Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(OCC)=O.[F:29][C:30]1[CH:53]=[CH:52][C:33]([CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47]([O:49]CC)=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[C:39](=[O:40])[N:38]([C:41]3[S:42][C:43]([C:47]([OH:49])=[O:48])=[C:44]([CH3:46])[N:45]=3)[CH:37]=[N:36]2)=[CH:52][CH:53]=1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Yield: 99 %

Procedure:
Following the procedure as described in Example 20, making variation as required to replace ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with ethyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 99% yield: 1H NMR (300 MHz, DMSO-d6) δ 13.40 (br s, 1H), 8.74 (s, 1H), 7.37-7.31 (m, 2H), 7.19-7.11 (m, 2H), 4.96 (s, 2H), 2.57 (s, 3H); MS (ES−) m/z 333.0 (M−1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][NH2:12].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].Cl>O.[Cu]>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Reactant: CN
Agent: [Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CNc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2'-chloroacetophenone (182 g), industrial methylated spirit (290 ml), methylamine (33% w/w solution in industrial methylated spirit, 3)3 ml) and copper powder (2.8 g) was stirred in a sealed pressure vessel for 5 hours at 90°. The reaction vessel was allowed to cool to ambient temperature and the mixture washed out of the vessel with industrial methylated spirit (2×100 ml). The combined reaction mixture and washings were stirred at 50°, a solution of sodium sulphide nonahydrate (24 g) in water (100 ml) was added over a period of 10 minutes, and stirring and heating were continued for a further 15 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE) and the filter bed washed with industrial methylated spirit (100 ml). The filtrate was evaporated to give an oil which was stirred with hydrochloric acid (5M, 800 ml) for 1 hour. The resultant mixture was extracted with dichloromethane (600 ml, then 2×300 ml) and the combined extracts were washed with water (500 ml), dried over magnesium sulphate and evaporated to give an oil which was then distilled. The fraction distilling at 100°-110° and 5 mmHg was collected to give 2'-(methylamino)acetophenone, m.p. 36°-38°. The aqueous acid phase from above was basified by the addition of aqueous sodium hydroxide (specific gravity 1.5, 230 ml). The resultant mixture was extracted with dichloromethane (500 ml, then 250 ml) and the combined extracts were washed with water (300 ml), dried over magnesium sulphate and evaporated to give an oil. Trituration with petroleum ether (b.p. 40°-60°, 200 ml) gave a second crop of 2'-(methylamino)acetophenone, m.p. 36°-38°.
Reaction SMILES: [O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])[C:3]=1[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31]>ClCCl.C(O)(C(F)(F)F)=O>[O-:1][N+:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14]([OH:16])=[O:15])=[O:11])[C:3]=1[S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)CCOc1no[n+]([O-])c1S(=O)(=O)c1ccccc1)C(=O)O

Procedure:
A solution of the compound obtained in Step A (3 g-5.5 mmol) in 100 ml of dichloromethane and 15 ml of TFA is stirred for 6 hours under argon. The solvents are distilled off in vacuo. The residue is triturated in diisopropyl ether, filtered off with suction and then dried in vacuo to yield the expected product in the form of white crystals.
Reaction SMILES: ClC1C=C(SC2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.C(O)C1C=CC=CC=1.N1C=CC=CC=1>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=2)=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: OCc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c(C(=O)OCc3ccccc3)c(Sc3ccc(Cl)cc3)c2c1
Yield: 37 %

Procedure:
Following the method used to prepare 24a, the use of 1b (0.23 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with benzyl alcohol (35 μL, 0.34 mmol) in presence of pyridine (54 μL, 0.68 mmol) provided 35 mg (37%) of product 16 as a pale yellow foam. 1H NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3H), 5.35 (s, 2H), 7.00 (d, J=9 Hz, 2H), 7.20 (d, J=9 Hz, 1H), 7.26 (d, J=9 Hz, 2H), 7.29-7.38 (m, 6H), 7.47 (d, J=9 Hz, 1H), 12.44 (s, 1H). LC-MS (CI): m/z 408.1 [(M+H)+ C23H18ClNO2S requires 407.6]. Purity (100%). Calcd for C23H18ClNO2S: C, 67.72; H, 4.45; N, 3.43; S, 7.86; Cl, 8.69. Found: C, 67.53; H, 4.55; N, 3.42; S, 8.09; Cl, 8.45.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+].Cl>O1CCCC1.O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:19][C:6]1[C:5]([CH2:4][C:3]([OH:2])=[O:20])=[C:9]([CH3:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:30]#[C:29][C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[N:7]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(Br)cc2)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccc(C#Cc3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)O
Reaction time: 1 h

