Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH3:17])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: CCC1CCCCN1c1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1CCCCN1c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 5-bromo-2-(2-ethylpiperidin-1-yl)benzaldehyde (obtained in step 1, 10 g, 0.0484 mol) in methanol (100 mL) under nitrogen, was added sodium borohydride (1.28 g, 0.0484 mol) at 0° C. in portions. After being stirred at room temperature for a period of 1 h, the reaction mixture was evaporated to remove methanol. The resulting crude product was taken in water (100 mL) and extracted in ethyl acetate. The separated organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to afford the titled compound as yellow liquid (8.8 g, 88%). 1H NMR (DMSO-d6, 400 MHz) δ 7.54-7.55 (1H, s), 7.34-7.54 (1H, m), 7.07-7.09 (1H, d), 5.17-5.20 (1H, t), 4.59-4.64 (1H, d), 4.43-4.48 (1H, d), 2.77-2.84 (2H, m), 2.442-2.449 (1H, m), 1.74 (2H, t), 1.53-1.56 (2H, t), 1.32-1.34 (2H, m), 1.15-1.19 (2H, m), 0.60-0.64 (3H, t).
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[N+:6]([CH3:9])([O-:8])=[O:7].[F-].[K+]>C1COCC1>[N+:6]([CH2:9][CH2:2][CH2:1][C:3](=[O:4])[CH3:5])([O-:8])=[O:7]
Reactant: C=CC(C)=O
Reactant: C[N+](=O)[O-]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)CCC[N+](=O)[O-]
Yield: 93.2 %

Procedure:
Methyl vinyl ketone (4.17 ml, 0.05 moles), nitromethane (24.4 ml, 0.45 moles) and THF (250 ml) were mixed and stirred together under nitrogen. Potassium fluoride on alumina (10 g) was added and the mixture stirred for 2 hours at ambient temperature. The reaction was filtered and the filtrate was evaporated to give crude 5-nitro-2-pentanone as a pale yellow oil (6.11 g, 93%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.[CH3:12][C:13](OC(C)=O)=[O:14].N1C=CC=CC=1>ClCCl>[C:13]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][CH:9]=1)(=[O:14])[CH3:12]
Reactant: CCCCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10 g of 4-n-butylphenol, 10 ml of Ac2O and 8 ml of pyridine is stirred at reflux in 10 ml of dichloromethane. After 2 hours, the medium is cooled to ambient temperature, diluted in dichloromethane, washed with water, washed with a 1M HCl solution, washed in a saturated CuSO4 solution, washed with water, and dried over MgSO4. After evaporation, 10.8 g of the expected compound are recovered in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[C:27]2[N:26]=[CH:25][N:24]=[C:22]([NH2:23])[C:21]=2[N:20]=[CH:19]1.C[Si](Cl)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[NH4+]>N1C=CC=CC=1.O>[C:33]([NH:23][C:22]1[C:21]2[N:20]=[CH:19][N:18]([C:27]=2[N:26]=[CH:25][N:24]=1)[C@@H:11]1[O:12][C@H:13]([CH2:16][OH:17])[C@@H:14]([OH:15])[C@H:10]1[O:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[O:2][CH3:1])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CO[C@@H]1CCCC[C@H]1O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CO[C@@H]1CCCC[C@H]1O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2′-O-(trans-2-methoxy-cyclohexyl)adenosine (0.056 mol) in pyridine (100 mL) is evaporated under reduced pressure to dryness. The residue is redissolved in pyridine (560 mL) and cooled in an ice water bath. Trimethylsilyl chloride (36.4 mL, 0.291 mol) is added and the reaction is stirred at 5° C. for 30 minutes. Benzoyl chloride (33.6 mL, 0.291 mol) is added and the reaction is allowed to warm to 25° C. for 2 hours and then cooled to 5° C. The reaction is diluted with cold water (112 mL) and after stirring for 15 min, concentrated ammonium hydroxide (112 mL). After 30 min, the reaction is concentrated under reduced pressure (below 30° C.) followed by coevaporation with toluene (2×100 mL). The residue is dissolved in ethyl acetate-methanol (400 mL, 9:1) and the undesired silyl by-products are removed by filtration. The filtrate is concentrated under reduced pressure and purified by silica gel flash column chromatography (800 g, chloroform-methanol 9:1). Selected fractions are combined, concentrated under reduced pressure and dried at 25° C./0.2 mmHg for 2 h to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9]OC(=O)CC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].[SH:27][C:28]1[S:29][C:30]([CH3:33])=[N:31][N:32]=1>O>[NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:27][C:28]3[S:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
In water (30 ml) was dissolved 7β-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (3.14 g) together- with sodium hydrogen carbonate (1.84 g) and 2-mercapto-5-methyl-1,3,4-thiadiazole (1.6 g) and the resultant solution was adjusted its pH to 6.4, followed by stirring for one hour at 60° C. After cooling, the reaction solution was washed with dichloromethane and pH of the aqueous layer was adjusted to 3.5 under ice-cooling, followed by stirring for one hour. The precipitated materials were collected by filtration and washed with water, methanol and acetone in this order, followed by drying to give 7β-amino-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.9 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:27]([C:26]4[C:22]([CH3:21])=[N:23][O:24][C:25]=4[CH3:30])=[O:28])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Reactant: Cc1noc(C)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(C)c1C(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a solution of 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36, 0.047 g, 0.177 mmol) in DMF (1 mL) were added 3,5-dimethylisoxazole-4-carboxylic acid (0.037 g, 0.266 mmol) and TBTU (0.063 g, 0.195 mmol) followed by Hünig's base (0.048 g, 0.372 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was purified directly by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH—H2O (0.05% TEA) gradient to give the title compound (0.041 g, 59%) as a colorless solid. MS: 391.3 (M+H+).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>ClCCl>[C:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: C=CC(=O)OC1CCCCO1
Yield: 26 %

