Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.C(S(O)=O)(N)=N.[Cl-].[NH4+].C(OCC)(=O)C>[OH-].[Na+].O>[CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C@H:20]([OH:21])[CH2:22][CH2:23][C@@:9]34[OH:24])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: N=C(N)S(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc2c3c1O[C@H]1[C@H](O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a suspension of naltrexone base 3 (6.81 g, 20.0 mmol) (Mallinckrodt, St. Louis, Mo.), under argon was added 100 ml (enough to afford complete solution) of 0.533M aqueous NaOH. The alkaline solution of naltrexone was treated dropwise at ambient temperature during 20 min. with 8.64 g (80 mmol) of formamidinesulfinic acid dissolved in 200 ml of 0.533M aqueous NaOH. After the addition was complete, the solution was heated and stirred at 80°-85° C. for 1.5 h when TLC indicated the reaction to be complete. The reaction mixture was cooled (ice-bath) and then treated dropwise under argon with a solution of ammonium chloride (10.27 g, 192 mmol) in distilled water (100 ml). The aqueous mixture was extracted with 5×100 ml of CHCl3 and the combined organic extract was filtered through a pad of Na2SO4 and evaporated in vacuo to afford crude 5.(base) as a foam which was dissolved in 20 ml of warm (50° C.) ethyl acetate and diluted to 60 ml with warm n-hexanes. Crystallization occurred spontaneously on cooling. The crystals were collected by filtration, washed with 2×10 ml of cold ethyl acetate/n-hexanes (1:3), and oven dried in vacuo at 60° C. to give 5 (6.11 g, 89%) (free of any 6α-epimer 4): [α]D =-156° (c 0.604, MeOH). mp 707°-708° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19]([O:21]C)=[O:20])[CH:12]=[C:13]([Cl:15])[N:14]=1)C1C=CC=CC=1.O.CO.Cl>C1COCC1>[Cl:15][C:13]1[N:14]=[C:9]([O:8][CH3:1])[C:10]2[N:11]([N:16]=[CH:17][C:18]=2[C:19]([OH:21])=[O:20])[CH:12]=1
Reactant: COC(=O)c1cnn2cc(Cl)nc(OCc3ccccc3)c12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1nc(Cl)cn2ncc(C(=O)O)c12
Reaction time: 5 h

Procedure:
methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate (5.35) (894 mg, 2.81 mmol) was suspended in THF (7.5 mL), water (2.5 mL), and MeOH (2.5 mL). After stifling at 30° C. for 5 h, HPLC demonstrated one primary product. The reaction mixture was acidified with aqueous HCl and was partitioned between water, EtOAc and 2-Me-THF. The phases were separated and the aqueous phase was extracted 3 times with a mixture of EtOAc and 2-Me-THF. The combined organic phase was concentrated to afford crude 6-chloro-4-methoxypyrazolo[1,5-a]pyrazine-3-carboxylic acid that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C8H7ClN3O3: 228.0; found: 228.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].Br[CH:19]([CH3:21])[CH3:20].C(=O)([O-])O.[Na+]>ClCCl>[CH:19]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C(C)C)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl indole-6-carboxylate (497 mg) in dichloromethane (15 mL) were added aluminum chloride (831 mg) and 2-bromopropane (0.27 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (65 mg) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]2[C:16]([O:18]CC)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>O1CCCC1.O>[C:1]1([N:7]2[CH:11]=[C:10]([Si:12]([CH3:13])([CH3:14])[CH3:15])[NH:9][N:8]2[C:16]([OH:18])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1NC([Si](C)(C)C)=CN1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C1=CN(c2ccccc2)N(C(=O)O)N1
Temperature: 25 °C
Yield: 23236.9 %

Procedure:
Ethyl 3-phenyl-5-trimethylsilanyl-1H-[1,2,3]triazole-2-carboxylate (3.0 mg) which is the compound prepared in the above 2) was dissolved in 20 ml of tetrahydrofuran/water, 1.0 ml of 3N lithium hydroxide was dropped thereinto and the mixture was stirred at room temperature for one night. The solvent was evaporated in vacuo, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, the mixture was subjected to a back extraction with ethyl acetate, an aqueous layer was neutralized with 1M hydrochloric acid and extracted with ethyl acetate and the ethyl acetate layer washed with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 630 mg of the title compound as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)(=[O:11])[CH3:10]>>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:9](=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:21]=[CH:20]2
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Product: COc1ccc2cc(C(=O)C=Cc3ccccc3)ccc2c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and commercial 2-acetyl-6-methoxynaphthalene, 1-(6-methoxy-2-naphthalenyl)-3-phenylprop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:14]([NH:22][C:23](=[S:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=S)NC(=O)c2ccccc2)n1

