Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.Cl[C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][CH2:21]2>N1C=CC=CC=1>[C:31]([O:30][C:28]([N:23]1[CH2:22][CH2:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([NH:17][C:5]([O:7][C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[O:6])[CH:19]=2)[CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a dichloromethane (10 mL) solution of 4-nitrophenyl chloroformate (812 mg), a dichloromethane (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (1.00 g) and pyridine (0.33 mL) was gradually added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours and then concentrated. The residue was vigorously stirred in a mixed solution of diisopropyl ether and water (diisopropyl ether/water). The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (1.46 g, 88%) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:19]=[C:20]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:21]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:19]=[C:20]([CH:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:30])[CH:21]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(=O)c2ccc(F)cc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
Sodium borohydride (0.077 g) was added portionwise to a suspension of 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-(4-fluorobenzoyl)benzenepropanoic acid (0.50 g) in ethanol (12 ml), and the resulting solution was stirred at room temperature for 18 hours. 2N hydrochloric acid (5 ml) was added dropwise followed by ethyl acetate (50 ml), and the mixture was stirred for 1 hour. The organic layer was separated, washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. The column was eluted with hexane/ethyl acetate (5:1), followed by hexane/ethyl acetate/acetic acid (50:50:1), gradually increasing the polarity to give a ratio of 10:90:1. The product fractions were combined and evaporated to give the title compound as a gum (0.36 g), Rf 0.45 (SS 15). Found: C,58.58; H,4.71; N,2.65. C24H23ClFNO5S requires C,58.59; H,4.71; N,2.85%.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH2:50]([N:52]([CH:56]1[CH2:60][CH2:59][NH:58][CH2:57]1)[C:53](=[O:55])[CH3:54])[CH3:51]>>[C:28]([C:32]1[N:33]=[C:34]([N:58]2[CH2:59][CH2:60][CH:56]([N:52]([CH2:50][CH3:51])[C:53](=[O:55])[CH3:54])[CH2:57]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CCN(C(C)=O)C1CCNC1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CCN(C(C)=O)C1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N-ethyl-N-(pyrrolidin-3-yl)acetamide. MS (m/e): 456.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2.CC1C=CC(S(O[CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:36][S:33]([CH2:32][CH2:31][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2)(=[O:35])=[O:34]
Reactant: CCOC(=O)c1cc2cc(O)cc([N+](=O)[O-])c2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A mixture of ethyl 5-hydroxy-7-nitro-1H-indole-2-carboxylate (300 mg), 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (410 mg), potassium carbonate (170 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. Ethyl 5-hydroxy-7-nitro-1H-indole-2-carboxylate (100 mg) was added to the reaction mixture, and the mixture was further stirred at 50° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was washed with diisopropyl ether to give the title compound (400 mg, yield 77%) as yellow crystals. The crystals were recrystallized from acetone-hexane to give yellow prism crystals. melting point 162-163° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.C(C1C=CC(C2N=CC(C(Cl)=O)=C[N:35]=2)=CC=1)CCC.N>O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([NH2:35])=[O:19])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1
Reactant: CCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Agent: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCc1ccc(-c2ncc(C(N)=O)cn2)cc1

