propionaldehyde (8.7 g, 150 mmol, 1.5 eq.) dissolved in 50 ml methanol was slowly added dropwise over 1 hour and the solution allowed to stir at room temperature for 48 hours. After adjustment to pH 1 with 37% hydrochloric acid, the reaction mixture was evaporated to dryness and the residue taken up into 300 ml of dichloromethane. The organic layer was washed with water (150 ml), dried over anhydrous sodium sulphate, filtered and concentrated to yield the crude product. Recrystallisation from toluene afforded the pure product (14.5 g, 78.9%) as a white crystalline solid. m.p. 134-136° C. [lit. 132-135° C. Ellis (1993)].