Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[CH2:5][OH:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[CH2:5][OH:6]
Reactant: [N-]=[N+]=NC(CO)c1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(CO)c1cccc(Br)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 14.1 %

Procedure:
To a solution of 2-(3-bromo-phenyl)-oxirane (2.5 g, 12.6 mmol) in CH2Cl2 (20 mL) was added azidotrimethylsilane (2.5 mL, 18.84 mmol), followed by aluminium isopropoxide (256 mg, 1.26 mmol). The reaction mixture was stirred at room temperature for 18 h. Sodium potassium tartrate 1M (30 mL) was added, the aqueous layer was extracted with CH2Cl2, and the organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the crude compound is purified by flash chromatography (10% EtOAc/Hex) to provide 2-azido-2-(3-bromo-phenyl)-ethanol (876 mg, 29%). To a solution of 2-azido-2-(3-bromo-phenyl)-ethanol (876 mg) in THF (10 mL) was added polymer supported triphenylphosphine (3 mmol/g) (2 g, 6 mmol), and the mixture was heated to 60° C. for 30 min. The polymer was then filtered and washed with CH2Cl2. The polymer was suspended in THF (20 mL) and concentrated NH4OH (10 mL) was added, and this mixture was agitated for 24 h. The polymer was filtered and the liquid phase was evaporated in vacuo to afford the title compound (110 mg, 14%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][CH2:17][CH2:18][CH2:19][CH:20]([CH2:23][NH:24][CH2:25][CH:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[CH2:21][CH3:22]>C(O)(C)(C)C>[CH2:27]([CH:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][N:24]([CH2:23][CH:20]([CH2:21][CH3:22])[CH2:19][CH2:18][CH2:17][CH3:16])[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[N:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:28]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)(C)O
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=NC1CCCCC1)NC1CCCCC1

Procedure:
41.3 Gm. (0.2 mole) of dicyclohexylcarbodiimide, 72.4 gm. (0.3 mole) of bis-2-ethylhexylamine, and 200 ml. of t-butanol were refluxed for 7 hours. The t-butanol was distilled off at atmospheric pressure and the residue stripped to a temperature of 180° C. at 0.08-0.09 mm Hg. The residue weighed 60.8 gm. and was 90% pure by NMR with a trace of amine and approximately 5% dicyclohexylcarbodiimide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH2:23]([SH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([S:30][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CSCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 43, 0.100 g) and benzyl mercaptan (0.30 g) in acetonitrile (10 ml) was treated with potassium carbonate (0.46 g) and the mixture stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water the organic layer as collected, dried over magnesium sulfate and concentrated. The residue was purified by SPE (Si cartridge) eluting initially with cyclohexane:chloroform (5:1) and then cyclohexane:chloroform (1:3) to give the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
3-chlorobenzylamine (3.54 g, 25 mmol) was added dropwise to trimethylacetyl chloride (2.65 ml, 21.5 mmol) and Et3N (3.5 ml, 25 mmol) in DCM (25 ml). After two hours, the reaction mixture was washed with 1 N HCl and the organic layer collected and dried over MgSO4. N-3-chlorobenzyltrimethylacetamide was precipitated from DCM/hexane as a white solid, 3.95 g,
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH:4]=[C:5]([CH3:7])[N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1c[nH]c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(CCCN2C(=O)c3ccccc3C2=O)c(C)n1

Procedure:
In a similar manner to Example A, a mixture of 2,4-dimethylimidazole (24.0 g) was added to a suspension of sodium hydride (10.0 g, 60% dispersion) in DMF (300 ml). After stirring for. 1.5 hours, DMF (80 ml) was added followed by a slurry of N-(3-bromopropyl)phthalimide (63.8 g) in DMF (100 ml). The mixture was reacted and worked up as in Example A and the residue triturated with petroleum ether b.p. 60°-80° C. and then with ether. The residue was recrystallised from ethyl acetate to give N-[3-(2,4-dimethylimidazol-1-yl)propyl]phthalimide, m.p. 191°-122° C. 1H nmr indicated the presence of approximately 10% of N-[3-(2,5-dimethylimidazol-1-yl)propyl]phthalimide.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=[CH2:2].Cl.C(OCC)C.[OH-].[Na+]>ClCCl>[CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)=[CH2:2]
Reactant: C=Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: C=Cc1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(4-ethenyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 4, Step A) (471 mg, 1.6 mmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in diethyl ether (2.0 M, 7 mL, 14 mmol). The reaction mixture was stirred under nitrogen at room temperature for 4 h, and then 1 N aqueous sodium hydroxide solution was added until pH of the reaction mixture increased to about 10. The resulting mixture was extracted with dichloromethane (2×). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 302 mg of the title compound as an oil.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>C1(C)C=CC=CC=1>[C:1]([NH:26][CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCN(CC)CCN
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NCCN(CC)CC