Procedure:
Heck coupling: A solution of [1-(4-bromo-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 12.1.1, 500 mg, 1.5 mmol), 4-trifluoromethyl-phenylacetylene (0.24 ml, 1.5 mmol) and diisopropylethylamine (0.51 ml, 3 mmol) in 15 ml tetrahydrofurane was degassed, and CuI (28 mg, 0.15 mmol) and bis-(triphenylphosphin)-palladium dichloride (104 mg, 0.15 mmol) were added to the solution. The mixture was refluxed for 12 h, the solvent evaporated under reduced pressure, and the residue was purified by MPLC (silica gel, cyclohexane/ethyl acetate 98:2). Saponification: The ester intermediate (170 mg, 0.4 mmol) was dissolved in 1 ml dioxan, 1 ml water and aqueous NaOH solution (0.8 ml, 1 M) was added. After stirring for 1 h, aqueous HCl solution (0.84 ml, 1 M) was added. The mixture was extracted with ethyl acetate, the organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 9:1) and preparative reversed phase HPLC (gradient of methanol in water+0.1 NH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1.O>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:1]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: ClCCNCCCl
Reactant: Nc1cc(Cl)cc2cccnc12
Agent: Cl
Solvent: Clc1ccccc1
Solvent: O
Product: Clc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 135 °C
Reaction time: 120 h
Yield: 29.4 %

Procedure:
8-amino-6-chloroquinoline (Step 1, 0.49 g) and bis(chloroethyl)amine hydrochloride (0.49 g) were dissolved in chlorobenzene (13 mL) and heated with vigorous stirring at 135° C. for 5 days. The reaction was cooled to room temperature, diluted with water and extracted with Et2O. The aqueous phase was made basic by addition of solid Na2CO3 and then extracted with Et2O. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give the desired compound (0.20 g) as a yellow semi-solid; MS (ES) m/z (relative intensity) 248 (M+H)+ (100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C.[OH-].[Na+]>[Br:26][C:14]1[S:13][C:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:11][C:10]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(-c2csc(C3CCOCC3)n2)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2nc(C3CCOCC3)sc2Br)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole (113 mg, 0.390 mmol) in acetic acid (10.5 mL), sodium acetate (71 mg, 0.866 mmol, 2.2 eq.) was added, and the mixture stirred for 30 min. To the solution so obtained, bromine was added dropwise and the reaction followed by HPLC up to completion (total Br2: 44 μL, 137 mg, 0.86 mmol, 2.2 eq). The solution was poured in 100 mL of 1M sodium hydroxide and extracted three times with ethyl acetate. The organic layer was washed with brine, dried up with sodium sulfate and evaporated to dryness to yield 5-bromo-4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole (141 mg, 100%)
Reaction SMILES: [OH:1][CH2:2]CN1C(C)(C)CCCC1(C)C.[O:14]1[CH2:30][CH:15]1[CH2:16][O:17][CH2:18][CH2:19]N1C(C)(C)CCCC1(C)C>>[CH2:18]([O:17][CH2:16][CH:15]1[O:14][CH2:30]1)[CH:19]1[O:1][CH2:2]1
Reactant: CC1(C)CCCC(C)(C)N1CCO
Reactant: CC1(C)CCCC(C)(C)N1CCOCC1CO1
Product: C(OCC1CO1)C1CO1

Procedure:
From 1-(2-hydroxyethyl)-2,2,6,6-tetramethylpiperidine: 1-(5,6-epoxy-3-oxahexyl)-2,2,6,6-tetramethylpiperidine, boiling point 88°-90° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][CH2:35][OH:36])[CH:29]=[CH:28]2)(C)C>C1COCC1>[C:24]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][CH2:35][OH:36])[CH:29]=[CH:28]2)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1ccc2c(ccn2CCO)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(ccn2CCO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere 29 g (91.8 mmol) TBAF are added to a solution of 21.5 g (83.5 mmol) 2-(5-trimethylsilanylethynyl-indol-1-yl)-ethanol in 500 mL THF and the reaction mixture is stirred for 1.5 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 300 mL EtOAc, the organic phase is washed twice with in each case 200 mL water and once with 200 mL saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the desired product is obtained in the form of a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2].[CH2:21](OC(C1C=CN(CC2C=CC=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:21]=2)[C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(Cc2ccccc2)c1C
Reactant: CCOC(=O)c1c(Br)c(Br)n(-c2ccccc2)c1CBr
Product: CCOC(=O)c1c(Br)c(Br)n(Cc2ccccc2)c1CBr

