Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH:7]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C@@H:21]([CH3:35])[CH2:20]2)=[O:18])[CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[F:38].[ClH:39]>C(Cl)Cl>[ClH:1].[ClH:39].[NH2:9][CH2:8][CH:7]([CH2:6][C:5]1[CH:36]=[CH:37][C:2]([Cl:1])=[C:3]([F:38])[CH:4]=1)[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]3[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=3[N:28]=[CH:29][N:30]=2)[C@@H:21]([CH3:35])[CH2:20]1)=[O:18]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(CNC(=O)OC(C)(C)C)Cc4ccc(Cl)c(F)c4)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(CN)Cc4ccc(Cl)c(F)c4)C[C@@H]3C)c21
Yield: 99 %

Procedure:
tert-Butyl 2-(4-chloro-3-fluorobenzyl)-3-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate was treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours to provide 2-(aminomethyl)-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (50 mg, 99%). MS (APCI+) [M+H] +446.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:33]([C@@H:38]([C@H:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[OH:41])O)([O:35][CH2:36][CH3:37])=[O:34]>C1(C)C=CC=CC=1>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[O:41][CH:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:38]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[O:8]3)=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)C1OC(c2ccc3c(c2)OCO3)OC1C(=O)OCC
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of piperonal (60 g, 0.4 mol), triethyl orthoformate (59.2 g, 0.4 mol), toluene (250 mL) and p-toluenesulfonic acid (2 g, 0.01 mol) was heated at 100°-110° C. for 0.5 h. Diethyl L-tartrate (103 g, 0.5 mol) was added to the hot solution over a 10 min. period. The mixture was then heated at reflux for 2 h. Subsequently over a 3 hour period, distillate (150 mL) was collected (pot temperature 84° C. to 110° C). The mixture was cooled (25° C.) and washed with sodium bicarbonate solution (2×50 mL) and brine (1×50 mL). Evaporation of solvents under reduced pressure provided 130.7 g of crude product. Recrystallization from methanol provided 90 g (67% yield) of (4R,5R)-2-(3,4-methylenedioxyphenyl-4,5-dicarboethoxy-1,3-dioxolane, mp 39°-40° C., [α]D25 -34.8° (c, 1.0 methanol). 1H-NMR (CDCl3)δ7.12 (1H,d,J=1.5 Hz), 7.03 (1H,dd,J= 1.5 Hz and 7.9 Hz), 6.80 (1H,d,J=7.9 Hz), 6.06 (1H,s), 5.97 (2H,s), 4.91 (1H,d,J=4.0 Hz), 4.80 (1H,d,J=4.0 Hz), 4.36-4.26 (4H, 2 q, overlapping, J=7.0 Hz), 1.38-1.30 (6H, 2 t, overlapping, J=7.0 Hz). IR (KBr) 2980, 2900, 1735, 1490, 1445, 1415 cm-1. MS m/e (% abundance) 338 (3), 265 (16), 166 (100), 149 (96), 135 (54), 121 (35), 93 (10), 65 (12), 43 (8).
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:30](=[N:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:21]2.[CH:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:30](=[N:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:22]1([CH2:27][CH2:26][N:25]([C:39]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:40])[CH2:24][CH2:23]1)[CH2:21]2
Reactant: O=C(O)C1CCCC1
Reactant: O=C1Nc2ncc(Br)cc2CC12CCNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCCC1)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
DIPEA (1.22 mL, 8.82 mmol) was added to a stirred solution of 6-bromo-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Intermediate-14) (600 mg, 1.47 mmol), cyclopentanecarboxylic acid (250 mg, 2.20 mmol), HOBt (390 mg, 2.94 mmol) and EDC.HCl (700 mg, 3.67 mmol) in dry DMF (5 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (100 mL), obtained solid was filtered, washed with water and dried under vacuum to get the desired compound as an off-white solid (250 mg, 43%); 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 3.76-3.67 (m, 3H), 3.47-3.41 (m, 1H), 2.99 (s, 2H), 2.96-2.94 (m, 1H), 1.90-1.72 (m, 4H), 1.71-1.56 (m, 4H), 1.55-1.42 (m, 2H), 1.38-1.23 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9].[CH3:20][C:21]1[C:22]([CH2:28][N:29]([CH2:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:8]([N:33]1[CH2:34][CH2:35][CH:30]([N:29]([CH2:28][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[CH2:36][C:37]2[C:42]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:31][CH2:32]1)=[O:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(=O)Nc3ccccn3)CC2)c(C)c1
Yield: 80.5 %

