Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH:14]2[N:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][N:29]=3)[C:21](=[O:22])[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:15]2=3)=[O:12])[CH2:7][CH2:6]1.C(OC(=O)C(C(C(OC(=O)C1C=CC=CC=1)=O)O)O)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C@@H:14]2[N:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][N:29]=3)[C:21](=[O:22])[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:15]2=3)=[O:12])[CH2:7][CH2:6]1
Reactant: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Agent: O=C(OC(=O)C(O)C(O)C(=O)OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(C(=O)O[C@H]2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 36 °C
Reaction time: 0.75 h

Procedure:
Mixture of dichloromethane 300 ml, 6-(5-chloropyridin-2-yl)-5-(4-methylpiperazin-1-yl)-carbonyloxy-7-oxo-5,6-dihydropyrrolo-[3,4-b]-pyrazine D (+)-O,O′-dibenzoyltartaric acid salt 100 g (Chiral purity 97%) and water 250 ml was warmed to 35-37° C. Sodium bicarbonate (28.1 g) was added to the mixture and maintained at 35-37° C. Reaction mixture was stirred for 30-60 min and cooled to 25-30° C. Organic layer was separated. The organic layer was washed with 200 ml water and then with activated carbon (5 g) for 30 min at 20-25° C. Carbon was filtered over hyflo and washed with 100 ml dichloromethane. The filtrate was concentrated to 150 ml at atmospheric pressure. Cyclohexane (600 ml) was added to residual solution at 25-30° C. in 60 min. The slurry was slowly cooled to 0 to 5° C. and stirred for 60 min at same temperature. The solid was filtered and washed with chilled 50 ml Cyclohexane (10° C.) and then dried at 50-60° C. to obtained 44 g Eszopiclone with chiral purity ˜97%
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N2CCC3(CCNC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1.2 ml) was added to a solution of tert-butyl 8-(4-methoxyphenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, 0.57 mmol, 1.0 eq.) in methylene chloride (5 ml) at 0° C. and the reaction mixture was stirred at RT for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure to give the desired product as a yellow sticky solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1>C(O)CCC>[N:12]1([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reaction time: 17 h
Yield: 26.2 %

Procedure:
8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80° C. for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CO>[CH3:20][C:5]1([CH3:21])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:3]=2)[N:7]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]1=[O:19]
Reactant: CC(C)CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(CCC(C)C)C(=O)C3(C)C)cc1
Yield: 27.3 %

Procedure:
N-[3,3-Dimethyl-1-(3-methyl-butyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide is prepared from A9 (419 mg) and 4-methoxy-benzoyl chloride (491 mg; 2.88 mmol) as described in Example 1a. N-[3,3-dimethyl-1-(3-methyl-butyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide (167 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (50:1)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[C:10](O)[CH:9]=[N:8][CH:7]=1.IC.CN(C)[CH:18]=[O:19]>>[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:19][CH3:18])=[N:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 90 %

Procedure:
To sodium hydride (0.42 g, 10.5 mmol, washed with hexanes ×3) in dimethylformamide (15 mL) was added 5-hydroxy-nicotinic acid methyl ester (1.53 g, 10.0 mmol) in dimethylformamide (10 mL). After three minutes, iodomethane (0.65 mL, 10.5 mmol) was added dropwise while stirring at room temperature. After 1 h, the reaction was quenched with methanol and concentrated to a brown oil. The solution was dissolved in 20% isopropanol/chloroform, washed with saturated aqueous sodium bicarbonate solution, brine (×3), dried over magnesium sulfate and concentrated to give 1.46 g of 6-methoxynicotinic acid methyl ester. The resulting oil was dissolved in tetrahydrofuran (50 mL), and added to a solution of 5N NaOH (20 mL, 100 mmol) and water (5 mL). After 30 minutes, an additional 25 mL of 5N NaOH was added to the solution. After one hour, the reaction was acidified to pH 3 with 5N HCl and concentrated. To the resulting white solids was added 20% MeOH/CHCl3 and the mixture was sonicated for 20 minutes. The mixture was filtered, and the mother liquor was dried over MgSO4 and concentrated to give 1.38 g as a light yellow solid, 90% yield.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(=O)c3ccccc3oc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2ccccc2oc2c(CBr)cccc12
Yield: 70.3 %