Procedure:
The reaction described in Preparation 1 was repeated, but using 20 g of ethyl 2-aminothiazol-4-ylglyoxylate, 16.5 g of benzoyl isothiocyanate, and 100 ml of dimethylformamide, giving the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)=[CH:10][N:9]=[N:8]1)=[O:4].[C:39]([OH:42])(=[S:41])[CH3:40].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl-].[Na+]>C1(C)C=CC=CC=1>[C:39]([S:41][CH:12]([C:11]1[N:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:8]=[N:9][CH:10]=1)[C:13]1[CH2:14][N:15]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][CH2:17][CH:18]=1)(=[O:42])[CH3:40]
Reactant: CC(O)=S
Reactant: COC(=O)CCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1nncc1C(SC(C)=O)C1=CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of (E)-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (13.22 g) in toluene (200 ml) were added thioacetic acid (3.7 ml) and N,N-dimethylformamide dineopentyl acetal (14.5 ml) with stirring at room temperature, and the resulting mixture was stirred at the same temperature for 2 hours. After addition of aqueous sodium chloride solution, products were extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography using a mixed solvent of ethyl acetate and hexane (2:1) as the eluent to afford 5-((acetylsulfanyl){1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (8.17 mg, yield: 55%) as a pale yellow amorphous solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:27][NH2+:28][CH3:29]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:28]([CH3:29])[CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[NH2+]C
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Agent: [Cl-]
Product: CN(C)C(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and dimethylammonium chloride and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:11]=2[O:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])=[C:4]([F:26])[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:21][C:19]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][C:4]=2[F:26])[CH:20]=1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(Br)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCC(=O)O)c(C(=O)NCc2ccc(Br)cc2F)c1
Yield: 72.1 %

Procedure:
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid (1.10 g, 2.76 mmol) was dissolved in ethyl alcohol (40 mL, 0.1 M), treated with 10% Pd on carbon (Degussa, 0.10 g) and placed under a balloon of hydrogen for 12 h. The reaction was filtered through Celite and concentrated to give a crude solid which was recrystallized from heptane and ethyl acetate to give [4-amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid (0.79 g, 66%): mp 204° C. (dec.); Rf 0.10 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.16 (br t, J=6.3 Hz, 1 H), 7.85 (d, J=2.7 Hz, 1 H), 7.46–7.11 (m, 5 H), 4.91 (s, 2 H), 4.57 (br d, J=3.6 Hz, 2 H). ESI-LC/MS m/z calcd for C16H14BrFN2O4: 396.0 found 395.0 (M−1)−. Anal. calcd for C16H14BrFN2O4: C, 48.38; H, 3.55; N, 7.05. Found C, 48.05; H, 4.02; N, 6.94.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])C=C)([OH:3])=[O:2].[Cl-].C[N+]1C=CN(CC)C=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[C:1]([CH2:4][NH:5][C:6]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=1)([OH:3])=[O:2]
Reactant: C=CCCCC(C=C)NCC(=O)O
Agent: CCn1cc[n+](C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CNC1=CCCCC1

Procedure:
92 mg (0.5 mmol) of N-carboxymethyl-3-amino-1,7-octadiene and 4 mg of bis(tricyclohexylphosphine)-benzylidene-ruthenium(IV) dichloride (1 mol %) were dissolved in a liquid mixture of 586 mg of 1-methyl-3-ethylimidazolium chloride (4 mmol) and 533 mg of aluminium trichloride (4 mmol) under an argon atmosphere in a baked-out Schlenk tube. The mixture was allowed to react for two hours at 50° C. After an aqueous work-up, the mixture was filtered through a very short silica gel column (0.5 cm), washed four times with 1 ml each time of acetonitrile and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[CH3:17]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure AA above and using 3,5-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([OH:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:30][O:26][C:25]([C:9]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[C:11]2[CH:10]=1)=[O:27]
Reactant: CI
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
The solution of 0.2 g (0.54 mmol) 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester in 2 ml N,N-dimethylformamide was cooled down to 0° C. and 26 mg (0.54 mmol; 55% dispersion in mineral oil) sodium hydride were added. After 15 min., 38 μl (85 mg, 0.6 mmol) methyl iodide were added and the cooling bath was removed. After 5 hours the reaction mixture was poured on water and was extracted five times with dichloromethane. The organic layers were dried over magnesium sulfate, filtered and evaporated to give 0.19 g (93%) the compound as a light yellow oil which was pure enough for the subsequent steps without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[N:10][CH:9]=[C:8]2[C:13]([OH:15])=[O:14])[CH3:2].[CH2:16]1COCC1.C([O-])(=O)C.[Na+]>CO>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[N:10][CH:9]=[C:8]2[C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: C1CCOC1
Reactant: CCc1cccc2c(C(=O)O)cnnc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cccc2c(C(=O)OC)cnnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.1 g of 53, 70 ml of dry THF and 0.98 g of CDII was stirred under nitrogen at room temperature until no more gas evolved (4 hours), 0.35 g of methanol and 0.03 g of sodium acetate were added and the mixture was stirred at room temperature for 3 hours. The THF was evaporated, the residue was dissolved in methylene chloride, the solution was washed with water, dried (MgSO4) and stripped of solvent. The residue was recrystallized from hexane to give 54, as a yellow solid, m.p.: 59°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4](C(=O)C1C=CC=CC=1)[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])([CH3:8])[CH3:7].C(=O)([O-])[O-:27].[K+].[K+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][O:2][C:3](=[O:25])[CH:4]([OH:27])[CH2:5][C:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])([CH3:8])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(CC(C)(C)c1cc(F)ccc1Br)C(=O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cs+]
Solvent: CI
Solvent: CO
Product: COC(=O)C(O)CC(C)(C)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.8 %

