Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][N:9]2[N:10]=1)=[O:5])C.C(OC(C1C=NN2CCCC=12)=O)C.C(#N)C.[OH-].[Na+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[N:10]1[N:9]2[CH2:11][CH2:12][CH2:13][C:8]2=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2n(n1)CCC2
Agent: CCOC(=O)c1cnn2c1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1cc2n(n1)CCC2

Procedure:
Based on the general enzymatic conditions described above, 1.50 g of mixed esters, 5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole-2-carboxylic acid ethyl ester and 5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole-3-carboxylic acid ethyl ester is hydrolyzed with about 100 mg of Pseudomonas sp. Lipase (L-6) in 50 ml 0.1M potassium phosphate buffer pH 7.25 to which, 0.5 ml acetonitrile is added for even distribution of the substrate in the buffer. The reaction is mixed at 37° C. The acid released after enzyme hydrolysis lowers the reaction pH. Periodically pH of the reaction is checked and if it is 7.0 or below, 1N sodium hydroxide is added to bring the pH to about 7.30. Thus, the pH is maintained above 7.0. After 72 h incubation the desired ester hydrolysis reached about 70%, based on HPLC analysis. Enzyme reaction is filtered through a 0.2μ membrane to remove the insoluble material from the crude enzyme preparation. The clear enzyme reaction mix is extracted twice with ethyl acetate (1:1) at pH 7.0, which removes all the remaining esters, leaving only 5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole-2-carboxylic acid in the aqueous phase. The aqueous phase containing the acid product is lyophilized and the recovered solid is dissolved in methanol. The salts that were not soluble in methanol are separated and discarded. Methanol containing 5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole-2-carboxylic acid (pale yellow) is evaporated and about 0.5 g of 5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole-2-carboxylic acid is recovered. The LC-MS and NMR data are consistent and indicated that only the desired acid is present with isomeric purity at 100%. The acid purity by HPLC is over 97%. HPLC conditions are: Prodigy ODS3 column 4.6×150 mm. Solvent A: 0.02% Trifluoroacetic acid (TFA) in water. Solvent B: 0.02% TFA in acetonitrile. Gradient used is, 90% A and 10% B at zero time with gradient reaching at 20 minutes, 5% A and 95% B and continue until 25 minutes.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[Cl:18].[Li]CCCC.[B:24](OC(C)C)([O:29][CH:30]([CH3:32])[CH3:31])[O:25][CH:26]([CH3:28])[CH3:27]>>[Cl:18][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:16]=[CH:17][C:2]=1[B:24]([O:29][CH:30]([CH3:32])[CH3:31])[O:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN1CCN(CCOc2ccc(Br)c(Cl)c2)CC1
Agent: [Li]CCCC
Product: CC(C)OB(OC(C)C)c1ccc(OCCN2CCN(C)CC2)cc1Cl

Procedure:
1-[2-(4-Bromo-3-chlorophenoxy)ethyl]-4-methyl-piperazine was reacted with n-BuLi at 0° C. in the presence of triisopropyl borate to give diisopropyl 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenylboronate upon warming to room temperature.
Reaction SMILES: N([O-])=[O:2].[Na+].Cl[C:6]1[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]=[C:8]([S:16][CH3:17])[N:7]=1>CN(C)C=O>[F:14][CH:13]([F:15])[O:12][C:10]1[CH:11]=[C:6]([OH:2])[N:7]=[C:8]([S:16][CH3:17])[N:9]=1
Reactant: O=N[O-]
Reactant: CSc1nc(Cl)cc(OC(F)F)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(O)cc(OC(F)F)n1
Reaction time: 0.83 h
Yield: 70.8 %

