Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C@H:10]2[C@@:15]3([CH2:21][C:20](=[O:22])[NH:19][CH2:18][CH2:17][S:16]3(=[O:24])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1>CS(C)=O.C(OCC)(=O)C>[C:3]1([CH2:9][C@H:10]2[C@@:15]3([CH2:21][C:20](=[O:22])[N:19]([CH2:31][C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH2:18][CH2:17][S:16]3(=[O:23])=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccnc1
Reactant: O=C1C[C@]2(CCCC[C@H]2Cc2ccccc2)S(=O)(=O)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1C[C@]2(CCCC[C@H]2Cc2ccccc2)S(=O)(=O)CCN1Cc1cccnc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
A stirred suspension of sodium hydride (5.5 g, 60% dispersion in mineral oil) in dimethyl sulfoxide (400 ml) was heated at 60° C. for 1 hour under nitrogen atmosphere. (1S,6S)-1-Phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]-dodecane 7,7-dioxide (40.0 g) and 3-pyridylmethyl chloride (25 g) were added to the nearly clear solution and the mixture was allowed to stand at room temperature for 15 minutes. The mixture was diluted with ethyl acetate (2 l) and washed with saturated aqueous sodium bicarbonate (2 l) and brine (2 l). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate and recrystallized from ethanol to give (1S,6S)-1-phenylmethyl-10-(3-pyridylmethyl)-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (14.0 g).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>O.O1CCCC1.CCCCCC>[N:16]1[CH:21]=[CH:20][C:19]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:18][CH:17]=1
Reactant: c1cncnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.8 ml of a hexane solution containing 2.52 mol of n-butyllithium was slowly added dropwise into a solution of 20 ml of tetrahydrofuran containing 2.5 ml of 2,2,6,6-tetramethylpiperidine. After stirring at 0° C. for 30 minutes, a mixture of 0.98 ml of pyrimidine, 4.6 ml of tri-n-butyltin chloride and 20 ml of tetrahydrofuran was slowly added dropwise thereinto. After stirring at −78° C. for 4 hours, water was added to the reaction solution and then extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. Then, the residue was subjected to silica gel column chromatography to elute with hexane/ethyl acetate (10:1), to give 474 mg of the target compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:55]=[CH:54][C:49]3[C:50](=[O:53])[O:51][CH2:52][C:48]=3[CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:53]=[C:50]1[C:49]2[CH:54]=[CH:55][C:46]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:47][C:48]=2[CH2:52][O:51]1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc5c(c4)COC5=O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Yield: 70.8 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-benzofuran-1(3H)-one (80 mg, ca.0.267 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.09 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:2) to afford the desired product (39 mg, 71%) as a white solid. 1HNMR (CDCl3) 400 MHz δ: 8.15 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.03 (d, J=4.0 Hz, 1H), 7.87-7.83 (m, 2H), 7.74-7.72 (m, 1H), 7.65-7.59 (m, 2H), 7.41 (d, J=8.6 Hz, 1H), 7.34 (td, J=7.4 Hz and 1.7 Hz, 1H), 7.19-7.16 (m, 2H), 6.97 (d, J=7.4 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 6.61 (dd, J=8.0 Hz and 4.6 Hz, 1H), 6.26 (s, 1H), 5.27 (s, 2H), 5.15 (br s, 1H), 2.59-2.52 (m, 2H), 2.50-2.40 (m, 2H), 2.21-2.12 (m, 1H), 1.96-1.87 (m, 1H), 1.39 (br s, 9H). LCMS: 612 [M+H].
Reaction SMILES: [H-].[Na+].ICCO[CH:7]([O:9][CH2:10][CH2:11][I:12])[CH3:8].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])([CH2:20][CH2:19][O:18][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])[CH2:15][CH2:16][O:17][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])[CH3:20]
Reactant: CCOC(=O)CC#N
Reactant: CC(OCCI)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)(CCOCCOCCI)CCOCCOCCI
Temperature: 25 °C
Yield: 95.7 %