Procedure:
A well-stirred mixture of the above 4-methylxanthenone (6.5 g, 31 mmol), N-bromosuccinimide (5.5 g, 31 mmol) and benzoyl peroxide (30 mg) in dry CCl4 (250 mL) was heated under reflux with powerful illumination for 3 h. The hot mixture was filtered, the filtrate was evaporated and the residue was crystallized from the minimum volume of boiling petroleum ether (ca. 1800 mL) to give 4-bromomethylxanthenone (VII: R1 =H, Z=CH2Br) (6.3 g, 71%) as colourless needles, mp 191°-192° C. Anal. (C14H9BrO2) C,H,N,Br.
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([O-:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1.[Cl-].[K+].[O-]S([O-])(=O)=O.[Mg+2].C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(NCCS([O-])(=O)=O)=O.[Na+]>C(O)C(N)(CO)CO.[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3]>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Fe+3]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
An experiment was conducted to measure, by chronoamperometry, the response of ferrocyanide generated bio-chemically from an enzyme catalysed electrochemical reaction between ferricyanide and nicotinamide adenine dinucleotide (NADH). Two solutions of ferricyanide solution comprising 25 mM K3[Fe(CN)6] (Aldrich) in Tris pH 9 buffer (Sigma) with 100 mM KCl (BDH), 50 mM MgSO4 (Sigma) and 1% sodium taurocholate (Sigma) were prepared. To one solution, Putidaredoxin reductase (PdR) was added and to the other diaphorase was added (both were used at a concentration of 5 mgml−1). NADH solutions were prepared at the following concentrations: 7, 5, 3, 2 and 1 mM in Tris pH 9 buffer (Sigma) with 100 mM KCl (BDH), 50 mM MgSO4 (Sigma) and 1% sodium taurocholate (Sigma).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:18]([C:19]([NH:21][CH3:22])=[O:20])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: CNC(=O)c1cccc(O)c1
Product: CNC(=O)c1cccc(OCc2ccc(Cl)cc2C(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-hydroxy-N-methylbenzamide (WO 2003018566):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C.C(Cl)Cl>[CH2:16]([C:7]1([CH2:10][CH2:11][CH:3]=[CH2:4])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCBr
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCCC1(CCC=C)Cc2cc(OC)ccc2C1=O
Reaction time: 20 h

Procedure:
To a solution of 5-methoxy-1-indanone (1 g, 6.17 mmol) in DMF (6 mL) at rt was added NaH (740 mg, 61% in oil, 18.5 mmol) and 4-bromo-1-butene (2.5 mL, 24.7 mmol). After 20 h at rt, the solution was diluted with CH2Cl2 and quenched with saturated aqueous NH4Cl. The slurry was dried with MgSO4 and filtered through a plug of silica and rinsed with 10% EtOAc in hexanes. The filtrate was concentrated and provided crude 2,2-di(3-butenyl)-5-methoxy-1-indanone.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(=O)[O:34][C:32](=[O:33])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:32](=[O:33])[C:31]3[C:30](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:29]2=[O:34])=[CH:25][CH:26]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(C[PH](=O)OCCc1ccc(N)cc1)C(=O)OCc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CC(C)CC(C[PH](=O)OCCc1ccc(N2C(=O)c3ccccc3C2=O)cc1)C(=O)OCc1ccccc1
Yield: 50.6 %