Procedure:
A solution of 10.5 g (146 mmol, 10 ml) acrylic acid and 14.0 g (166 mmol, 15.2 ml) dihydropyran in 40 ml dichloromethane was stirred at room temperature for one day. The mixture was washed with saturated aqueous sodium bicarbonate and the organic layer was concentrated in vacuo. The residue was distilled to give 5.93 g (38.0 mmol, 26% yield) tetrahydropyran-2-yl acrylate, bp 40° C. at 0.2 torr.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH:20]=[CH2:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:27]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:27])[CH:16]([CH:20]=[CH2:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=O
Reactant: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Solvent: O=CO
Product: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1C

Procedure:
A mixture of 200 mg of 1-cyclopropyl-7-(3-ethenyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.3 ml of 90% formic acid and 0.24 ml of 37% formalin is heated for 2 hours, then evaporated. The residue is diluted with water, neutralized to pH 7 with 1N sodium hydroxide, the solid collected, and washed with water, ether and dried in vacuo, giving 150 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]O)[C:7]=2[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][I:34])[C:7]=2[CH:14]=1
Reactant: II
Reactant: COc1ccc2occ(CCO)c2c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2occ(CCI)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(5-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was then extracted with chloroform, washed well with 5% Na2S2O3 and the organic layer dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as a brown liquid. Yield: 1.1 g (73%); (M+H): 302.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6](=[S:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[NH2:17][C:3]1[C:4](=[O:16])[NH:5][C:6](=[S:15])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1ccccn1
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N)n(Cc2ccccn2)c(=S)[nH]c1=O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
6-Amino-1-(pyridin-2-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.60 g, 2.56 mmol, obtained from Example 1(b)) was dissolved in acetic acid (90% aq., 10 mL) and was heated at 75° C. for 5 minutes. Sodium nitrite (0.20 g, 2.95 mmol) was added and heating was continued for another 30 minutes. The solvent was removed in vacuo and the residue was suspended in water (6 mL), and ammonia (32% aq., 6 mL) was added. The reaction mixture was heated at 75° C. and sodium dithionite (1.1 g, 6.4 mmol) was added and the resulting mixture was continued stirring at 75° C. for 5 minutes, and then stirred at r.t. for 30 minutes. After adjusting the solution to neutral pH with 2M sulfuric acid the precipitated solid was collected by filtration, washed with a small amount of water and dried, giving the title compound (0.331 g, 52%) as a solid. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)NCC2
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Yield: 28 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-26b: 400 mg, 2.259 mmol) was reacted with 3-iodo-4-methyl-pyridine (495 mg, 2.259 mmol), 1,4-dioxane (25 mL), copper iodide (43 mg, 0.225 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (96.23 mg, 0.677 mmol) and potassium phosphate (1.197 g, 5.647 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 170 mg of the product (23% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)[CH:31]=[CH:32][C:27]=1[F:26])=[O:37]
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: COC(=O)c1cc(B(O)O)ccc1F
Product: COC(=O)c1cc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)ccc1F

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and (4-fluoro-3-methoxycarbonylphenyl)boronic acid was prepared the title compound as a yellow oil, MS (ESI+): m/z=468.1977 ([M+H]+).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]=1[NH:17][C:18](=[O:35])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[O:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[NH:17][C:18](=[O:35])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[O:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C)cc1OC

Procedure:
3.0 ml (6.0 mmol) of a 2 N aqueous aqueous solution of sodium hydroxide were added to a solution of 1.11 g (2.34 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(2-methoxy-4-methylphenyl)octanamide [prepared as described in step (ii) above] in 30 ml of methanol, and the resulting mixture was heated under reflux for 1 hour, after which the solvent was removed by distillation under reduced pressure. The resulting residue was acidified with 1 N aqueous hydrochloric acid, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, giving 1.02 g (a quantitative yield) of the title compound as crystals, melting at 163.5-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: CCCCC/C(=C/C=C/C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
As in Example 115. (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid (2.8 g) and 4-nitrophenol (1.71 g) in 20 mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (2.1 g). The mixture was stirred at room temperature for 18 hours and the usual work up furnished 4.0 g of (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([C:3](=[O:2])[NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: CN(C)CCN
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 76.1 %

