Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:54]=[CH:55][CH:56]=1)[CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:17]=[C:15]([N:51]1[CH2:50][CH2:49][N:48]([CH2:47][C:46]2[CH:54]=[CH:55][CH:56]=[C:44]([C:43]([F:57])([F:58])[F:42])[CH:45]=2)[CH2:53][CH2:52]1)[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
To 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.057 g, 0.244 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.098 g, 0.257 mmol) and 1-(3-(trifluoromethyl)benzyl)piperazine (0.066 g, 0.269 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.064 mL, 0.367 mmol) and the reaction was allowed to stir at room temperature. After stirring overnight, the reaction was loaded directly onto a silica gel column (Analogix®, SF15-12), and the product was eluted using a gradient of 0.4% to 3.75% methanol/dichloromethane over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.58-7.60 (br s, 1H), 7.49-7.55 (m, 2H), 7.41-7.47 (m, 1H), 7.27-7.35 (m, 3H), 7.18-7.26 (m, 2H), 4.47 (d, J=15.7 Hz, 1H), 4.03 (d, J=15.7 Hz, 1H), 3.68-3.73 (m, 1H), 3.59-3.67 (m, 2H), 3.56-3.62 (m, 1H), 3.53-3.59 (m, 2H), 3.47-3.52 (m, 2H), 3.39-3.45 (m, 1H), 2.42-2.49 (m, 4H), 2.17-2.28 (m, 1H), 1.87-2.05 (m, 3H); MS (ESI−) m/z 458 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5](O)=[O:6].[Cl:15]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([Cl:15])=[O:6]
Reactant: ClCCl
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Temperature: 0 °C

Procedure:
A round bottom flask was charged with 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (available from Paragos Product List, 10.2 g, 47.5 mmol), dichloromethane (158 ml) and oxalyl chloride (8.29 ml, 95 mmol). The reaction mixture was cooled to 0° C. in an ice/water bath prior to the addition of N,N-dimethylformamide (0.158 ml). The solution was allowed to warm to ambient temperature overnight. The solvent was evaporated to yield the title compound as a cream solid (11.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[N+](C)=CCl.[Cl-].[C:22]([O-])(=[O:24])C.[Na+]>ClCCCl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([CH:22]=[O:24])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)N1CCc2cc(C=O)sc2CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylic acid ethyl ester (1.50 g, 6.65 mmol) in 1,2-dichloroethane (20 ml) was added Vilsmeier reagent (1.49 g, 11.65 mmol). The reaction mixture was heated to 70° C. for 5 hours. The reaction mixture was allowed to cool to RT followed by addition of 1 M sodium acetate (20 ml). The mixture was vigorously stirred for 2 hours and then diluted with water (50 ml). The resulting solution was extracted with DCM (3×). The combined DCM extracts were washed with water, brine, and dried over MgSO4. The resulting mixture was filtered and solvent evaporated in vacuo to give the subtitled compound as a tan oil (1.56 g) that was used without further purification. MS: ESI (positive): 254 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:6]=1[NH:7][C:8]1[C:9]([C:16]([O:18]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=1>C1COCC1>[F:4][C:5]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:6]=1[NH:7][C:8]1[C:9]([C:16]([N:2]([CH3:3])[CH3:1])=[O:18])=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=1
Reactant: CNC
Reactant: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2F)cc1=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
Dimethylamine (40% in aqueous solution) was added to 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate in THF as for example 37, step B, and the solution stirred at RT for 15 h. The resultant precipitate was removed by filtration and washed with hexane and Et2O. The filtrate was concentrated under reduced pressure and triturated with hexane to give 4-(2-fluoro-4-iodoanilino)-N,N,1-trimethyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow solid (58%); m.p. 106-111° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2SO] δ 8.21 (s, 1H), 7.79 (s, 1H), 7.72 (dd, J=10.2, 1.9 Hz, 1H), 7.56 (dt, J=8.4, 1.2 Hz, 1H), 7.16 (t, J=8.4 Hz, 1H), 5.41 (d, J=1.2 Hz, 1H), 3.34 (s, 3H), 2.98 (s, 6H). HRMS (FAB+) calcd for C15H16FIN3O2 416.0271 (M+), found 416.0270. HPLC 97.2% (254 nm).