Procedure:
Prepared in analogy to that of 4,5-dibromo-2-bromomethyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (Example 1(a)) from 1-benzyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester; the title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=7.30 (m, 3H), 7.00 (m, 2H), 5.40 (s, 2H), 4.77 (s, 2H), 4.35 (q, 2H, J=6.8 Hz), 1.40 (t, 3H, J=6.8 Hz).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:16][C:17](=[O:22])[NH:18][CH2:19][C:20]#[CH:21])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:16][C:17](=[O:22])[NH:18][CH2:19][C:20]#[CH:21])=[CH:11][CH:10]=1
Reactant: C#CCNC(=O)CC(NC(=O)NCC(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCNC(=O)CC(NC(=O)NCC(=O)OCC)c1ccc(N)cc1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
ethyl 2-(3-(1-(4-(tert-butoxycarbonylamino) phenyl)-3-oxo-3-(prop-2-ynylamino)propyl)ureido)acetate (108 mg) was dissolved in 4 ml of DCM and 2 ml of TFA was added then the reaction mixture was let 2 h at room temperature. The mixture was concentrated and the crude was purified on reverse phase (H2O/MeCN) to afford the amine 201 (50 mg, 60%) as a white solid, Rf=0.45 (EtOAc/MeOH 90/10). 1H NMR (200 MHz, DMSO) δ 8.25 (t, J=5.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 2H), 6.56 (d, J=8.5 Hz, 1H), 6.50 (d, J=8.3 Hz, 2H), 6.27 (t, J=6.0 Hz, 1H), 5.05-4.79 (m, 3H), 4.10 (q, J=7.1 Hz, 2H), 3.86-3.71 (m, 4H), 3.14-3.08 (m, 1H), 2.58-2.45 (m, 2H), 1.21 (t, J=7.1 Hz, 3H). HPLC method A tr=5.12 nm (98.1%). ESI-MS m/z: 347.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>CO>[CH3:13][O:12][C:8](=[O:11])[CH2:9][CH2:10][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=CC(=O)OC
Reactant: CCCCCNC
Solvent: CO
Product: CCCCCN(C)CCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
106 g (1.05 mol) N-methyl-N-pentylamine was added to cooled methanol of a temperature of 0–5° C. 108 g (1.25 mol) methyl acrylate was added to the solution and the mixture was stirred at room temperature for 8 hours. Then methanol was distilled off in vacuo and the residue was purified by distillation to obtain 188.6 g N-methyl-N-pentyl-β-alanine methyl ester (96.1%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2([C:15]([O-:17])=[O:16])[CH2:14][O:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+]>C(OCC)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2([C:15]([OH:17])=[O:16])[CH2:14][O:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C1(CCCCCc2ccccc2)CO1
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)C1(CCCCCc2ccccc2)CO1
Temperature: 0 °C

Procedure:
3 g of sodium 2-(5-phenylpentyl)oxirane-2-carboxylate are thoroughly shaken with 70 ml of ice-cold 1 N hydrochloric acid and 50 ml of diethyl ether; the organic phase is collected, dried over sodium sulfate and concentrated. 1.7 g of the title compound remain as a viscous, colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CS(O[CH:26]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[CH3:27])(=O)=O>>[F:34][C:32]1[CH:33]=[C:28]([CH:26]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:12]3[C:7]4[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:20][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:15][CH2:16]2)[CH3:27])[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: CC(OS(C)(=O)=O)c1cc(F)cc(F)c1
Reactant: CC(C)Cc1cc2c(NC3CCNCC3)ncnc2s1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4cc(F)cc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (127 mg, 69%) from 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (125 mg, 0.43 mmol) and 1-(3,5-difluorophenyl)ethyl methanesulfonate (243 mg, 1.03 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.75 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.15 (m, 1H), 3.45 (m, 1H), 2.95 (m, 1H), 2.80 (m, 1H), 2.70 (d, 2H), 2.20 (m, 4H), 1.95 (m, 1H), 1.55 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed: 431.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(O[C:29](N(C)C)=[N+:30](C)[CH3:31])C2C=CC=CC=2N=N1.Cl.CNC.C(N(CC)C(C)C)(C)C>ClCCl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:11])[N:30]([CH3:31])[CH3:29])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
(R)-2-(tert-Butoxycarbonylamino)propanoic acid (1.0 g, 5.3 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.8 g, 5.6 mmol) were dissolved in 13 mL of dichloromethane. Dimethylamine hydrochloride (0.64 g, 7.8 mmol) and N,N-diisopropylethylamine (3.6 mL, 20.8 mmol) were added and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and water was added. The layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 1.16 g (100%) of ((R)-1-dimethylcarbamoyl-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1.[OH-].[Na+].O>O1CCOCC1.C(Cl)Cl>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([N:27]([CH3:26])[CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CNC1CCN(C)CC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N(C)C3CCN(C)CC3)n2)cc1Cl
Yield: 30.9 %