Procedure:
2-[(4-Aminobenzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid benzyl ester (prepared as described in Example 2/Step A) (242 mg, 0.60 mmole) and phthalic anhydride (133 mg, 0.90 mmole) in acetic acid (10 ml) were refluxed for 1 hour. The cooled reaction mixture was concentrated and the residue dissolved in ethyl acetate (100 ml). This solution was washed with saturated sodium bicarbonate solution (3×20 ml) and dried with magnesium sulfate. Filtration and concentration gave a light yellow oil which was purified by chromatography (ethyl acetate) yielding 162 mg (51%) of 2-{[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)benzyl]methoxyphosphinoyl methyl}-4-methylpentanoic acid benzyl ester as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6](=[CH2:10])[C:7]([OH:9])=[O:8].[C:14]([OH:17])(=[S:16])[CH3:15]>>[C:14]([S:16][CH2:10][CH:6]([CH2:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([Br:1])[CH:3]=1)[C:7]([OH:9])=[O:8])(=[O:17])[CH3:15]
Reactant: C=C(Cc1cccc(Br)c1)C(=O)O
Reactant: CC(O)=S
Product: CC(=O)SCC(Cc1cccc(Br)c1)C(=O)O
Temperature: 50 °C
Yield: 95 %

Procedure:
To a 5 ml pear-shaped flask containing 2-(3-bromobenzyl)acrylic acid (0.44 g, 1.83 mmol) was added thioacetic acid (1 ml, 1.065 g, 13.99 mmol). The mixture was heated at 50° C. for 2.5 hours, after which excess thioacetic acid was removed under reduced pressure. The residue was co-evaporated with toluene twice, then purified via silica gel column chromatography eluting with 0 to 2% MeOH in CH2Cl2, giving 2-(acetylsulfanylmethyl)-3-(3-bromophenyl)propionic acid as a colorless glue, 0.55 g, 95% yield, HPLC purity: 96.9%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:10]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CCCCCCNCCCCCCC(C)C
Reactant: O=C(O)c1cnccn1
Product: CC(C)CCCCCCN(CCCCCCC(C)C)C(=O)c1cnccn1

Procedure:
N,N-diisononylpyrazine-2-carboxamide was prepared from pyrazine-2-carboxylic acid and commercial di-isononylamine using the general method of Example 11. The product had a boiling range of 163°-165° C. at 0.15 mm of mercury pressure.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[H-].[Na+].N[CH2:14][CH2:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:18][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:17])[CH2:15][CH2:14][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[O:10]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CC(C)(CCN)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: CC(C)(CCn1c(=O)oc2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
4.0 g (29.6 mmol) benzoxazol-2-one are dissolved in 40 mL DMPU and cooled with an ice bath. Under protective gas 897 mg (95%; 35.5 mmol) sodium hydride are added batchwise to this solution. The reaction mixture is heated to ambient temperature and then stirred for another hour. 9.85 g (44.4 mmol) tert-butyl (3-amino-1,1-dimethyl-propyl)-carbamate and 1.97 g (5.3 mmol) tetrabutylammonium iodide are added and the mixture is stirred overnight. The reaction is stopped by the careful addition of sodium hydrogen carbonate solution. Ethyl acetate is added, the aqueous phase is separated off and extracted repeatedly with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried with sodium sulphate and evaporated down. Purification of the residue by column chromatography (silica gel; petroleum ether/ethyl acetate=7:3) yields the desired product in the form of an oil. Yield 4.1 g (43%); mass spectroscopy: [M+H]+=321.
Reaction SMILES: [CH:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.OS(O)(=O)=O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(O)CC1NCCc2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid (7.90 g, 41.3 mmol) was dissolved in methanol (200 ml), and H2SO4 (4.4 ml, 82.6 mmol) was added under a nitrogen atmosphere. The reaction solution was heated under reflux and, when the reaction was complete, was stirred overnight at room temperature. The methanol was removed in vacuo and the resulting residue was taken up in ethyl acetate (200 ml). The solution was washed with saturated NaHCO3 solution (150 ml), dried (sodium sulfate) and concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.S1(C2[C:17](=[CH:18]C=CC=2)[C:15](=O)N1)(=O)=O.C([Mg]Br)#CC.CO>C1COCC1.[Cl-].[Cl-].[Zn+2].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.[Cu]I>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:15]#[C:17][CH3:18]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: N#Cc1ccc(O)c(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC#C[Mg]Br
Solvent: CO
Solvent: C1CCOC1
Product: CC#Cc1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 186.5 %