Procedure:
1.71 g (0.036 mol) of sodium hydride was added to 40 ml of tetrahydrofuran dried with metallic sodium, and to this solution was added dropwise a mixed solution of 17.6 g (0.048 mol) of bis(2-iodoethoxy)ethane and 1.35 g (0.012 mol) of ethyl cyanoacetate, followed by 5-hours reflux under heating. Tetrahydrofuran was distilled off and the residue was cooled to room temperature, added with 1N hydrochloric acid until the litmus paper came to show acidity and then extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the oily residue was passed through a basic alumina (activity II)-packed column and eluted with petroleum ether-ether (2:1) to obtain 3.43 g of 2,2-bis(8-iodo-3,6-dioxaoctyl)cyanoacetic acid ethyl ester, ##STR33## (yield: 48%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[N:5]=[C:4]([CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20][C:21]#[N:22]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[C:21]([NH2:22])=[N:1][C:2]2[N:3]=[C:4]([CH3:11])[N:5]=[C:6]([CH3:10])[C:7]=2[CH:8]=1
Reactant: Cc1nc(C)c(C=O)c(N)n1
Reactant: N#CCc1c(Cl)cccc1Cl
Product: Cc1nc(C)c2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1

Procedure:
4-Amino-2,6-dimethylpyrimidine-5-carboxaldehyde is then condensed with 2,6-dichlorophenylacetonitrile. The product is isolated and purified in the manner described in Example 6, yielding 6-(2,6-dichlorophenyl)-2,4-dimethylpyrido[2,3-d]pyrimidin-7-amine, mp 239°-240° C., after recrystallization from ethyl acetate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][CH2:17][NH2:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CO>[Si:8]([O:15][CH2:16][CH2:17][NH:18][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([C:11]([CH3:13])([CH3:14])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCCN
Reactant: O=C1CCOCC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Reaction time: 1 h
Yield: 345 %

Procedure:
To a stirred cooled solution of tetrahydro-pyran-4-one (2 g, 19.98 mmol) in methanol (30 mL) were added 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (2.5 mg, 13.98 mmol). Stirring was continued for 1 h at room temperature. The reaction mixture was cooled and Na(CN)BH3 (2.5 g, 39.96 mmol) was added portion-wise, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the methanol was removed. The mixture was subsequently extracted with dichloromethane (3×30 mL) and the organic part was concentrated, dried and purified by Combi-Flash column (eluted at 20-50% ethyl acetate in hexane) to get [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) (2.5 g, 48.23 mmol) as a light yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.O>CO.[Pd]>[OH:8][C@H:7]1[C@H:6]([OH:9])[C@@H:5]([OH:10])[CH2:4][CH2:3][C:2]1=[O:1]
Reactant: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C1CC[C@H](O)[C@@H](O)[C@@H]1O
Yield: 95.3 %

Procedure:
205 mg of (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one obtained in Example 3 was dissolved in 3.5 mL of methanol. 20 mg (50 weight % of water contained) of 5 weight % Pd/C was added thereto and hydrogenated at room temperature (25 degrees centigrade) under ordinary pressure (1 atm). After the completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to obtain 198 mg (yield: 96%) of (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[N:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3cccnc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
The mixture of 2-[(quinoline-8-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (47) (190 mg, 0.53 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give the pure product (48) as white solid (152 mg, 86%).
Reaction SMILES: Cl.[CH3:2][C@:3]([C:7]([OH:9])=[O:8])([CH2:5][SH:6])[NH2:4].[OH:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[C:13]#N.C(N(CC)CC)C.[OH-].[K+]>C(O)C.O>[OH:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[C:13]1[S:6][CH2:5][C@:3]([CH3:2])([C:7]([OH:9])=[O:8])[N:4]=1
Reactant: N#Cc1ccc(O)cc1O
Reactant: C[C@@](N)(CS)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@]1(C(=O)O)CSC(c2ccc(O)cc2O)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
4.00 g (S)-2-methylcysteine hydrochloride (23.3 mmol,1.0 meq) and 3.14 g 2,4-dihydroxy benzonitrile (23.3 mmol, 1.0 meq) were suspended in 40 mL ethanol. After degassing this mixture with nitrogen (30 min) 4.95 g triethylamine (6.8 mL, 48.9 mmol, 2.05 meq) were added. The obtained suspension was heated under reflux in an atmosphere of nitrogen for 20 hours and then cooled to room temperature. From this suspension ethanol was evaporated under reduced pressure until an oil (20% of the initial volume) was obtained. This oil was dissolved in 50 mL water. The solution was adjusted to pH 7.5 with 1.20 ml 20% KOH and was extracted two times each with 20 mL methyl t-butyl ether (MTBE). The aqueous layer was separated, adjusted with 20% KOH to pH 11 and again extracted two times each with 20 mL MTBE. After separating the aqueous layer the pH was set with concentrated HCl to 7.5 and traces of MTBE were distilled off. Then the aqueous solution was acidified with 1.50 ml concentrated HCl to pH 1.5. The product precipitated. This suspension was stirred at 4° C. for 1 hour. Then the precipitate was filtered, washed two times each with 10 mL water (5° C.) and dried at 45° C. under vacuum. The reaction yielded 5.17 g (87.6%) of crude 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid product. 1H-NMR showed no significant impurity.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.[CH2:19]([O:21][C:22](=[O:27])[CH:23]=[C:24](Cl)[CH3:25])[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22](=[O:27])/[CH:23]=[C:24](/[O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]([F:17])([F:18])[F:7])[CH:11]=1)\[CH3:25])[CH3:20]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OC(F)(F)F)c1
Temperature: 23 °C
Yield: 68.9 %

