Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4
Reactant: COC(=O)CCCBr
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound J5, 30 mg, 0.099 mmol), 4-bromo-butyric acid methyl ester (24.9 μl, 0.198 mmol) and cesium carbonate (64.5 mg, 0.198 mmol) were dissolved in DMA (0.20 ml) and stirred at room temperature for 4 hr. Water was added to the reaction solution, which was then extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The yellow solid obtained after concentration under reduced pressure was purified by silica gel column chromatography (methylene chloride/MeOH) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-butyric acid methyl ester as an intermediate.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>C(O)(=O)C>[ClH:25].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccccc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(Oc3ccccc3)cc2C1

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-phenoxyindan (120 mg, 0.36 mmol), 4N hydrochloric acid-dioxane (1.7 ml) and acetic acid (5.1 ml), a similar procedure to Example 24 was carried out to obtain 2-amino-5-phenoxyindan hydrochloride (99 mg, 0.36 mmol) having the following physical properties:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[F:20][CH:21]([F:25])[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[F:20][CH:21]([F:25])[C:22]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:23]
Reactant: COc1nccc(I)c1-c1cc2ccc(N)cc2[nH]1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(I)c1-c1cc2ccc(NC(=O)C(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of 2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (30 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added 2,2-difluoroacetic acid (12 mg, 0.12 mmol) and HATU (47 mg, 0.12 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2,2-difluoro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-acetamide (24 mg, 67%) as a white solid. MH+ 443.9.
Reaction SMILES: FC1C=CC([C:8](C2C=CC(F)=CC=2)=[C:9](C2N(C(C)C)N=NN=2)[CH:10]=[O:11])=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:35]([C:38]2[N:39]=[N:40][N:41]([CH:43]([CH3:45])[CH3:44])[N:42]=2)C=O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:35]([C:38]2[N:39]=[N:40][N:41]([CH:43]([CH3:44])[CH3:45])[N:42]=2)[CH:8]=[CH:9][CH:10]=[O:11])=[CH:30][CH:29]=1
Reactant: CC(C)n1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: CC(C)n1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)n1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 82 %

Procedure:
The general procedure of Example 23, Step A was repeated, except that the 3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenal utilized therein was replaced by 3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenal and there was thereby produced mostly 5,5-bis(4-fluorophenyl)-4-[2-(1-methylethy)-2H-tetrazol-5-yl]-2,4-pentadienal in 82% yield; MS (CI): m/e=381 for (M+H)+. This product was then subjected to the general procedure of Example 23, Step B and there was thereby produced ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate containing some inseparable rthyl 7,7-bis(4-fluorophenyl)-5-hydroxy-6-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6heptenoate in 69% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC(N(C)C)=O.CCOC(C)=O>[C:8]([C:7]1[C:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(N3CCOCC3)c(C#N)cn1)CCC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 60 mg, 0.155 mmol) and morpholine (500 μl, 5.74 mmol) were dissolved in DMA (1 ml) under argon. The mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, diluted in EtOAc and washed 2× with NH4Cl aq sat and 1× with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) followed by reverse phase chromatography (4.3 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.13 min; ESI-MS 439.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][CH:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:13]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCCc2ccccc21
Temperature: 60 °C
Yield: 74741.8 %