Procedure:
A suspension of the product of Step A (0.3 g; 1.22 mmol) in HMDSA (2 ml) and saccharine (0.1 g) was refluxed under N2 until reaction became homogenous (˜30 min). After cooling to room temperature, the HMDSA was removed in vacuo and the residue was diluted to 4 ml with anhydrous THF. At the same time ZnCl2 (0.2 g; 1.47 mmol) was heated to ˜110° C., in separate flask, in vacuo, cooled to room temperature under N2 and diluted to 4 ml with anhydrous THF. To it 0.5 M prop-1-ynyl-magnesium bromide in THF (4.9 ml; 2.45 mmol) was added at room temperature and this was stirred for 10 min under N2. To it a solution of silinated product of Step A was added, followed by Pd(PPh3)4 (0.11 g; 0.095 mmol) and CuI (0.05 g; 0.26 mmol). After stirring for 1 h at room temperature under N2, MeOH (5 ml) was added and solvents were removed under reduced pressure. The residue was diluted to 20 ml with EtOAc, washed with saturated NH4Cl (2×5 ml), H2O (10 ml), brine, dried anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, CH2Cl2) to give title compound (0.16 g; 78%), as colourless solid. 1H-NMR (CDCl3) 2.14 (s, 3H); 6.26 (s, 1H); 6.97 (d, 1H, J=8.5 Hz); 7.46 (dd, 1H, J=2.1 Hz, 8.5 Hz); 7.57 (d, 1H, 2.1 Hz).
Reaction SMILES: [N:1]1[C:6]([C:7]2[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[O:9][N:8]=2)=[CH:5][CH:4]=[CH:3][C:2]=1[C:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[O:19][N:18]=1.[OH-].[Na+]>O>[OH2:9].[N:1]1[C:2]([C:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[O:19][N:18]=2)=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[O:9][N:8]=1
Reactant: CCOC(=O)c1cc(-c2cccc(-c3cc(C(=O)OCC)on3)n2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2cccc(-c3cc(C(=O)O)on3)n2)no1
Temperature: 25 °C

Procedure:
A mixture of 2.5 g. (0.005 mole) of diethyl 3,3'-(2,6-pyridinediyl)di-5-isoxazolecarboxylate and 250 mg. of sodium hydroxide in 50 ml. of water is refluxed for ninety minutes. The reaction mixture is cooled to room temperature and the insoluble material removed by filtration. The filtrate is acidified with concentrated hydrochloric acid. The gelatinous precipitate is removed by filtration and washed with water. There is obtained 610 mg. of a tan solid (38%) melting at 284° (dec.).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:32]CCl.Cl>C(O)C>[ClH:32].[CH:25]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[CH:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCC=C2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The above ester (4.4 g, 11 mmol) was dissolved in ethanol (40 ml) and 4N sodium hydroxide (8.3 ml) was added. The mixture was stirred vigorously at ambient temperature for 7 h. Dichloromethane (700 ml) was added followed by 2.5N hydrochloric acid until pH 1. The phases were separated, the organic phase dried (MgSO4) and the solvent was evaporated in vacuo. The residue was re-evaporated twice with acetone and then triturated with a mixture of acetone and diethyl ether. The solid was isolated by filtration and dried in air to give 2.2 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Brc1nccs1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1nccs1)OCC2c1ccc(C(C)C)cc1
Yield: 64 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromo-1,3-thiazole, the title compound was obtained in the same manner as in Example 107. Yield: 64%. Melting point: 164-166° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Li+].[CH3:12]C([N-]C(C)C)C.CI>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2-methylbenzonitrile (0.4 g, 2.0 mmol) in dry THF (10 mL) was slowly added LDA (1.3 mL, 1.8 M in THF) at −78° C. and stirred at this temperature for additional 30 min. Methyl iodide (0.15 mL, 2.4 mmol) was added) at −78° C. to the above dark purple solution and the mixture was warmed to room temperature over 3 h. The reaction was quenched with water, extracted with ether, which was then was washed with brine, dried and concentrated. 4-Bromo-2-ethylbenzonitrile (0.34 g) was purified by Combiflash.