Procedure:
Over 50 minutes, a solution of 8.8 g (0.127 mole) of sodium nitrite in 10 ml of dimethylformamide is added dropwise at 140° C. to a solution of 8.7 g (0.038 mole) of 4-chloro-6-difluoromethoxy-2-methylthiopyrimidine in 10 ml of dimethylformamide. When the addition of the sodium nitrite is complete, the mixture is stirred for 2 hours at 140° to 150° C. The solvent is then evaporated off in vacuo and the residue is crystallised from 1N hydrochloric acid, affording 5.6 g (70% of theory) of 4-difluoromethoxy-6-hydroxy-2-methylthiopyrimidine with a melting point of 236°-237° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccco4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes. 2-Furoyl chloride (0.4 g, 3.2 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (60 mL) and 2N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (20 mL) to give furan-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 58%) as a white solid: mp 219-221° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.30-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.39-4.49 (m, 3H), 4.53 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=5.0 and 13.1 Hz, 1H, CH), 6.62-6.63 9m, 1H), 7.14 (d, J=3.4 Hz, 1H), 7.47-7.65 (m, 3H, Ar), 7.84 (s, 1H), 8.00 (t, J=5.8 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.18, 38.72, 46.24, 51.58, 111.87, 113.69, 121.70, 128.32, 130.74, 131.61, 134.55, 140.11, 145.15, 147.61, 157.84, 168.05, 171.01, 172.85; Anal. calcd. for C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 61.91; H, 4.64; N, 11.38.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>>[ClH:34].[ClH:34].[CH3:33][O:32][C:30]([CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([CH2:15][NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:17][CH2:18]2)=[CH:23][CH:24]=1)=[O:31]
Reactant: COC(=O)COc1ccc(N2CCC(CNC3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(N2CCC(CNC3CCNCC3)CC2)cc1

Procedure:
Prepared from 4-[(1-tert-butyloxycarbonylpiperidin-4-yl)aminomethyl]-1-(4-methoxycarbonylmethyloxyphenyl)piperidine and ethereal hydrochloric acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:21]([O:23]CC)=[O:22])[CH2:10][CH2:9][N:8]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2].O.C(OCC)(=O)C.Cl>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:21]([OH:23])=[O:22])[CH2:10][CH2:9][N:8]([C:11](=[O:20])[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)c2ccc(OC)cc2)C1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)O)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 30 °C
Reaction time: 144 h
Yield: 53.4 %

Procedure:
1-(4-Methoxy-benzoyl)-pyrrolidine-3,3-dicarboxylic acid diethyl ester (679.9 g, 1.95 mol) (see Preparation 7) in acetonitrile (1000 mL) was added to pH 7 buffer solution (10 L, 0.1M potassium phosphate) then Savinase 16T Type W enzyme (3200 g) was added and the resulting slurry was heated to 30° C. The pH of the reaction mixture was kept at 8.5 using a pH stat (TIM856 Titration Manager) and stirred for 6 days. Water (6 L) and ethyl acetate (12 L) was added to the reaction mixture then acidified to pH1 using 2M HCl aqueous solution (6 L). This was filtered through Arbocel™ and the organic layer was separated, washed with water (5 L) then extracted with 0.5M NaOH aqueous solution (7 L). The aqueous phase was acidified using 2M HCl aqueous solution (5 L) and extracted with ethyl acetate (6.5 L). The organic phase was concentrated under reduced pressure to afford the title compound as an orange oil (334.3 g, 53%). (92.9:7.1 ratio of isomers)
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=O)=[N:8]1.[OH-].[Li+].ON1C2C=CC=CC=2N=N1.[F:62][C:63]1[CH:69]=[CH:68][C:66]([NH2:67])=[CH:65][CH:64]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>O1CCCC1.O.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:67][C:66]3[CH:68]=[CH:69][C:63]([F:62])=[CH:64][CH:65]=3)=[O:45])[CH:47]=[CH:48][CH:49]=2)=[N:17]1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)cc1)c1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 7 %