Procedure:
A solution of 0.9 g (2.13 mmol) of 2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl ester in 50 ml of MeOH is mixed with 1.47 g (10.6 mmol) of potassium carbonate and stirred for 3 hours at room temperature. The batch is acidified (pH 3) with 10% sulfuric acid, and it is extracted with ethyl acetate. The combined extracts are washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is taken up in 8 ml of DMF and stirred with 1.92 g (5.9 mmol) of cesium carbonate and 0.38 ml (5.9 mmol) of methyl iodide for 3 hours at room temperature. The batch is mixed with 10% citric acid and extracted with MTBE. The organic phase is washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 250 mg of product.
Reaction SMILES: C1(C)C=CC(S(O[C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:27][NH2:28]>C(O)C>[CH3:27][NH:28][C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)4-penten-2-ol p-toluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 2.10 g (31.0%) of a colorless oil bp 90–100° C. at 0.5 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:18]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)(=[O:20])[CH3:19]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)CCNC2=O
Temperature: 110 °C
Yield: 78.4 %

Procedure:
To a flask charged with 1.55 g of (PPh3)2PdCl2 and 5.0 g of 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one was added 25 mL of DMF. Then 9.58 g of Tributyl-(1-ethoxy-vinyl)-stannane was added and the reaction mixture was heated to 110° C. and stirred until completion of the reaction. The reaction mixture was filtered over celite and diluted with diethyl ether. After washing with saturdated ammonium carbonate, water and brine, the solutin was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting mixture dissolved in THF and treated with 3.0 M aqueous HCl to effect hydrolysis. The mixture was then partitioned between water and diethyl ether. The organic phase was washed sequentially with saturated sodium bicarbonate, water, and brine and then dried over sodium sulfate. After filtration, the solution was concentrated and purified by flash chromatography to afford the 3.28 g of 6-Acetyl-3,4-dihydro-2H-isoquinolin-1-one.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C[N:14](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH2:14])=[O:4]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C(N)=O)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of 2-methyl-2-phenylpropionic acid in 100 mL of CH2Cl2 was added 0.50 mL of DMF and oxalyl chloride (3.40 g, 26.8 mmol). The mixture was stirred at 23° C. for 4 hours then the solvent was removed under reduced pressure. The crude material was dissolved in 50 mL of THF and 30 mL of NH4OH was added. The mixture was stirred at 23° C. for 1 hour then and the mixture was concentrated under reduced pressure. The crude product was dissolved in 150 mL of EtOAc and washed with 100 mL of 2 N HCl, 100 mL NaHCO3, and 100 mL of brine. The organic phase was dried over Na2SO4 and concentrated. The product was purified by recrystallization from EtOAc/hexanes to provide 3.50 g (88% yield) of the desired product as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[C:34](B(O)O)=[CH:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[C:34]2[C:33]([F:32])=[CH:38][N:37]=[C:36]([O:39][CH3:40])[CH:35]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1
Reactant: COc1cc(B(O)O)c(F)cn1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2=CCCC2(C)C)c1
Temperature: 87 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a flask with methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(trifluoromethylsulfonyloxy)benzoate 66.61 (404 mg, 1068 μmol) was added Pd(PPh3)4 (123 mg, 107 μmol), potassium carbonate (443 mg, 3203 μmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid 66.12A (456 mg, 2669 μmol, commercially available from Asymchem). The mixture was then degassed, and DMF (3 mL) was added. The reaction was stirred overnight at 87° C. and worked up with EtOAc and water. Silica gel chromatography (0-50% EtOAc/Hexanes) afforded methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)benzoate 66.12B 295 mg (78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-dimethyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=O.[C:21](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6](=[O:8])[CH3:21]
Reactant: COC(=O)CC(NC(=O)CCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC(NC(=O)CCc1ccccc1)C(C)=O
Temperature: 90 °C

Procedure:
2-(3-Phenyl-propionylamino)-succinic acid 4-methyl ester (10 g, 36 mmol), pyridine (50 mL) and acetic anhydride (45 mL) were combined in a 500 mL flask. The reaction mixture was heated at 90° C. for 2 h and then cooled to ambient temperature. After concentrating the reaction mixture under reduced pressure, DI water was added (100 mL). (Potential exotherm!). The reaction mixture was partitioned between water and CH2Cl2. The organic phase was washed with 1N HCl and then dried (MgSO4), filtered and concentrated under reduced pressure. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 6.79 (br d, J=7.6 Hz, 1H), 4.72 (X of ABX, 1H), 3.65 (s, 3H), 3.01-2.93 (m, 3H), 2.71-2.62 (m, 3H), 2.11 (s, 3H); MS (EI) 278.1 (M+H).