Procedure:
13.8 g (0.1 mmol) of 1,2,3,4-tetrahydroquinoline was dissolved in 60 ml of N,N-dimethylformamide, followed by the addition of 21.1 g (0.124 mmol) of isopropyl iodide and 20.6 g (0.208 mol) of potassium carbonate. The obtained mixture was stirred under heating at 60° C. for 5 hours. Water was added to the resulting reaction mixture, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (3% ethyl acetate/n-hexane) to give 13.1 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:16]=[CH:17][CH:18]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.CN([CH:27]=[O:28])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[N:5]2[N:16]=[CH:17][C:18]([CH:27]=[O:28])=[C:4]2[N:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc2ccnn12
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc2c(C=O)cnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To tert-butyl 5-chloropyrazolo[1,5-a]pyrimidin-7-ylcarbamate (3.7 g, 13.8 mmol) in DMF (36 mL), POCl3 (7.7 mL, 82.9 mmol) was added dropwise at 0° C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 8 hours. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water then the solid was collected by filtration. The solid was washed several more times with water and dried under vacuum overnight. The product, tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylcarbamate, was collected as a solid in 27% yield. The product did not ionize on LCMS unless first deprotected using TFA/DCM (1:1). LCMS (M+1=197)
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][OH:8])[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)N1CCNCC1
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: CCO
Product: CCOC(=O)N1CCN([C@H](CO)c2ccccc2)CC1
Yield: 25.3 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer, 15 g (125 mmoles) of (R)-phenyloxirane, 19.75 g (125 mmoles, 18.3 ml) of ethyl-N-piperazine carboxylate, and 80 ml of ethyl alcohol were introduced. The mixture was heated at reflux for 3 hours. Volatile substances were removed under reduced pressure and the resulting mixture was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/aqueous ammonia 98.5/1.5/0.5 (v/v/v)), affording 8.8 g of (S)-4-(2-Hydroxy-1-phenyl-ethyl)-piperazine-1-carboxylic acid ethyl ester (compound 2) as a colorless oil. Yield: 25%.
Reaction SMILES: CC([N:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Br:19])=[CH:16][C:15]([O:20][CH3:21])=[CH:14][C:13]=2[F:22])C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:19][C:18]1[C:17]2[C:12](=[C:13]([F:22])[CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]=[CH:10][C:9]=1[NH2:5]
Reactant: COc1cc(F)c2ncc(N(C(=O)[O-])C(C)(C)C)c(Br)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c2ncc(N)c(Br)c2c1
Yield: 100.2 %

Procedure:
1,1-Dimethylethyl[4-bromo-8-fluoro-6-(methoxy)-3-quinolinyl]carbamate (6.4 g, 17.3 mmol)) was treated with trifluoroacetic acid (50 ml) in dichloromethane (50 ml) at room temperature for two hours then evaporated to dryness. The residue was basified with sodium bicarbonate. A precipitate was formed which was filtered and dried in vacuo to afford the product as a white solid (4.7 g, 100%). MS (+ve ion electrospray) m/z 272 (MH+).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:18][C:19]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:20]=1[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:19]=1[CH2:18][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)#[N:22]
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)c(C#N)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)cc2C#N)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-(hydroxymethyl)-5-methylbenzonitrile according to the procedure for the preparation of Example 125, part B. 1H NMR (400 MHz, CDCl3): δ 3.40 (3H, s), 3.97 (3H, s), 5.40 (2H, s), 5.83 (1H, d, J=1.2 Hz), 7.43 (1H, d, J=8.8 Hz), 7.50 (1H, s), 7.58-7.62 (2H, m), 7.76 (1H, d, J=5.2 Hz), 8.33 (1H, s), 8.68 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H16N4O3, 349. Found, 349.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:22][CH3:23])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].OS(O)(=O)=O>O1CCOCC1.O>[OH:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:22][CH3:23])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COc1cc(C2CCCCC2)ccc1C(=O)CCC(=O)O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C2CCCCC2)ccc1C(O)CCC(=O)O
Reaction time: 5 h