Procedure:
The title compound was prepared as described in Example 381, using methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.62 mmol) and lithium hydroxide (0.046 g, 1.92 mmol) in tetrahydrofuran (3 mL) and water (2 mL); 1-hydroxybenzotriazole (0.254 g, 1.88 mmol), 4-flouroaniline (0.176 mL, 1.86 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.361 g, 1.88 mmol), and additional tetrahydrofuran (2 mL); 4 N hydrochloride solution in dioxane (10 mL). The final crude product was purified by preparative HPLC (30–80% acetonitrile in H2O, 20 min.) (0.017 g, 7% yield over 3 steps): 1H NMR (CD3OD) δ 8.82 (dd, 1H), 8.57 (t, 1H), 8.37 (s, 1H), 8.26 (dt, 1H), 8.13 (dd, 1H), 8.01 (dt, 1H), 7.75 (m, 4H), 7.13 (t, 2H); ES-MS (m/z) 399 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:14]=1)[CH:10]=[O:11].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>C(C(C)=O)C>[CH:10]([C:9]1[CH:8]=[C:7]([CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:12]=1)[O:6][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: CCCc1cc(O)cc(C=O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1cc(C=O)cc(OCC(=O)OC)c1

Procedure:
A mixture of 3-hydroxy-5-propyl-benzaldehyde potassium carbonate (0.7 g) and methyl bromoacetate (0.8 ml) in methyl ethyl ketone (6 ml) were heated at 70° for 4 hours. The reaction was filtered and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N-:12]=[N+:13]=[N-:14].[Na+].Cl.CCOC(C)=O>O.[Br-].[Zn+2].[Br-]>[N:9]1[NH:12][N:13]=[N:14][C:8]=1[C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2nn[nH]n2)cc1

Procedure:
Ex-78A: A suspension of 4-acetylbenznitrile (2.9 g, 20.0 mmol), sodium azide (1.43 g, 22.0 mmol) and zinc bromide (4.5 g, 20.0 mmol) in water (50 mL) was refluxed for one day. Additional water (40 mL), HCl (3M, 30 mL) and EtOAc (200 mL) were added subsequently. The mixture was stirred until no solid in the aqueous layer. The mixture was then portioned. The aqueous solution was further extracted with EtOAc (3×60 mL). The combined EtOAc was concentrated. The residue was treated with NaOH (0.25 M, 200 mL). After stirred for 50 min, insoluble material was filtered, washed with NaOH (1M). The filtrate was then acidified with HCl (conc.) to pH 3. The resulting white precipitate was filtered, washed with water and dried in vacuo to obtain 1-[4-(2H-tetrazol-5-yl)-phenyl]-ethanone as white solid. 1H NMR (DMSO-d6) δ 8.17–8.10 (m, 4H), 2.61 (s, 3H). MS m/z=188 (M+).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=O.S(Cl)(Cl)=O.Cl.[CH3:30][NH:31][O:32][CH3:33].N1C=CC=CC=1>O1CCCC1.C(OCC)C>[CH3:30][N:31]([O:32][CH3:33])[C:3](=[O:5])[CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([Cl:23])=[CH:9][C:8]=1[Cl:24]
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CNOC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CON(C)C(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Yield: 64.2 %

Procedure:
A mixture of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound 2) and 5 mL of thionyl chloride was stirred at reflux for three hours. The mixture was cooled, and excess thionyl chloride was removed by distillation under reduced pressure leaving a residue. The residue was added to a cold solution of 0.13 g (0.0014 mole) of N,O-dimethylhydroxylamine hydrochloride and 0.11 g (0.0014 mole) of pyridine in 20 mL of tetrahydrofuran. The resultant mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was diluted with diethyl ether and was washed in succession with a 1N hydrochloric acid solution, an aqueous 10% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to give 0.37 g of N-methyl-N-methoxy-2-chloro-3-[2,4 -dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionamide as an oil, Compound 22 of Table 1.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(N2CCNCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 84 %