Procedure:
Potassium t-butoxide (1.23 g, 0.013 mol) was added to a stirred solution of 3-trifluoromethoxy-phenol (1.19 g, 0.007 mol) in tetrahydrofuran (15 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 1.00 g, 0.007 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 72%) as a yellow oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:22]=[CH:21][C:20]([C:23]([C:25]3[N:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]4=[C:27]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([O:42]C)=[O:41])[CH:35]=4)[N:26]=3)=[O:24])=[CH:19][C:14]=2[C:15](OC)=[O:16])=[O:11])=[CH:6][CH:5]=1.Cl>CO.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C:14]3[C:13](=[CH:22][CH:21]=[C:20]([C:23]([C:25]4[N:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]5=[C:27]([C:34]5[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=5)[C:40]([OH:42])=[O:41])[N:26]=4)=[O:24])[CH:19]=3)[NH:12][C:10]2=[O:11])=[CH:44][CH:45]=1
Reactant: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(NC(=O)NCc4ccc(F)cc4)c(C(=O)OC)c3)n3ccccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2nc(C(=O)c3ccc4[nH]c(=O)n(Cc5ccc(F)cc5)c(=O)c4c3)n3ccccc23)c1
Yield: 98.8 %

Procedure:
2.85 ml (0.0285 mol) of a 1N aqueous solution of sodium hydroxide are added to 3.3 g (5.7 mmol) of methyl 2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate dissolved in 250 ml of methanol. After refluxing for 2 hours, the reaction medium is acidified with 50 ml of a 1N aqueous solution of hydrochloric acid and then diluted with 700 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 40° C. overnight. 3.01 g of a yellow solid are obtained.
Reaction SMILES: C1(C2C3C([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([C:26](=[O:36])[CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])[C@@H:21]4[C:37]([O:39][CH2:40]C)=[O:38])=CC=CC=3C3C2=CC=CC=3)C=CC=CC=1.FC(F)(F)C(O)=O>C(#N)C.O>[CH2:31]([O:30][P:28]([CH2:27][C:26]([C@H:22]1[CH2:23][CH2:24][CH2:25][NH:20][C@H:21]1[C:37]([O:39][CH3:40])=[O:38])=[O:36])([O:33][CH2:34][CH3:35])=[O:29])[CH3:32]
Reactant: CCOC(=O)[C@H]1[C@@H](C(=O)CP(=O)(OCC)OCC)CCCN1c1cccc2c1C(c1ccccc1)c1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CCOP(=O)(CC(=O)[C@H]1CCCN[C@H]1C(=O)OC)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve N-(9-phenylfluorenyl)-3(S)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, ethyl ester (1 g) in acetonitrile (7 mL) and water (1 mL). Cool to 0° C. and add, by dropwise addition, trifluoroacetic acid (7 mL). Stir at 0° C. for 1 hour then warm to room temperature over 1 hour. Extract into ethyl acetate (10×100 mL) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH2:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[CH2:10][CH3:11].C(N(CC)CC)C>C1COCC1>[CH2:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:19][CH:20]=1)[CH2:10][CH3:11]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: NCCc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)NCCc2cccs2)cc1
Yield: 85.7 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 4-propylbenzoyl chloride (92 μL, 0.55 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 4-propyl-N-(2-thiophen-2-yl-ethyl)-benzamide (100 mg, 0.36 mmol, 85% yield) as a off-white powder after purification on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28]([C:30]5[CH:39]=[CH:38][CH:37]=[C:36]6[C:31]=5[CH:32]=[CH:33][N:34]=[CH:35]6)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]3)[CH:19]=2)=[C:21]2[CH:29]=[C:28]([C:30]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:31]=3[CH:32]=[CH:33][N:34]=[CH:35]4)[O:27][C:22]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cccc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-(isoquinolin-5-yl)furo[2,3-c]pyridin-7-amine (25 mg, 0.046 mmol) was dissolved in THF (1.00 mL) and tetra-n-butylammonium fluoride (1.0 M in THF, 1.00 mL, 1.00 mmol) was added and stirred at RT for 16 h. The reaction was then washed with sodium bicarbonate and water (2×). The organic layer was collected, dried over sodium sulfate, filtered, and then concentrated in vacuo to a solid. Purification by flash chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 5.5 mg (28%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 9.33 (d, J=0.51 Hz, 1H), 8.57 (d, J=6.06 Hz, 1H), 8.49 (d, J=6.06 Hz, 1H), 8.35 (dd, J=7.33, 1.26 Hz, 1H), 8.24 (d, J=8.08 Hz, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.90 (d, J=0.76 Hz, 1H), 7.83 (dd, J=8.21, 7.45 Hz, 1H), 7.50 (s, 1 H), 4.25 (tt, J=11.84, 3.82 Hz, 1H), 3.69 (tt, J=10.89, 4.26 Hz, 1H), 2.07-2.22 (m, 4H), 1.95-2.05 (m, 2H), 1.45-1.57 (m, 2H); MS (ESI): 427.19 [M+H]+; HPLC tR=0.87 min (TOF: polar—3 min).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH3:13])=[C:8]([CH3:14])[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([CH3:13])[CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2cc(C#N)c(=O)[nH]c2cc1C
Product: Cc1cc2cc(C#N)c(Cl)nc2cc1C