Procedure:
1.06 g of NaBH4 in 90 ml of dioxane-water (1:1) are added dropwise with stirring at room temperature to 1.16 g of 4-oxo-4-(4-cyclohexyl-2-methoxyphenyl)-butyric acid in 200 ml of dioxane-water (1:1). This is left to stand for 5 hours at 22° and then acidified with 2N H2SO4 to pH=2. Most of the dioxane is removed on rotary vapouriser and the aqueous solution is extracted three times with ethyl acetate. The organic phases are washed once with water, dried over Na2SO4 and concentrated. The residue is recrystallised twice from ether-petroleum-ether. M.p. 105°-106°.
Reaction SMILES: Br[C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[O:7]2.[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:15][C:6]1([CH3:16])[CH2:5][CH2:4][C:3]2[C:8](=[C:9]([CH3:14])[C:10]([CH3:13])=[C:11]([OH:12])[C:2]=2[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=2)[O:7]1
Reactant: Cc1c(C)c2c(c(Br)c1O)CCC(C)(C)O2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C)c2c(c(-c3cccc([N+](=O)[O-])c3)c1O)CCC(C)(C)O2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2,2,7,8-tetramethyl-chroman-6-ol (400 mg, 1.40 mmol), 3-nitrophenyl boronic acid (300 mg, and Pd(PPh3)4 (100 mg, 5% mol) in glycol dimethyl ether (DME, 20 mL) and 2M Na2CO3 solution (5 mL) was stirred at 120° C. for 3-5 h. After pouring it into water, the mixture was extracted with EtOAc. The EtOAc layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 10% EtOAc in hexane to give a yellow solid (140 mg). 1H NMR (300 MHz, CDCl3): 8.25-8.16 (μ, 2H), 6.76 (μ, 2H), 4.13 (σ, 1H, OH), 2.27 (μ, 2H), 2.21, 2.19 (2ρ, 6H), 1.68 (μ, 2H), 1.32 (σ, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 167.36, 148.79, 145.85, 143.34, 138.27, 136.95, 130.10, 126.51, 125.56, 122.76, 122.29, 115.84, 73.10, 32.83, 27.07, 26.71, 12.95, 12.24, 12.14 ppm. MS: m/z: 328 (MH+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:37]([C:34]3[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, white solid (92 mg, 70%), MS (ISP) m/z=523.6 [(M+H)+], mp 171° C., was prepared in accordance with the general method of example 36 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butyl-benzenesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[CH2:12][CH2:13]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ncccn3)CC2)nc1
Temperature: 80 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (500 mg, 3.2 mmol) and 2-piperazin-1-yl-pyrimidine (520 mg, 3.2 mmol) in DMF (15 mL) was added diisopropylethylamine (2.70 mL, 15.5 mmol). The mixture was heated in a sealed tube at 80° C. for 24 hours. The mixture was concentrated to dryness and triturated in methanol to give 2-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-pyrimidine. The NMR spectrum on this sample is compatible with its structure.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH3:9])=[C:6]([CH3:10])[N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(C#N)c(O)nc1C
Product: Cc1cc(C#N)c(Cl)nc1C
Yield: 53.6 %