Procedure:
To a solution of (3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester I-4c (30 mg, 0.08 mmol) in CH2Cl2 (1 mL) was added with trifluoroacetic Acid (0.5 mL) and the resulting mixture was stirred at ambient temperature for 19 h. The reaction mixture was poured into 1N NaOH (10 mL) and extracted with ethyl acetate (1×40 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated to give the title compound 4-A (19.3 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:7]([C:20]([F:23])([F:22])[F:21])([OH:19])[CH2:6][C:5]([CH3:25])([CH3:24])[C:4]=2[C:3]=1[OH:26].[C-:27]#[N:28].[Na+].O>CN1CCCC1=O.C(OCC)(=O)C.[Ni](Br)Br>[OH:26][C:3]1[C:4]2[C:5]([CH3:25])([CH3:24])[CH2:6][C:7]([OH:19])([C:20]([F:23])([F:22])[F:21])[CH:8]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:9]=2[CH:10]=[CH:11][C:2]=1[C:27]#[N:28]
Reactant: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccnc2)c2ccc(Cl)c(O)c21
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccnc2)c2ccc(C#N)c(O)c21
Yield: 19.3 %

Procedure:
50 mg of the 2-chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol that is described in Example 159 is dissolved in 0.12 ml of 1-methyl-2-pyrrolidinone and mixed with 12.6 mg (0.258 mmol) of sodium cyanide and 28.2 mg (0.129 mmol) of nickel(II) bromide. The reaction mixture is brought to reaction in the microwave as described in the literature (J. Org. Chem. 68, 9122 (2003) (200° C., 20 bar). After cooling, the reaction mixture is diluted with ethyl acetate and then a small amount of water is added. The mixture is filtered over Extrelut (mobile solvent ethyl acetate). The solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent methanol/dichloromethane). 9.4 mg (19.2%) of the desired nitrile is isolated.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:20])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C(=O)O)c1ccc(N)nc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc(N)nc1
Temperature: 25 °C

Procedure:
A solution of 2-(6-aminopyridin-3-yl)-2-methylpropanoic acid hydrochloride (35.0 g, 0.162 mmol) and concentrated H2SO4 (5 mL) in MeOH (250 mL) was heated at reflux overnight. After cooling to ambient temperature, the reaction was quenched cautiously with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (.Yen.3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue (31.6 g, 100%) was judged pure by a combination of TLC and 1H nmr analysis and was used without further purification in the subsequent reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10](=O)/[CH:11]=[CH:12]/N(C)C)[C:7]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:5]=1[NH:21][C:22](=[O:24])[CH3:23].[CH3:26][O:27][CH2:28][CH2:29][NH:30][NH2:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[N:30]([CH2:29][CH2:28][O:27][CH3:26])[N:31]=[CH:12][CH:11]=2)[C:7]([C:17]([F:18])([F:20])[F:19])=[CH:6][C:5]=1[NH:21][C:22](=[O:24])[CH3:23]
Reactant: COCCNN
Reactant: COC(=O)c1cc(C(=O)/C=C/N(C)C)c(C(F)(F)F)cc1NC(C)=O
Solvent: Cc1ccccc1
Product: COCCn1nccc1-c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 40 h
Yield: 54.7 %

Procedure:
A mixture of 2-acetylamino-5-((E)-3-dimethylamino-acryloyl)-4-trifluoromethyl-benzoic acid methyl ester (600 mg, 1.67 mmol) and (2-methoxy-ethyl)-hydrazine (151 mg, 1.68 mmol) in toluene (10 mL) was stirred at 90° C. for 40 h. Four portions of (2-methoxy-ethyl)-hydrazine (one equiv each day) were added over 4 d and the mixture was kept at 90° C. The mixture was concentrated to dryness in vacuo. The crude product was purified by flash chromatography (silica gel, DCM/MeOH (100:0 to 60:40)) to provide the title compound as a yellow syrup (352 mg, 55%). ES-MS: m/z 386.3 [M+H]+, rt 5.50 min.
Reaction SMILES: [OH-].[Na+].[O:3]=[S:4]1(=[O:36])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:19]([O:21]CC)=[O:20])[CH3:18])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1.CC(O)=O>CCO>[O:36]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:16][CH:17]([C:19]([OH:21])=[O:20])[CH3:18])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C)C(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C)C(=O)O)cc2S(=O)(=O)C1
Yield: 65.7 %