Procedure:
142.24 (0.5 mole) stearic acid and 58.09 g (0.5 mole) 2-diethylaminoethylamine are heated in toluene to produce 0.5 mole stearamidoethyl diethylamine. 76.53 g (0.2 mole) of the stearamidoethyl diethylamine are then reacted with 49.60 g (0.1 mole) 1,12-dibromoheptaethylene glycol to yield compound FF, N,N'di(stearamidoethyl)-N,N,N',N'-tetraethyl-1,12(3,6,9,12,15-pentaoxadodecylene)diammonium dibromide of the formula: ##STR15##
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=2)[N:3]=1>CO.[Pd]>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[C:9]([CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:12]=2)[NH2:17])[N:3]=1
Reactant: Cc1ccn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccn(-c2cc(N)cc(C(F)(F)F)c2)n1
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (300 mg, 1.106 mmol) in MeOH (10 mL) was added Pd/C (11.77 mg, 0.111 mmol) in one portion. Then the mixture was stirred under H2 for 12 h. LCMS analysis showed the starting material disappeared. The suspension was filtered through a pad of Celite® and the filter cake was washed with MeOH (2 mL). The combined filtrates were concentrated to dryness to give crude product which was purified by preparative TLC (PE/EA=5/1, Rf=0.35) to afford pure product 3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (300 mg, 1.045 mmol, 94% yield). 1H NMR (400 MHz, CD3OD): δ 8.05 (d, J=2.4 Hz, 1H), 7.18-7.12 (m, 2H), 6.82 (s, 1H), 6.30 (d, J=2.2 Hz, 1H), 2.32 (s, 3H). ES-LCMS: m/z 242.1 (M+H).
Reaction SMILES: [CH:1]([O:4][P:5]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=2)[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH3:48][Si:49]([CH3:54])([CH3:53])[CH2:50][CH2:51]O>C(Cl)Cl>[CH3:48][Si:49]([CH3:54])([CH3:53])[CH2:50][CH2:51][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=[C:16]([O:15][C:14]2[CH:29]=[CH:30][C:11]([P:5]([O:7][CH:8]([CH3:10])[CH3:9])([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])=[CH:12][CH:13]=2)[CH:17]=1
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)O)c1
Reactant: C[Si](C)(C)CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid (Example 3, route 3, step E) (10 g, 22.9 mmol) in DCM (115 mL) was added DMF (0.09 mL, 1.15 mmol) and oxalyl chloride (4.0 mL, 45.8 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was concentrated. The resulting residue was azeotroped with 50 mL anhydrous toluene and then re-dissolved in DCM (40 mL), cooled to 0° C. A solution of pyridine (3.1 mL, 36.6 mmol) in DCM (10 mL) was added slowly to the reaction flask followed by 2-trimethylsilanylethanol (3.6 mL, 25.2 mmol). The resulting mixture was stirred at rt overnight. On second day solvents were removed and the residue was partitioned between EtOAc and saturated sodium bicarbonate. The organic layer was separated, washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel using an ethyl acetate-hexanes gradient to afford 5.0 g (41%) of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl ester. 1H NMR (500 MHz, DMSO-dc): δ 7.72 (dd, 13, 9 Hz, 2H), 7.26 (dd, J=3, 2 Hz, 1H), 7.16 (dd, J=9, 3 Hz, 2H), 7.06 (dd, J=3, 2 Hz, 1H), 6.99 (t, J=3 Hz, 1H), 4.69 (m, 1H). 4.54 (m, 2H), 3.48 (t, 2H), 1.28 (dd, J=8, 3 Hz, 12H), 1.18 (d, J=6 Hz, 6H), 1.04 (t, 2H), −0.16 (s, 9H).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]=[O:2])=[CH:7][CH:8]=1
Reactant: COC(COc1ccc(F)cc1)OC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=CCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dissolve 1-(2,2-dimethoxyethoxy)-4-fluorobenzene (1.00 g, 4.99 mmol) in chloroform (5.0 mL) and treat the mixture with trifluoroacetic acid (0.755 mL, 9.99 mmol). Stir the mixture at room temperature for two days, then heat to 65° C. and stir for 4 h. Concentrate the mixture under reduced pressure to furnish the title compound as a colorless oil in ca. 70% purity, as indicated by 1H NMR analysis (550 mg, 71% uncorrected yield). 1H NMR (400 MHz, CDCl3): δ 9.85 (t, J=0.5 Hz, 1H), 7.00 (dd, J=8.9, 8.5 Hz, 2H), 6.85 (dd, J=9.5, 4.3 Hz, 2H), 4.55 (br s, 2H).
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][N:55]([C:58]([C:60]2[CH:61]=[C:62]([S:66]([C:69]3[CH:70]=[C:71]4[C:76](=[C:77]([CH3:79])[CH:78]=3)[N:75]=[CH:74][C:73]([C:80]([NH2:82])=[O:81])=[C:72]4[NH:83][C:84]3[CH:89]=[CH:88][CH:87]=[C:86]([O:90][CH3:91])[CH:85]=3)(=[O:68])=[O:67])[CH:63]=[CH:64][CH:65]=2)=[O:59])[CH2:54][CH2:53]1>>[CH3:91][O:90][C:86]1[CH:85]=[C:84]([NH:83][C:72]2[C:71]3[C:76](=[C:77]([CH3:79])[CH:78]=[C:69]([S:66]([C:62]4[CH:63]=[CH:64][CH:65]=[C:60]([C:58]([N:55]5[CH2:56][CH2:57][N:52]([CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]=[O:45])[CH2:53][CH2:54]5)=[O:59])[CH:61]=4)(=[O:68])=[O:67])[CH:70]=3)[N:75]=[CH:74][C:73]=2[C:80]([NH2:82])=[O:81])[CH:89]=[CH:88][CH:87]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCCCCCO)CC5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCCCCC=O)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using Intermediate 89 as a substrate. ES/MS calcd. for C35H40N5O6S+ 658.3. Found m/z=658.3 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH3:5][CH:4]1[O:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:1][CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CC1CCSC(c2ccccc2)O1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 5.8 grams (0.055 moles) of benzaldehyde is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 10.1 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1.[O:15]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[N:16]1>>[O:14]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH2:3][NH:2][C:20]([C:17]2[CH:18]=[CH:19][O:15][N:16]=2)=[O:21])=[N:5][NH:6]1
Reactant: NCc1n[nH]c(=O)c2ccccc12
Reactant: O=C(Cl)c1ccon1
Agent: Cl
Product: O=C(NCc1n[nH]c(=O)c2ccccc12)c1ccon1

