Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH2:34][C:35]([F:38])([F:37])[F:36])[C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]4[CH2:31][CH2:32][CH2:33][C@H:28]([N:27]([CH3:26])[CH2:34][C:35]([F:36])([F:38])[F:37])[CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN(CC(F)(F)F)[C@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)CC(F)(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-methyl-N-(2,2,2-trifluoroethyl)piperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.92 (m, 4 H) 2.26-2.41 (m, 4 H) 2.59-2.80 (m, 2 H) 2.93-3.36 (m, 3 H) 3.55 (br. s., 1 H) 3.75-4.19 (m, 2 H) 4.36-4.54 (m, 1 H) 7.55-7.68 (m, 1 H) 7.71-7.78 (m, 1 H) 8.53 (s, 4 H). ESI-MS m/z [M+H]+ 517.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:22]2[CH2:24][CH2:23]2)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:10][CH:11]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[CH:22]1([C:7]2[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1cnc(-c2cccc(C(F)(F)F)c2)nc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1cnc(-c2cccc(C(F)(F)F)c2)nc1C1CC1

Procedure:
1.250 g (3.717 mmol) of the above prepared 4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 19 ml of abs. THF was cooled down to −15° C. and reacted with 11.2 ml of DIBAL-H-solution (1.0 M in toluene, 3 eq.) for 1/2 h. Careful quenching with ice/HCl dil., twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=1/1l) to yield finally 1.096 g of the title compound as white solid of mp. 108–09° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:16]CC)(=[O:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1>C(O)(C)(C)C>[CH2:13]([O:12][C:10](=[O:11])[C:9](=[CH:25][CH:22]1[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1)[CH2:8][C:7]([OH:16])=[O:15])[CH3:14]
Reactant: O=CC1CCCCC1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=CC1CCCCC1)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 11.2 g (0.1 mol) potassium tert-butoxide in 100 ml tert-butanol was added a mixture of 17.4 g (0.1 mol) diethyl succinate and 11.2 g (0.1 mol) cyclohexylcarboxaldehyde over a period of 30 min. The mixture was allowed to stir at room temperature for one hour and heated to 50° C. for an additional hour. The solvent was removed under reduced pressure, the residue was dissolved in 100 ml water and transferred into a separation funnel. The solution was extracted twice with 50 ml ethyl acetate to remove neutral impurities, acidified with 6M HCl and extracted again twice with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 18.9 g (79%) of a yellow brown oil. 1H-NMR: 66% E-isomer, 13% Z-isomer, 15% cyclohexenyl-isomer, 6% other unsaturated olefelinic compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[N:7]1([C:12](N2C=CN=C2)=[S:13])[CH:11]=[CH:10][N:9]=[CH:8]1>C(#N)C.O1CCCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:12]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[S:13]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccs1
Solvent: C1CCOC1
Solvent: CC#N
Product: S=C(Nc1nccs1)n1ccnc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To thiazol-2-amine (2.12 g, 21.17 mmol) in acetonitrile (30 mL) and tetrahydrofuran (5 mL) was added di(1H-imidazol-1-yl)methanethione (4.90 g, 27.5 mmol). The reaction was stirred at 60° C. for 5 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with cold acetonitrile (2×15 mL) to afford an orange-brown powder. The product, N-(thiazol-2-yl)-1H-imidazole-1-carbothioamide (3.70 g, 17.60 mmol, 83% yield), was taken directly to the next step without any further characterization.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=CC=1>[Cu]>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COc1cccc(Br)c1
Reactant: CCc1cccc(NC(C)=O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cccc(Nc2cccc(OC)c2)c1
Temperature: 200 °C
Reaction time: 72 h
Yield: 98.4 %

Procedure:
A mixture of 11 g of N-(3-ethylphenyl)acetamide, 9 g of copper powder, 19.8 g of potassium carbonate and 26.7 g of m-bromoanisole was stirred at 200° C. for 3 days. Insolubles were filtered off from the reaction mixture, and the filtrate was purified by silica gel column chromatography [ethyl acetate-hexane (1:3)]. To the resulting substance were added 16.6 g of potassium hydroxide, 8.7 ml of water and 170 ml of ethanol, and the whole was refluxed for 1 hour. The solvent was removed from the reaction mixture by evaporation, and water and ethyl acetate were added to the residue. After the organic layer was collected by separation, washed and dried, the solvent was removed by evaporation to afford 15.08 g of N-(3-ethylphenyl)-N-(3-methoxyphenyl)amine as an oil. IR (Nujol) (cm-1): 3400, 1600, 1490, 1460, MS (m/z): 227 (M+, base).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH3:31])[C:27]([O:29]C)=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:32].[Li+].[OH-].Cl>C1COCC1.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10](=[O:33])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH3:31])[C:27]([OH:29])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:32]