Procedure:
Sodium hydroxide (0.045 g, 1.13 mmol) was added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1-(ethoxycarbonyl)ethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 1; 0.050 g, 0.090 mmol) in EtOH (4 ml, 95%) and heated under reflux. After 1.5 hours AcOH (0.2 ml) was added and most of the solvent was removed under reduced pressure. The crude product was extracted (DCM/H2O), dried (MgSO4) and evaporated to give the title compound 0.031 g (65%) as white solid. NMR (500 MHz, CD3OD) 0.70–0.85 (m, 6H), 0.95–1.25 (m, 4H), 1.35–1.70 (m, 4H), 2.65 (d, 3H), 3.10–3.35 (m, 2H), 3.45–3.95 (m, 2H), 4.70 (q, 1H), 6.90–7.35 (m, 6H), 7.45 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1>O1CCCC1.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccsc2)n1
Yield: 58.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (5 mol %) was added to a degassed and stirred mixture of 2,6-dibromopyridine (3.78 g, 15.6 mmol) and thiophene-3-boronic acid (2.20 g, 16.8 mmol) in tetrahydrofuran (40 ml) under an atmosphere of nitrogen then heated to reflux for 24 h. Solvent was removed in vacuo and purification by chromatography on silica gel eluting with a gradient of diethyl ether-isohexane (5-10%) gave 2-bromo-6-(thien-3-yl)pyridine (2.20 g) as a white solid: δH (400 MHz, CDCl3) 7.32-7.41 (2H, m), 7.53-7.55 (2H, m), 7.61-7.64 (1H, m), 7.94-7.96 (1H, m); m/z (ES+) 240/242 (M++H).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:6](OC)=[O:7])[CH3:2].[OH-].[NH4+:15].Cl>CO>[C:6]([C:5](=[N:4][O:3][CH2:1][CH3:2])[C:10]([O:12][CH3:13])=[O:11])(=[O:7])[NH2:15]
Reactant: [NH4+]
Reactant: CCON=C(C(=O)OC)C(=O)OC
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCON=C(C(N)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of dimethyl ethoxyiminomalonate (57.4 g) and conc. ammonium hydroxide (50 ml) in methanol (150 ml) was stirred for 2.5 hours at room temperature. The mixture was adjusted to pH 4 with conc. hydrochloric acid under cooling and concentrated to 70 ml under reduced pressure. The aqueous solution was stood in a refrigerator for one hour and the resulting precipitates were collected by filtration, washed with cold water and dried to give methyl 2-carbamoyl-2-ethoxyiminoacetate (syn isomer) (31 g), mp 68° to 71° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].O>CC(C)=O>[CH3:21][O:20][C:18](=[O:19])[CH2:17][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH:11]=[O:12])[CH:9]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc(C=O)c1
Yield: 93.3 %

Procedure:
Powdered potassium carbonate (5 g) was added to a solution of 3-hydroxybenzaldehyde (3.1 g, 25 mmol) and methyl bromoacetate (4.6 g, 30 mmol) dissolved in acetone (40 mL), and the mixture was stirred under reflux for 4 hours. The reaction mixture was then poured into excess water, extracted with dichloromethane, and evaporated. The resultant yellow oil was distilled on the Kugelrohr (1 mmHg, 150° C.) to give (3-formylphenoxy)acetic acid methyl ester as a colorless oil (4.53 g, 93%).