Procedure:
8.3 G. of 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid are reacted with 50 ml. of thionyl chloride with the exclusion of moisture and worked up in a manner analogous to that given in Example 7. The remaining 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid chloride is dissolved in 100 ml. of absolute dioxane and added to a solution of 200 ml. of absolute dioxane saturated with ammonia at room temperature with stirring and further treated in a manner analogous to that described in Example 7. The obtained crude 2-(p-n-butylphenyl)-5-pyrimidinecarboxamide can be sublimed in a high vacuum at 185° C. for purification; melting point 264.0°-266.0° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+:10].[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1.[C:25]([O:32][CH2:33][CH3:34])(=[O:31])[C:26]([O:28]CC)=O>CC1CCCCC1>[CH2:33]([O:32][C:25]([C:26](=[O:28])[CH:20]([CH3:21])[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:23])[F:24])=[CH:18][CH:17]=1)[O-:22])=[O:31])[CH3:34].[Li+:10]
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC1CCCCC1
Product: CCOC(=O)C(=O)C(C)C([O-])c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of 118 ml of lithium bis(trimethylsilyl)amide (Lithium Hexamethyldisilazide; 0.9 M in methylcyclohexane) was added dropwise over 15 min, 20 g of 1-(4-Trifluoromethyl-phenyl)-propan-1-one in 51 ml methylcyclohexane at while maintaining the reaction mixture at 15-25° C. After stirring for 2 h, 15 ml of diethyl oxalate were added dropwise over 30 min and the reaction mixture was stirred for 16 h. Then, the precipitated product was collected by filtration and washed with n-heptane. The isolated crude product was used in the next reaction step after drying in vacuo. Yield: 19 g.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH3:29])=[CH:8]2)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH3:29])[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(-c3cccnc3)c2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-methyl-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (95 mg, 0.24 mmol), glycine (2.85 g, 38 mmol) and NaOMe solution (57 mL, 28 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 3 with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 71 mg of the title compound as a yellow solid. MS: (+) m/z 445.11 (M+1).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29].Cl>O.CO>[CH3:28][C:27]1[C:20]2[C:19]([CH2:18][N:11]3[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[C:10]3=[O:29])=[CH:23][S:22][C:21]=2[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc2scc(Cn3c(=O)n(CCC(=O)O)c4ccccc43)c12
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Lithium hydroxide monohydrate (99 mg, 2.4 mmol) is dissolved in water (12 mL) and this solution is added into 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester (600 mg, 1.6 mmol) in methanol (12 mL) at room temperature. The mixture is stirred for 2 hr and then 1.0 M HCl aqueous solution (3 mL) is added along with water (100 mL). Then the mixture is extracted with EtOAc (3×100 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give about 560 mg (97%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid which is used in the next step without further purification.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]([CH2:17][CH2:18][CH2:19][C:11]=2[CH:10]=1)=O.[C-]#N.[Li+]>O1CCCC1.CN(C)C=O>[C:5]([C:15]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=2)[CH2:19][CH2:18][CH:17]=1)#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [C-]#N
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC=C2C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
Trimethylsilylcyanide (50.0 g, 510 mmol) was added to a suspension of 75.0 g (430 mmol) of 6-methoxy-α-tetralone (commercially available from Aldrich Chemical Company) in 75 mL of anhydrous tetrahydrofuran (THF) at ambient temperature. Lithium cyanide (100 mL of a 0.5M solution in N,N-dimethylformamide (DMF)) was added to the resultant mixture in one portion. The reaction mixture was stirred at ambient temperature for 1.5 h and then the THF was removed under reduced pressure. The concentrate was partitioned between diethyl ether and water (5:1 v/v). The aqueous layer was extracted with diethyl ether and the combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 400 mL of anhydrous toluene, containing 15 g of p-toluenesulfonic acid, previously refluxed in order to remove residual water by azeotropic distillation. The mixture was heated at reflux (with a Dean Stark trap) for 1 h. The resultant solution was cooled to ambient temperature and washed with cold 1N aqueous sodium hydroxide solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel eluted with 10% ethyl acetate in hexane to afford 48.09 g (60% yield) of the title compound. The physical properties of the product were identical to the properties reported for this compound by F. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2 (1985).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: NCCCSc1ccncc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 0.30 ml (3.48 mmol) of propionyl chloride and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 483 mg of the desired compound (74.2%, yellow prisms), mp: 50.0°-51.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: N#Cc1ccc(OCC(=O)O)c(Br)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(C#N)cc1Br
Yield: 28.1 %

Procedure:
A solution of (2-bromo-4-cyano-phenoxy)-acetic acid (910 mg, 3.5 mmol) and benzoic acid N′-isopropyl-hydrazide (749 mg, 4.2 mmol) in DMF (20 ml) was treated with diisopropylethyl amine (1.52 mL, 8.75 mmol) and PyBroP (2.45 g, 5.25 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (410 mg, 0.9849 mmol, 28%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([OH:11])=[C:5]1[CH3:12].[CH2:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:14]#[CH:15]>>[CH2:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][N:4]2[CH:9]=[CH:8][C:7](=[O:10])[C:6]([OH:11])=[C:5]2[CH3:12])[CH2:18][CH2:17]1)[C:14]#[CH:15]
Reactant: Cc1c(O)c(=O)ccn1CCCl
Reactant: C#CCN1CCNCC1
Product: C#CCN1CCN(CCn2ccc(=O)c(O)c2C)CC1

Procedure:
The title compound was prepared as described in Scheme D by reaction of N-(2-chloroethyl)-2-methyl-3-hydroxy-4-pyridinone (H2, Appendix VII) (prepared as described in Bijaya L. Rai, Lotfollah Dekhordi, Hicham Khodr, Yi Jin, Zudong Liu, and Robert C. Hider J. Med. Chem. 1998, 41, 3347-3359) with N-propargylpiperazine (obtained as in step (iii) in Example 2):
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1([C:13]([O:15][CH3:16])=[O:14])[C:11](=[O:12])[CH:10]=[CH:9][S:8]1>C(O)(=O)C>[OH:12][C:11]1[CH:10]=[C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[S:8][C:7]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: c1cn[nH]c1
Solvent: CC(=O)O
Product: COC(=O)c1sc(-n2cccn2)cc1O
Reaction time: 48 h

Procedure:
Pyrazole (18 mmol) was added to a solution of 2-chloro-2-methoxycarbonylthiophene-3(2H)-one in acetic acid (10 ml). The mixture was allowed to stand at room temperature for 2 days and the precipitate filtered, m.p. 162°-164° C. (acetic acid).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14].CCCCCC.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])(=[O:24])[CH3:23]
Reactant: CC=CC=CCCCCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C/C=C/C=C/CCCCCCCCCOC(C)=O