Reactant: COC(=O)C(C)NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cc(C(=O)NC(C)C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A mixture of Methyl 2-(3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxamido)propanoate (Example 101) (1.0 equiv.) and LiOH (3.0 equiv.) in 25 ml of 4:1 THF/water was stirred at room temperature for 15 min. The mixture was slightly acidified to pH <7 by adding 2N HCl and then the solvent was evaporated. The solid was suspended in water and filtered, given water washings and air-dried. The resulting solid was triturated with acetone and methanol and collected by filtration. This yielded the title compound as a white solid (43%) after drying in vacuo; 1H NMR (300 MHz, DMSO-d6) δ: 1.38-1.40 (d, J=7.2 Hz, 3H), 2.32 (s, 3H), 4.38-4.43 (m, 1H), 7.12-7.18 (m, 2H), 7.27-7.32 (m, 1H), 7.60 (S, 1H), 7.67-7.70 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 8.05-8.08 (d, J=8.7 Hz, 1H), 832 (s, 1H), 8.65 (s, 1H), 9.18-9.21 (d, J=7.2 Hz, 1H), 12.76 (brs, 1H); ms (ESI) m/z 445.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C@H:20]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[NH:22]1[CH2:23][CH2:24][C@H:20]([CH2:19][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN(Cc2ccccc2)C(=O)OCc2ccccc2)C1
Solvent: CC(=O)Cl
Solvent: CO
Product: O=C(OCc1ccccc1)N(Cc1ccccc1)C[C@H]1CCNC1
Yield: 95.2 %

Procedure:
tert-Butyl (S)-3-[N-benzyl-N-(benzyloxycarbonyl)aminomethyl]pyrrolidine-1-carboxylate (Intermediate 167, 11 g) was added dropwise to a solution of acetyl chloride (15 g) in methanol (50 mL) and the resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was purified by HPLC (C18) to give benzyl N—((S)-pyrrolidin-3-ylmethyl)-N-benzylcarbamate (8.0 g) as an off white solid which was used without further characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([O:6][CH2:7][C:8]#[N:9])=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]([CH3:12])[C:5]=1[O:6][CH2:7][C:8]#[N:9]
Reactant: Cc1cc(Cl)cc(C)c1OCC#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(CBr)c1OCC#N

Procedure:
(4-Chloro-2,6-dimethyl-phenoxy)-acetonitrile (700 mg, 3.6 mmol), N-bromosuccinimide (510 mg, 2.9 mmol) and benzoyl peroxide (72 mg, 0.29 mmol) are heated at reflux in carbon tetrachloride (10 mL) for 16 h. The reaction is cooled, filtered and the filtrate is concentrated and purified by column chromatograpy (silica, 5% ethyl acetate in hexanes) to provide the title compound. MS (EI) 273, 275 (M)+, Br pattern.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][O:35]C(=O)C)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=O)[CH2:4][CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:51]([NH2:55])[CH2:52][CH2:53][CH3:54].O>CN(C)C=O>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([NH:55][CH2:51][CH2:52][CH2:53][CH3:54])=[O:13])[CH2:4][CH2:3]1
Reactant: CCCCN
Reactant: CC(=O)OCCOc1ccccc1C1(O)CCN(CCC(C(=O)O)(c2ccccc2)c2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)C(CCN1CCC(O)(c2ccccc2OCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
In 5 mL of anhydrous dimethylformamide was dissolved 81 mg (0.17 mmol) of 4-(4-hydroxy-4-(2-(2-acetoxyethoxy)phenyl)piperidino)-2,2-diphenylbutyric acid. The resulting solution was stirred at room temperature for 1 hour. To the reaction mixture were added 36 mg (0.22 mmol) of carbodiimidazole, and after one hour 16 mg (0.22 mmol) of n-butylamine. After stirring at 70° C. for 24 hours, stirring was conducted for further 3 hours at 130° C., whereby the reaction was completed. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with water and drying. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on an alumina column and then chromatography on a silica gel column, whereby 35 mg (yield: 38.9%) of 4-(4-hydroxy-4-(2-(2-hydroxyethoxy)phenyl)piperidino)-N-butyl-2,2-diphenylbutaneamide (Compound No. 73) was obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=1
Reactant: Oc1cccnc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccnc1

Procedure:
Sodium hydride (7.15 g) was added portion-wise to a stirred solution of 3-hydroxypyridine (19 g) in dry dimethylsulphoxide (100 ml) during 1 hr. Ethyl bromoacetate (33.4. g) was added during 1 h. and water (250 ml) slowly added. The solution was extracted with chloroform (3×150 ml) and the combined extracts washed with 2 N sodium carbonate (75 ml) and dried (Na2SO4). Evaporation of the solvent gave a liquid which was distilled (120°-130°/0.1 mm) to yield the title compound (8.7 g).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[CH3:8].C([O-])C.[Na+].O>C1COCC1>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2([C:12]3[CH:11]=[CH:10][C:9]([CH2:7][CH3:8])=[CH:24][CH:23]=3)[O:14][CH:2]2[C:3]([O:5][CH3:6])=[O:4])=[CH:16][CH:17]=1)[CH3:22]
Reactant: CCc1ccc(C(=O)c2ccc(CC)cc2)cc1
Reactant: COC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C2(c3ccc(CC)cc3)OC2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A solution of 15 ml (168 mmol) of methyl chloroacetate and 20 g (84 mmol) of 4,4′-diethylbenzophenone in 20 ml of THF was added dropwise to a suspension of 9.1 g (168 mmol) of sodium ethanolate in 80 ml of THF at −10° C. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was added to water and extracted with ether. The organic phase was washed with sodium bicarbonate solution and citric acid solution and dried over magnesium sulfate, and the solvent was distilled off. 15.4 g of a crude oil were isolated and were immediately employed further.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6]
Reactant: C1CCNCC1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCl)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-Chlorobutyryl chloride in dichlormethane was added to an ice cooled solution of piperidine (1.8 ml; 17.6 mmol) and triethylamine (2.5 ml) in dichloromethane (40 ml) under an atmosphere of nitrogen. The mixture was stirred for 5 min whilst being cooled, then stirred at ambient temperature for 3 h. The solution was washed with water, dried over sodium sulfate and evaporated to give 1-(4-chloro-1-oxobutyl)piperidine as a pale yellow oil (2.1 g).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: c1ccc(-c2cccs2)cc1
Product: Fc1ccc(Br)cc1Cc1ccc(-c2ccccc2)s1

Procedure:
2-Phenylthiophene and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 347/349 (M+H).
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])Cl)([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([CH3:24])[CH3:23].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C1C=C2CNCCC2S1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](Oc1cc2c(s1)CCNC2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluenesulfonate, 1.29 g of triisopropylchlorosilane, 0.66 g of triethylamine and 7 ml of methylene chloride was stirred at room temperature for 3 hours. The produced 2-triisopropylsilyloxy-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine-p-toluenesulfonate was not isolated, 0.96 g of 2-chlorobenzyl chloride and 1.21 g of triethylamine were added thereto, and the mixture was allowed to react under further stirring at 40° C. for 10 hours.
Reaction SMILES: [NH2:1][C:2](=[N:33][OH:34])[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=2[O:29]C)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCl>[NH2:1][C:2](=[N:33][OH:34])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=2[OH:29])=[CH:31][CH:32]=1
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C(N)=NO)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C(N)=NO)cc2)c(O)c1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 4-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (200 mg, 0.4 mmol) in 4 mL of dichloromethane at 0° C. is treated with aluminum chloride (292 mg, 2.2 mmol) and ethanethiol (4 mL, 54 mmol). After stirring at 0° C. for 1 hour, reaction mixture is partitioned between ethyl acetate and saturated ammonium hydroxide solution. The organic phase is dried with magnesium sulfate and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (10 g) with 5% methanol/dichloromethane as the eluent to afford 4-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]-3-hydroxy-N,N-bis(1-methylethyl)benzamide as a colorless foam;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:28][N:29]([CH3:42])[CH2:30][CH2:31][NH:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[N:36]=1)=[O:34]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([C:33](=[O:34])[NH:32][CH2:31][CH2:30][N:29]([CH3:28])[CH3:42])[N:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CN(C)CCNC(=O)c1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)NCCN(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-bromo-pyridine-2-carboxylic acid (2-dimethylamino-ethyl)-amide.