Procedure:
The title compound was prepared from 4-aminomethyl-2H-phthalazine-1-one hydrochloride (Geterotsikl, Soedin, 1972, (9), 15) and isoxazol-3-carbonyl chloride using the procedure described in Example 1, Part a. 1H NMR (360 MHz, d6-DMSO) δ 4.80 (d, J=6 Hz, 2H), 6.93 (s, 1H), 7.87 (t, J=7 Hz, 1H), 7.95 (t, J=7 Hz, 1H), 8.1 (d, J=7 Hz, 1H), 8.28 (dd, J=2 Hz, 7 Hz, 1H), 9.08 (s, 1H), 9.09 (t, J=2 Hz, 1H), 12.62 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[O:27]1[CH2:30][C:29]([CH2:33][NH2:34])([CH2:31][NH2:32])[CH2:28]1>>[NH2:32][CH2:31][C:29]1([CH2:33][NH:34][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=3)[N:5]=[C:4]([N:14]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]3)[CH:3]=2)[CH2:30][O:27][CH2:28]1
Reactant: NCC1(CN)COC1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Product: NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(CO)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 6-1 in Scheme 52 by using [4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinolin-6-yl]methanol and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 469, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, 1 H), 7.83 (m, 1 H), 7.75 (s, 1 H), 7.59 (m, 1 H), 7.42 (m, 1 H), 7.34 (s, 2 H), 7.25 (t, 1 H), 6.13 (s, 1 H), 5.10 (t, 1 H), 5.04 (s, 2 H), 4.47 (d, 2 H), 4.34 (m, 6 H), 3.58 (d, 2 H), 3.52 (d, 2 H), 2.96 (t, 2 H), 1.79 (m, 2 H).
Reaction SMILES: [CH2:1]([CH:8]([NH:32][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)=[O:34])[CH:9]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:10][CH:11]([C:18](=[O:23])[NH:19][CH2:20][CH2:21][OH:22])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.CCOCC>[CH2:1]([CH:8]([NH:32][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)=[O:34])[CH:9]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:10][CH:11]([C:18](=[O:23])[NH:19][CH2:20][CH:21]=[O:22])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCC=O
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid [1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-4-(2-hydroxy-ethylcarbamoyl)-7-methyl-octyl]-amide (250 mg, 0.400 mmol) in methylene chloride was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one [Dess-Martin periodinane] (340 mg, 0.800 mmol). The reaction was stirred for 2 hours and then diluted with ether and quenched with a 1:1 mixture of saturated aqueous sodium thiosulfate:sodium bicarbonate. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were washed with a 1:1 mixture of saturated aqueous sodium thiosulfate:sodium bicarbonate, water, and saturated sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave the title compound (233 mg, 94%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>C(N(CC)CC)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: CNCCc1ccncc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)CCc1ccncc1