Procedure:
The 2.4 g of tetradecadienol was dissolved in 55 ml of pentane containing 30 μl of thiophenol in a 100-ml round bottom flask. The flask was heated with a water bath, and the pentane was distilled off. Then a reflux condenser was connected to the flask, and the mixture was heated at 100° C. for 2 hours. The residue was dissolved in 600 ml of heptane which was removed by a rotary evaporator. The thiophenol was removed simultaneously. The yield of isomerized tetradecadienol was 2.01 g (84%). The isomer content by GC analysis was 62% EE, 19% EZ, 15% ZE, 4% ZZ. The tetradecadienol was recrystallized twice at low temperature from pentane to give 0.83 g of a product of 96.2% EE. 10,12-Tetradecadienol in 75 ml pyridine and 5 ml acetic anhydride was refluxed 1.5 hours. After the solution was cooled, 200 ml hexane was added, and the mixture was extracted successively with water, 6N hydrochloric acid (twice), and water. The pentane phase was dried over sodium sulfate, filtered, and the pentane was removed by rotary evaporation, leaving crude product, which was purified by silica gel liquid chromatography (elution in 10% ether/hexane); the yield was 1.0 g (94% based on the alcohol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[CH3:19].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[CH3:19][C:3]1[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:7][C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1-c1ccccn1
Temperature: 116 °C

Procedure:
To a reaction vessel under argon containing 2-(6-bromo-5-methylpyridin-2-yl)isoindoline-1,3-dione (85 mg, 0.27 mmol), 2-(tributylstannyl)pyridine (123 mg, 0.32 mmol), Pd(PPh3)4(31 mg, 0.027 mmol) is added anhydrous toluene (0.7 ml). The mixture is heated to 116° C. with an oil bath for 18 hours, cooled to room temperature, diluted with ethyl acetate and filtered through a celite pad to remove any solids. The filtrate is concentrated to afford 2-(3-methyl-2,2′-bipyridin-6-yl)isoindoline-1,3-dione as a brown solid (LC-MS m/z: 316.1 (M+1)) which is used without further purification in the next step.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=4[O:23][CH:24]([CH2:29][CH2:30][CH3:31])[C:25](=[N:27][OH:28])[NH2:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:44](OCC)=[O:45]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=4[O:23][CH:24]([C:25]4[NH:26][C:44](=[O:45])[O:28][N:27]=4)[CH2:29][CH2:30][CH3:31])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=NO
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)c1noc(=O)[nH]1
Yield: 47.5 %

Procedure:
2-{2-{[2-(4-tert-Butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanamide oxime (240 mg) and triethylamine (61 mg) were dissolved in tetrahydrofuran (3 ml). To this solution was added a solution of ethyl chloroformate (65 mg) dissolved in tetrahydrofuran (1 ml) under ice-cooling. The reaction mixture was stirred for fifteen minutes, filtered, and concentrated. The resulting material was dissolved in xylene (4 ml) and 1.8-diazabicyclo[5.4.0]undec-7-ene (152 mg) was added. The mixture was stirred at 50° C. for three hours. The mixture was cooled, diluted with toluene, and washed successively with 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. The crude material was purified on a silica gel column eluting with a mixed solvent of methylene chloride and methanol (1% vol.) to give partially purified product which was again purified on a silica gel column eluting with a mixed solvent of toluene and ethyl acetate (6:1) to give 3-{1-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}butyl}-1,2,4-oxadiazoline-5-one (120 mg).
Reaction SMILES: [CH3:1][C:2]([OH:16])([C@H:4]([CH3:15])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:3].[CH3:17][Si:18]([CH3:25])([CH3:24])N1C=CN=C1>CN(C)C=O>[CH3:17][Si:18]([CH3:25])([CH3:24])[O:16][C:2]([CH3:1])([CH3:3])[C@H:4]([CH3:15])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C(C)(C)O
Reactant: C[Si](C)(C)n1ccnc1
Solvent: CN(C)C=O
Product: C[C@H](CS(=O)(=O)c1ccccc1)C(C)(C)O[Si](C)(C)C
Temperature: 80 °C
Yield: 96 %

Procedure:
The compound of Example 10B (0.95 g, 3.9 mmol) was dissolved in 3 mL of dimethylformamide; 1 mL of 1-(trimethylsilyl)imidazole was added, and the resultant solution was stirred overnight at ambient temperature, then heated at 80° C. for 8 hours. The crude mixture was partitioned between ethyl acetate and water; the organic phase was washed with brine and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 0% to 20% ethyl acetate in hexanes to provide the titled compound (1.18 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:19].C(N(CC)CC)C>ClCCl>[CH3:17][C:12]1[O:11][N:10]=[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]=1[C:14]([NH:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([O:20][CH2:18][CH3:19])=[O:29])=[O:15]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2-Chloro-6-fluorophenyl)5-methylisoxaz-4-oyl chloride (7.9 g, 29.0 mmol) was added in portions to a stirred solution of ethyl-3-aminobenzoate (4.0 g, 29.0 mmol) and triethylamine (4.04 mL, 29.0 mmol) in dry dichloromethane at 0° C. Following the final addition, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The solution was washed with 0.5M aqueous hydrochloric acid, brine, aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated to a foam which was used in subsequent reactions without further purification.