Procedure:
To 133 (10.014 g, 26.2 mmol) in 1,4-dioxane (80 mL) was added slowly methyl-(1-methyl-piperidin-4-yl)-amine (3.8 mL, 26.2 mmol) dissolved in 1,4-dioxane (15 mL) by addition funnel. Then aqueous sodium hydroxide (10.5 mL, 2.5 N, 26.2 mmol) was added by addition funnel followed by water (26 mL). The reaction mixture was heated at reflux for about 2.5 hours under a nitrogen atmosphere. The reaction was cooled and diluted with methylene chloride. The reaction mixture was filtered using vacuum and the white solid 147 removed. The filtrate was then washed 1 time with brine. The aqueous layer was back extracted 1 time with methylene chloride. The organic layers were combined and dried over potassium carbonate. The organic solution was filtered and concentrated in vacuo to afford the crude product (5.89 g). The crude reaction product was purified by flash column chromatography (silica gel) eluting with 96:3:1 methylene chloride:methanol:15 M ammonium hydroxide. The fractions were combined, dried over sodium sulfate/potassium carbonate, filtered, and concentrated in vacuo to afford 137 as a white solid (3.84 g, 30.9%), mp 104-105° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 13.8 min, 97% purity); MS (ESI): m/z 474 (M+H, 41), 408 (2.3), 364 (2.8), 258 (13), 239 (14), 239 (47.5), 238 (100), 127 (5.3).
Reaction SMILES: [C:1]1([C:7]([C:24]2NN=[N:26][N:25]=2)([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:1]1([C:7]([C:24]2[O:31][C:29]([CH3:30])=[N:26][N:25]=2)([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C(CCN2CC3CCC2CC3)(c2cccnc2)c2nnn[nH]2)cc1
Solvent: c1ccncc1
Product: Cc1nnc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2cccnc2)o1

Procedure:
2.0 Parts of 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole was reacted with 4.0 parts of acetic anhydride in pyridine and refluxed for 2 hours to provide 5-[1-phenyl-1-(3-pyridyl)- 3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([Cl:32])[CH2:30][CH3:31]>CC(=O)CC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:31][CH2:30][CH2:29][Cl:32])[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Cl)Br
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCCCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
A mixture comprising 20 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 14.43 g of potassium carbonate, 16.44 g of bromochloropropane and 200 ml of 2-butanone, was refluxed under heating with stirring for 16 hours. The mixture was cooled to room temperature. Then, inorganic substances were filtered off, and the filtrate was distilled under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was crystallized from diethyl ether/n-hexane to obtain 23.19 g of the above-identified compound as white crystals.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH2:31].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:27][O:28][C:29](=[O:38])[C@H:30]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[NH:31][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Yield: 96.1 %

Procedure:
To a suspension of 0.89 g of 2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionic acid and 0.79 g of L-histidine methyl ester dihydrochloride in 23 ml of N,N-dimethylformamide were added 0.70 ml of diphenylphosphoryl azide and 1.50 ml of triethylamine with stirring under ice-cooling, and then the mixture was additionaly stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To the residue was added diethyl ether, and the precipitate was collected by filtration to obtain 1.25 g of N-[2-(1-naphthylmethyl)-3 -(morpholinocarbonyl)propionyl]-L-histidine methyl ester as a white powder. To a soluiton of 0.98 g of the ester compound in 10 ml of methanol was added 0.52 g of hydrazide monohydrate, and then the mixture was stirred for 4 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1 by volume) to obtain 0.23 g of N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-histidine hydrazide having an Rf1 value of 0.49 as a white powder.