Procedure:
The title compound was prepared according to the method of Example 3 from 4-[β-(methylamino)ethyl]pyridine (4.76 g, 0.035 mole), acryloyl chloride (3.15 g, 0.035 mole) and triethylamine (21 ml) to yield 3.4 g of product, m.p. ca. 129°-132° C. Analysis calc. for C11H14N2O(190.24): Calc.: C, 69.45; H, 7.42; N, 14.72. Found: C, 69.79; H, 7.62; N, 14.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(O)c(C(=O)O)c1
Product: COc1ccc(O)c(C(=O)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 29.8 %

Procedure:
Using 5-methoxysalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:43][C:44]4[NH:45][CH:46]=[CH:47][N:48]=4)[CH2:39][CH2:38]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([O:35][CH3:36])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:43][C:44]4[NH:45][CH:46]=[CH:47][N:48]=4)[CH2:39][CH2:38]3)[N:19]=2)=[CH:22][C:23]=1[O:35][CH3:36]
Reactant: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 2 mL) was added to a solution of tert-butyl N-(4-{4-amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (55 mg, 0.106 mmol) in dichloromethane (0.5 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. Solvents were then evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added to adjust the PH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give 3-(4-amino-3-methoxyphenyl)-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 68%). 1H NMR (CDCl3-d) δ 2.20 (m, 2H), 2.44 (m, 2H), 3.04 (m, 2H), 3.75 (s, 2H), 3.93 (s, 3H), 4.01 (s, 2H), 4.80 (m, 1H), 5.58 (bs, 2H), 6.82 (m, 1H), 7.01 (m, 4H), 8.34 (s, 1H).
Reaction SMILES: [NH2:1][C@:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:15][C:14]([C@@:2]1([NH2:1])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1)=[O:16]
Reactant: CO
Reactant: N[C@]1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@]1(N)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C

Procedure:
The (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid (79 g, 0.28 mol) suspended in MeOH (1.8 L) was cooled in an ice/water bath and thionyl chloride (178 mL, 2.44 mol) was added dropwise. Following the addition the reaction was heated to reflux, resulting in a nearly homogeneous solution. After refluxing for about 36 hours, the reaction mixture was cooled to room temperature, filtered, and rinsed with MeOH (2×200 mL). The filtrate was concentrated in vacuo to provide a white solid. The white solid was triturated with EtOAc (1 L), collected by filtration, rinsed with EtOAc (2×500 mL), and dried under vacuum to give the (1R,3S)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride as a white solid (79 g, 96%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[S:15][CH3:16])[CH:7]=[CH:6][C:5]=1[O:17][CH3:18].[OH-].[Li+].O.Cl>O1CCCC1>[CH3:18][O:17][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[S:15][CH3:16])=[CH:9][C:4]=1[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc(-n2cnnc2SC)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2cnnc2SC)cc1C(=O)O
Yield: 95.9 %

Procedure:
Stir a mixture of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methyl ester (0.28 g, 3.5 mmol), lithium hydroxide (0.041 g, 3.8 mmol), and 25% water in tetrahydrofuran (20 mL) overnight. Add 1N hydrochloric acid (3.9 mL) dropwise to pH 3. Concentrate to remove the tetrahydrofuran and collect the precipitate by vacuum filtration. Wash the filter cake twice with water and hexane, and dry in vacuo overnight to give 0.89 g of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid as a solid.