Procedure:
Thus CO was bubbled through a mixture of Intermediate 147(d) from Example 147 (1.5 g, 3.97 mmol), triethylamine (1.1 mL, 7.92 mmol), N,N-dimethylethylenediamine (0.7 g, 7.94 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.65 g, 0.796 mmol) in N,N-dimethylformamide (30.0 mL). Reaction conditions, work up and silica gel chromatography (eluted with 46:4:25 dichloromethane:methanol:ethyl acetate) were also carried out in an analogous manner and afforded the title compound (1.25 g, 3.02 mmol) in 76% yield.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[F:25])[NH:4][CH:3]=1.C([Li])CCC.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])=[CH:14][C:13]=2[F:25])[N:4]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1ccc(Cc2ccnc3[nH]cc(Br)c23)c(F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cc4ccc(NC(=O)C(F)(F)F)cc4F)ccnc32)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1.70 g (4.08 mmol) of N-{4-[(3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]-3-fluorophenyl}-2,2,2-trifluoroacetamide are dissolved in 50 ml of THF and cooled to −78° C. A solution of n-butyllithium (2.81 ml, 1.6M in hexane, 4.49 mmol) is added dropwise. After 15 min, a solution of 860 mg (4.49 mmol) of p-toluenesulfonyl chloride in 5 ml of THF is added dropwise. The mixture is allowed to warm to RT and stirred for 1 h. Water and saturated sodium bicarbonate solution are then added, and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase dichloromethane:ethanol=50:1).
Reaction SMILES: [OH:1][C:2]1([CH2:15][SH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[C:23](=[O:29])[CH:22]=[CH:21]2>C(#N)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25]([C:24](=[O:28])[C:23](=[O:29])[CH:22]=[C:21]2[S:16][CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)=[CH:26][CH:27]=1
Reactant: O=C1C=Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(O)(CSC2=CC(=O)C(=O)c3ccc(Cl)cc32)CC1

Procedure:
tert-butyl 4-{[(7-chloro-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylate was synthesized using tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate, 6-chloronaphthalene-1,2-dione, acetonitrile as the solvent and conditions outlined in procedure F [step (i)]. The intermediate was purified by flash column chromatography (SiO2, 30% EtOAc in hexanes to 50% EtOAc in hexanes).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[N:32][CH:31]=[N:30]1>O>[N+:1]([C:4]1[O:8][C:7]([C:9]([NH:37][CH2:36][CH2:35][CH2:34][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCCCn1cncn1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCn1cncn1)c1ccc([N+](=O)[O-])o1
Reaction time: 3 h

Procedure:
A mixture of about 4.71 g of 5-nitro-2-furoic acid, about 4.86 g of 1,1'-carbonyldiimidazole and about 100 ml of dry tetrahydrofuran was stirred in a 250 ml round bottom flask with a drying tube for about 3 hours. An approximately 4.0 g portion of 1H-1,2,4-triazole-1-propanamine was added and the mixture was stirred overnight at room temperature. The mixture was refluxed for about 3 hours, about 15 ml of water was added, refluxing continued for about 2 hours, then the mixture was concentrated to remove the solvents. An approximately 200 ml portion of methylene chloride and about 30 ml of 1N sodium hydroxide were added, the mixture was shaken and the organic layer separated and washed with two about 50 ml portions of water, then dried, filtered and evaporated to a solid. This solid was recrystallized from ethanol, giving about 290 mg of the desired product as beige crystals, mp 176°-177° C.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=[C:12]4[C:28]3[N:33]=[C:32]([CH:34]4[CH2:36][CH2:35]4)[CH:31]=[CH:30][N:29]=3)=[N:7][N:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.O>[CH:1]1([C:4]2[O:5][C:6]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[C:12]4[C:28]3[N:33]=[C:32]([CH:34]4[CH2:36][CH2:35]4)[CH:31]=[CH:30][N:29]=3)=[N:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: c1cc(C2CC2)nc(-c2c[nH]c3ccc(-c4nnc(C5CC5)o4)cc23)n1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
2-Cyclopropyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (78.6 mg, 0.158 mmol) in a 5 mL glass microwave tube, was suspended in dioxane (1.5 mL). The suspension was treated with NaOH 1.000 n (2 mL, 2.000 mmol) (Fluka Analytical). The tube was sealed and the contents were stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 10 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (0-10% MeOH in DCM) to give 2-cyclopropyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazole (19.2 mg, 0.056 mmol, 35.4%) as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 344.0 (M+1). 1H NMR (400 MHz, DMSO-d6) ppm 11.99 (br. s., 1H), 9.10 (s, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.28 (s, 1H), 7.77-7.84 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.20 (d, J=5.1 Hz, 1H), 2.29-2.38 (m, 1H), 2.09-2.20 (m, 1H), 1.12-1.33 (m, 8H).