Reaction SMILES: [OH:1][CH:2]([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])Cl)[CH3:17].O>CN(C)C=O>[CH2:10]=[C:6]([CH2:7][CH2:8][CH3:9])[CH:2]([O:1][Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:16][CH3:17])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(O)C(=C)CCC
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(O[Si](CC)(CC)CC)C(=C)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 30.0 g. of 4-hydroxy-5-methylene-1-octyne and 31.02 g. of imidazole in 80 ml of dimethylformamide at 0° C., is added 40.9 g. of triethychlorosilane. The mixture is stirred at room temperature for 30 minutes, poured into cold water and extracted with petroleum ether. The petroleum ether is removed and the residue is distilled. The product is recovered in the fraction boiling at 103°-106° C. (1.5 mm.).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.BrBr.C(OCC)(=O)C>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:15]2[C:14]3[C:13](=[O:16])[NH:12][CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1nc2ccc3c(c2s1)C(=O)NCC3
Temperature: -10 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Potassium thiocyanate (8.62 g, 0.088 mol) was added to a stirred solution of 7-amino-3,4-dihydroisoquinolin-1(2H)-one (I-66a: 1.8 g, 0.01 mol) in acetic acid (60 mL) at −10° C. and this was followed by the addition of bromine (5.33 g, 0.033 mol). The resulting reaction mass was stirred at −10° C. for 3 hours and further at room temperature overnight. The reaction was monitored by TLC (100% ethyl acetate). The reaction mass was diluted with ice water and filtered. The resulting mixture was basified at 0° C. using KOH solution to pH 10 and extracted using ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 1.4 g of the product (58.33% yield).
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[C:5](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:14])[C:12]=1[CH3:13])[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1>CCN(CC)CC>[NH2:14][C:11]1[C:12]([CH3:13])=[C:4]2[C:5](=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])[C:6](=[O:8])[N:43]([CH:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1)[C:3]2=[O:18]
Reactant: CN1CCC(N)CC1
Reactant: COC(=O)c1c(C(=O)O)cc([N+](=O)[O-])c(N)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(C1CCN(C)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To a solution of 4-Amino-3-methyl-5-nitro-phthalic acid 2-methyl ester (1.3 g, 5.12 mmol), EDCI.HCl (1.07 g, 5.63 mmol) and HOBt (0.69 g, 5.12 mmol) was added Et3N (3.64 mL, 25.6 mL) and stirred at room temperature for 10 min. 4-Amino-1-methylpiperidine dihydrochloride (1.04 g, 5.63 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was evaporated in vacuo, the residue was dissolved in CHCl3 (200 mL), washed with water (2×100 mL). The organic layer was filtered over Na2SO4 and concentrated in vacuo to afford 5-Amino-4-methyl-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (1.7 g, quant), which was used as such for further reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
2-chloro-4-nitrophenol (9.02 g, 52 mmol)), 3-fluorobenzyl bromide (9.85 g, 52 mmol) and acetonitrile (90 mL) was combined at room temperature under nitrogen. Potassium carbonate (7.9 g, 57 mmol)) was added and the reaction mixture stirred at 60° C. for 2 hours and then cooled to room temperature. After cooling the reaction mixture was poured into water. The solids were collected by filtration and washed with diethyl ether to afford the desired product (13.98 g, 95% yield). [TLC system=1:1 EtOAc:Hexanes, Rf=0.76]
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.O>CCOCC>[CH2:17]([O:16][C:14]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl alcohol (2.70g.; 0.025 mole) was added to a solution of ethyl 4-hydroxybenzoate (4.15g.; 0.025 mole) in dry ether followed by the careful addition of phosphorus pentachloride (2.5g). The mixture was boiled under reflux for 24 hrs. then poured into water and the ether layer removed. The aqueous solution was extracted with ether and the combined organic extracts dried (anhyd. MgSO4) to yield, on evaporation and purification by chromatography, 4-ethoxycarbonylphenoxy phenyl methane, m.p. 45° C.