Procedure:
An intimate mixture of 3-cyano-5,6-dimethyl-2-hydroxypyridine (42 g) and phosphorus pentachloride (81 g) was heated at 140°-160° for 2 hours. Phosphoryl chloride was removed by distillation under reduced pressure and icewater (500 g) was added to the residue. The mixture was adjusted to pH 7 with aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to an oil which was crystallised from ether/petroleum ether (b.p. 60°-80°) to give 2-chloro-3-cyano-5,6-dimethylpyridine (25.3 g) m.p. 83°-87°.
Reaction SMILES: [OH:1][CH:2]([C:30]1[O:31][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:33][N:34]=1)[CH:3]([NH:6][C:7](=[O:29])[C:8]([CH3:28])([S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16]O[CH2:14][CH2:13]1)=[O:11])[CH2:4][CH3:5].[CH3:41]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[O:11]=[C:10]([N:12]1[CH2:17][CH2:16][CH2:41][CH2:14][CH2:13]1)[CH2:9][C:8]([CH3:28])([S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])=[O:20])[C:7]([NH:6][CH:3]([C:2]([C:30]1[O:31][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:33][N:34]=1)=[O:1])[CH2:4][CH3:5])=[O:29]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCC(NC(=O)C(C)(CC(=O)N1CCOCC1)S(=O)(=O)Cc1ccccc1)C(O)c1nnc(-c2ccncc2)o1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CCC(NC(=O)C(C)(CC(=O)N1CCCCC1)S(=O)(=O)Cc1ccccc1)C(=O)c1nnc(-c2ccncc2)o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (222.7 mg, 0.45 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2SO3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 78 mg of 4-oxo-2-benzylsulfonyl-methyl-4-piperidin-1-yl-N-[1-(5-pyridin-4-yl-[1,3,4]oxadiazole-2-carbonyl)-propyl]-butyramide; H1 NMR(DMSO-d): 9.0–8.85(3H, m), 8.1–8(2H, m), 7.44–7.3(5H, m), 5–4.9(1H, m), 4.5–4.3(2H, m), 3.6–3.2(11H, m), 3.15–3.05(1H, m), 2.7–2.5(1H, m), 2.05–1.9(1H, m), 1.8–1.7(1H, m), 0.96(3H, t); MS: 568.6(M−1), 570.6(M+1).
Reaction SMILES: N[C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([O:26][CH3:27])[CH:5]=2.C(O)=[O:29]>>[C:12]([CH:11]1[CH:10]([C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]([O:26][CH3:27])=[CH:7][CH:8]=2)[O:3][C:2]1=[O:29])#[N:13]
Reactant: O=CO
Reactant: COc1ccc2c(c1)OC(N)=C(C#N)C2c1cc(OC)c(OC)c(OC)c1
Product: COc1ccc2c(c1)OC(=O)C(C#N)C2c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-3-cyano-7-methoxy-4-(3,4,5-trimethoxyphenyl)-4H-chromene (260 mg, 0.7 mmol) was dissolved into approximately 5 mL of formic acid. The obtained white suspension was stirred approximately 1 h at room temperature until it solubilized. The solvent was evaporated. The residue was dissolved into ethyl acetate (20 mL), washed with sodium bicarbonate saturated solution (2×20 mL), brine (20 mL), dried over sodium sulfate and concentrated to give approximately 210 mg of a mixture of diastereoisomers. 1H NMR (CDCl3): 7.12 (d, J=8.2 Hz, 0.5H), 6.82-6.67 (m, 2.5H), 6.41 (s, 1H), 6.37 (s, 1H), 4.48-4.43 (m, 1H), 4.25-4.02 (m, 1H), 3.86-3.78 (4s, 12H)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][N:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[C:22]#[N:23])[CH2:35][CH2:34]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N1CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-(2-cyanophenyl)piperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=473.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:8]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCCCC1

Procedure:
The title compound was synthesized from 2-(4-(trifluoromethyl)phenyl)-acetonitrile (4.11 g, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J and was obtained as a clear oil (4.98 g, 89%). 1H NMR (CDCl3) δ 1.23-1.39 (m, 1H), 1.76-1.92 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.63 (s, 4H). 13C NMR (CDCl13) δ 23.7, 25.0, 37.4, 44.7, 122.2, 126.0, 126.7, 130.2, 145.6,GC-MS m/z 253.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:13])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[CH:14](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([O:13][CH3:14])=[CH:11][N:12]=1)[C:8]#[N:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(C#N)c(O)cn1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COc1cnc(C(C)(C)C)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 2-tert-butyl-5-hydroxy-isonicotinonitrile (10.0 g, 73.5 mmol) in acetonitrile/methanol (9:1, 20 mL) was added N,N-diisopropylethylamine (1.48 mL, 8.52 mmol) followed by (trimethylsilyl)diazomethane (2.0M in hexane, 4.30 mL, 8.52 mmol). The red solution was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was dissolved in methylene chloride, washed with saturated aqueous NaHCO3 dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-tert-butyl-5-methoxy-isonicotinonitrile (1.10 g, 99%) as a pale yellow oil which was utilized without further purification.