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1C(OC(C)(C)C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[ClH:47]>CS(C)=O.O.ClCCl>[ClH:47].[NH:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[CH2:28][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (200 mg, 0.56 mmol), (S)-tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate (GRA-B-188) (298 mg, 1.12 mmol), and cesium carbonate (732 mg, 2.25 mmol) in methyl sulfoxide (5 mL) was stirred overnight at ambient temperature. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Isolation of the desired regioisomer was performed by column chromatography (silica gel, Et2O to 9:1 Et2O/90:9:1 Et2O/MeOH/concd NH4OH). To the desired regioisomer (100 mg, 0.18 mmol) was added dichloromethane (10 mL) and trifluoroacetic acid (2 mL). After stirring at ambient temperature for 2 h, the reaction was brought to pH=9 with 1N NaOH. The organic layer was washed with brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The dried residue (87 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.22 mL, 0.17 mmol) was added. The mixture was concentrated under reduced pressure and then triturated with dichloromethane/hexanes and the obtained solid was triturated with diethyl ether. The solid was dried to afford the title compound (43 mg, 16%) as an off-white solid: mp 241-245° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.05 (br s, 2H), 8.28 (s, 1H), 8.03-7.85 (m, 7H), 7.51 (d, J=8.5 Hz, 1H), 6.89 (s, 1H), 6.75 (d. J=7.0 Hz, 1H), 4.80 (d, J=6.0 Hz, 2H), 3.99-3.95 (m, 1H), 3.30-3.23 (m, 1H), 3.16-3.10 (m, 1H), 2.08-2.03 (m, 1H), 1.99-1.96 (m, 1H), 1.91-1.85 (m, 1H), 1.74-1.70 (m, 1H); ESI MS m/z 439 [M+H]+; HPLC (Method B) 98.7% (AUC), tR=15.5 min; [α]23D +20.5° (c 0.13, Methanol).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][S:17]([CH:20]=[CH:21][C:22]3[S:23][C:24](Cl)=[CH:25][CH:26]=3)(=[O:19])=[O:18])[C:11]2=[O:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][S:17]([CH2:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:18])[C:11]2=[O:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N2CCC[C@H](NS(=O)(=O)C=Cc3ccc(Cl)s3)C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCC(N2CCC[C@H](NS(=O)(=O)CCc3cccs3)C2=O)CC1

Procedure:
A mixture of (S)-2-(5-chloro-thiophen-2-yl)-ethenesulfonic acid (1′-isopropyl-2-oxo-[1,4′]bipiperidinyl-3-yl)-amide (example 31, 10 mg) in MeOH (1.0 mL) was hydrogenated in the presence of catalytic amount of 5% Pd/C at 1 atm 1 hr. Filtration and HPLC purification (30% to 100% acetonitrile/water gradient) gave the desired product as a white solid. LC-MS found: (M+1)+=414.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1)[C:6]([NH:8][NH:9]C(OCC1C=CC=CC=1)=O)=[O:7]>CO.[OH-].[Pd+2].[OH-].[C]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1)[C:6]([NH:8][NH2:9])=[O:7]
Reactant: COc1cc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
To a solution of benzyl N′-[3-methoxy-4-(4-methylimidazol-1-yl)benzoyl]hydrazinecarboxylate (1.25 g) in methanol (60 mL) was added 20% palladium hydroxide-carbon (50% wet, 250 mg) and the mixture was hydrogenated at an intermediate pressure (3.8 atm) for two hours and 30 minutes. The palladium-carbon was removed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain 826 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]2([CH2:4][O:22]2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CN2CCC3(CC2)CO3)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
60% sodium hydride (25.4 g) was added to anhydrous dimethylsulfoxide (400 mL) and the mixture was stirred at room temperature under nitrogen atmosphere. Trimethylsulfoxonium iodide (140 g) was added gradually to the mixture at 20 to 28° C., and the mixture was stirred at room temperature for sixty minutes. An anhydrous dimethylsulfoxide solution (400 mL) of 1-benzyl-4-piperidone (100 g) was added dropwise to the mixture. After stirring the resulting mixture at room temperature for sixty minutes, the reaction mixture was poured into ice-water (2.0 L) gradually with stirring. The mixture was extracted with ethyl acetate, and the organic layer was combined and washed with water (four times) and brine successively. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:9 to 1:1) to obtain the titled compound (86.7 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.C(N(CC)CC)C.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](Cl)=[O:37]>ClCCl>[Cl:34][C:35]([Cl:40])([Cl:39])[C:36]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8](=[O:9])[CH2:7][O:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:26])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:37]