Procedure:
A mixture was prepared from 67.5 g of 3-cyano-6,7-dimethyl-2(1H)-quinolinone and 340 ml of phosphoryl chloride and this was heated at reflux for 18 hours. The mixture was cooled, excess phosphoryl chloride was removed by vacuum evaporation, and the residue was carefully added to water with vigorous stirring. The solid which formed was separated by filtration and recrystallized from methylene chloride to give 2-chloro-3-cyano-6,7-dimethylquinoline melting at about 189°-190° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(S)-Hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared as described in Abreo, et al. J. Med. Chem. 1996, 39, 817-825) (9.7 g, 52 mmol) was taken up in dichloromethane (50 mL), treated with triethylamine (8.7 mL, 62 mmol), cooled to 0° C., treated dropwise with methanesulfonyl chloride (4.4 mL, 57 mmol), stirred overnight at ambient temperature, treated with sodium bicarbonate solution (50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 10:1, 5:1, 2:1 and 3:2 hexane:ethyl acetate to provide 10.7 g (78%). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9 H) 2.27 (m, 2 H) 3.05 (s, 3 H) 3.82 (m, 2 H) 4.28 (dd, J=10.85, 2.71 Hz, 1 H) 4.43 (m, 1 H) 4.54 (dd, J=10.85, 4.07 Hz, 1 H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=1)[C@@H:6]1[S:17][CH2:18][C@@H:19]([OH:25])[C@H:20]([OH:21])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(C(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c1
Yield: 84.9 %

Procedure:
If the procedure described in Preparation LXXXIV is followed starting from 1.36 g (3.3.10-3 mol) of 3-acetylphenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.2 ml of a solution of sodium methylate in methanol (8% w/v of Na), reacted in 50 ml of methanol for 30 min, 0.8 g (yield: 85%) of the expected product is obtained after crystallization from an ethanol/ether mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10](OC)OC)=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: COC(CSc1ccc(Br)cc1)OC
Solvent: Clc1ccccc1
Product: Brc1ccc2sccc2c1
Temperature: 180 °C
Reaction time: 48 h

Procedure:
A mixture of polyphosphoric acid (5.0 g) and chlorobenzene (100 mL) was refluxed for three hours, and then to the mixture was added 1-bromo-4-(2,2-dimethoxyethyl-sulfenyl)benzene (2.50 g, 9.00 mmol). The reaction mixture was stirred at 180° C. for two days.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:33]([CH3:32])[C:35]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 572 (M+H)+.