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of step B (2.70 mmol) and triethylamine (0.76 mL) in dichloromethane (15 mL) was added trichloroacetyl chloride (0.90 mL). This was stirred and allowed to warm to room temperature overnight. The reaction mixture was washed with water (2×), 0.1N hydrochloric acid (2×), dilute aqueous sodium bicarbonate (2×) and finally, with water (1×). The organic phase was dried over anhydrous sodium sulfate and evaporated. The product was purified by crystallization from warm ethyl acetate/hexane (3/1), m.p. 156-158° C. MS [(+)ESI, m/z]: 511 [M+H]+ Anal. Calcd for C23H18Cl4O3: C, 53.93; H, 3.54; N, 5.47. Found: C, 53.90; H, 3.45; N, 5.40.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].Br[CH2:16][C:17](Br)=[O:18].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[C:17]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])=[C:7]([CH3:12])[CH:8]=1)(=[O:18])[CH3:16]
Reactant: Cc1ccccc1NC(=O)C(F)(F)F
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(NC(=O)C(F)(F)F)c(C)c1
Yield: 39.3 %

Procedure:
2,2,2-trifluoro-N-o-tolylacetamide (8.0 g; 39.4 mmol) was dissolved in 20 mL CS2. Bromoacetic bromide (8.4 g; 68.3 mmol) was added dropwise. AlCl3 (16.0 g; 120 mmol) was added in portions, with drying tube attached to the reaction flask. The reaction mixture was refluxed overnight. After reaction, the solvent was removed. Ice and water were added, and some yellow solid precipitated. The solid was isolated by filtration, and purified by silica gel column chromatography, to afford 3.8 g (yield 39%) of product as off-white solid. 1H NMR (300 MHz; CDCl3), δ 8.30 (s, 1H, Ar—H), 7.91 (brs, 1H, NH), 7.81 (d, 3JHH=8.2 Hz, 1H, Ar—H), 7.36 (d, 3JHH=7.9 Hz, 1H, Ar—H), 2.60 (s, 3H, COCH3), 2.36 (s, 3H, CH3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[H-].[Na+]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)nc(Oc2ccc(I)cc2)n1
Yield: 68.4 %

Procedure:
Under an argon atmosphere, phosphorus oxychloride (2 ml) was added to 4,6-dimethyl-2-hydroxypyrimidine (400 mg), and the resulting mixture was stirred for 1 hour while heating the mixture to reflux. The reaction solution was cooled to room temperature, and the cooled solution was added in small portions to water. After adding sodium hydrogen carbonate in small portions to the resulting mixture to neutralize it, the mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to obtain 2-chloro-4,6-dimethylpyrimidine (350 mg). (2) In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethylpyrimidine (157 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (226 mg),
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]#[N:19])[C:16](=[O:17])[N:5]2[CH2:4]1)[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O.O>[CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)[C:16](=[O:17])[N:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1Cn2c(ncc(C#N)c2=O)-c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1Cn2c(ncc(-c3nnn[nH]3)c2=O)-c2ccccc21
Reaction time: 19 h
Yield: 87 %

Procedure:
A mixture of (±)-7-ethyl-6,7-dihydro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carbonitrile (208 mg., 0.836 mmole), sodium azide (59.8 mg., 0.92 mmole), and ammonium chloride (49.1 mg., 0.92 mmole) in N,N-dimethylformamide (2 ml.) was stirred for 19 hours at an oil bath temperature of 120°. The mixture was diluted with water and acidified with dilute hydrochloric acid to precipitate 215 mg. (87% yield) of the tetrazole, m.p. 254°-258° with decomposition. Recrystallization from acetic acid provided pale yellow crystals of the analytical sample, m.p. 282°-283.5° with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:10]1[CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:35][CH2:36][CH2:37][C:38](=[O:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: NCCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with 3-amino-1-phenyl-propan-1-one there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-oxo-3-phenyl-propylcarbamoyl)-phenyl]-piperidine-1-carboxylate as a colourless foam; MS: 593 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C=O)C.O.C(OCC)(=O)C>[CH2:16]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a stirred solution of 4-cyanophenol (50 g, 0.42 mol) and potassium carbonate (150 g, 1.1 mol) in DMF (800 ml) was added benzyl bromide (75 ml, 0.63 mol). The reaction mixture was stirred for 2 h at room temperature before filtering off solid and reducing the filtrate in vacuo to give an oil. The solid precipitate was dissolved in water and the pH adjusted to 0.5 using 6.0M hydrochloric acid and extacted into ethyl acetate. The solvent was dried over magnesium sulphate and removed by evaporation in vacuo to give an oil. The two oil products were combined and triturated with diethyl ether/hexane to give a white solid, which was washed with hexane and dried to give the title compound (81 g, 93%). 1H NMR (CDCl3) δ 7.5 (2H, d, 1 8.6 Hz), 7.45-7.30 (5H, br m), 7.0 (2H, d, J 8.6 Hz) and 5.14 (2H, s). MS (ES) m/e 210 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[C:3]([NH:5][C@H:6]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([N:9]1[CH2:26][CH2:25][CH2:24][C@:11]2([C:15](=[O:16])[N:14]([CH3:17])[CH2:13][C@H:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)=[O:8])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:2]([CH3:36])([CH3:1])[C:3]([NH:5][C@H:6]([CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:7]([N:9]1[CH2:26][CH2:25][CH2:24][C@:11]2([C:15](=[O:16])[N:14]([CH3:17])[CH2:13][C@H:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10]1)=[O:8])=[O:4]
Reactant: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 2-methyl-1-((R)-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxo-4-phenoxybutan-2-ylamino)-1-oxopropan-2-ylcarbamate (38.7 mg; 0.064 mmol) was solubilised in DCM (0.5 ml). TFA (0.125 ml; 1.622 mmol) was added and the solution stirred at RT for 20 minutes before being concentrated in vacuo. The residual oil was dissolved in methanol (1 ml) and passed through a 1 g SCX-2 cartridge eluting with 2M NH3 in methanol (4 ml. Evaporation gave the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C1C(=O)N([O:16][C:17]([C:19]2[C:24]([F:25])=[C:23]([F:26])[C:22]([N:27]=[N+:28]=[N-:29])=[C:21]([F:30])[C:20]=2[F:31])=O)C(=O)C1.Cl>CS(C)=O>[N:27]([C:22]1[C:21]([F:30])=[C:20]([F:31])[C:19]([C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:16])=[C:24]([F:25])[C:23]=1[F:26])=[N+:28]=[N-:29]
Reactant: NCCCCC(=O)O
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)ON2C(=O)CCC2=O)c(F)c1F
Agent: Cl
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)NCCCCC(=O)O)c(F)c1F
Reaction time: 8 h

Procedure:
To a solution of 5-aminovaleric acid (12 mg, 100 μmol) in dry DMSO (250 μL) was added N-succinimidyl 4-azido-2,3,5,6-tetrafluorobenzoate (25 mg, 75 μmol). The reaction was allowed to proceed overnight at 45° C. in the dark. The mixture was then acidified with 250 μL of 0.5 N hydrochloric acid and extracted with 400 μL of ethyl acetate three times. The combined extracts were concentrated in vacuo and purified by silica chromatography using 2:1 hexane-ethyl acetate to yield the desired product as a white powder. Yielded: 3 mg, 9 μmol, 12%. TLC: Rf=0.3 (1:1 hexane-ethyl acetate) 1H-NMR (300 MHz, (CD3)2SO): δ 12.03 (s, 1H), 8.89 (t, 1H, J=5.4), 3.23 (q, 2H, J=6.3), 2.22 (t, 2H, J=7.2), 1.497 (m, 4H). ESI-MS m/z: (neg) 333.07 [M−H]−. Calc. 334.23
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Br[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)[C:20](=[O:24])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: BrCc1cncnc1
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1cncnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyrimidinone and 5-(bromomethyl)pyrimidine. LC-MS (ESI): m/z 503 [M+H]+; 3.55 min (ret time).