Procedure:
To a solution of 2-aminopyridine (69 mg, 0.73 mmol) in CH2Cl2 (5 mL) was added 1,1′-carbonyldiimidazole (122 mg, 0.75 mmol) and the reaction stirred at reflux for 2 h 15 min. after which a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidine-4-yl-amine (87 mg, 0.247 mmol) in CH2Cl2 (3 mL) was added and the reaction stirred at reflux for 2.5 h. The solution was cooled, treated with saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 100:1:1 then 50:1:1) provided COMPOUND 284 (94 mg, 81%) as a colorless oil: 1H NMR (CDCl3) δ 0.92 (d, 6H, J=6.9 Hz), 1.62-1.75 (m, 2H), 1.92-1.98 (m, 3H), 2.16 (s, 3H), 2.28 (s, 3H), 2.72-2.85 (m, 4H), 3.77 (s, 2H), 3.83 (s, 2H), 4.17-4.21 (m, 2H), 6.92 (dd, 1H, J=6.6, 5.4 Hz), 7.14 (dd, 1H, J=7.8, 4.8 Hz), 7.24 (br s, 2H), 7.50 (dd, 1H, J=7.8, 1.2 Hz), 7.63 (dt, 1H, J=6.9, 1.8 Hz), 8.01 (d, 1H, J=8.4 Hz), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.5 Hz). 13C NMR (CDCl3) δ 18.29, 18.45, 23.60, 27.45, 44.80, 54.32, 57.34, 113.61, 118.62, 123.18, 132.28, 133.19, 133.86, 138.48, 139.06, 144.39, 146.08, 146.65, 147.81, 153.27, 154.03, 154.42, 156.23. ES-MS m/z 495 (M+Na). Anal. Calcd. for C28H36N6O.0.8CH2Cl2: C, 63.99; H, 7.01; N, 15.55. Found: C, 64.33; H, 7.28; N, 15.68.
Reaction SMILES: [C:1]1([S:11]([NH2:14])(=[O:13])=[O:12])[C:2]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C[Al](C)C.C[O:20][C:21](=O)[NH:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([O:31][CH3:32])[N:24]=[C:23]([NH:22][C:21]([NH:10][S:7]([C:2]2[C:1]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:9])=[O:8])=[O:20])[N:28]=1
Reactant: NS(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2S(N)(=O)=O)n1
Temperature: 25 °C
Yield: 17 %

Procedure:
To a suspension of 0.7 g of 1,2-benzenedisulfonamide and 1.5 ml of trimethylaluminum in 70 ml of anhydrous methylene chloride was added 0.6 g of 4,6-dimethoxypyrimidin-2-ylcarbamic acid methyl ester under N2 with stirring. After addition, the mixture was stirred at room temperature for 30 minutes and was then heated to reflux for 12 hours. The reaction mixture was then cooled down to room temperature. To this mixture was added 50 ml of methylene chloride, 100 ml of water, 10 ml of acetic acid and 5 drops of concentrated hydrochloric acid. The mixture was then stirred at room temperature for 20 minutes and was filtered. The organic layer was then separated, washed with water, dried over sodium sulfate and concentrated. The residue was then chromatographed on silica gel (CH2Cl2 /acetic acid 1:1) to yield 0.2 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-1,2-benzenedisulfonamide, m.p. 192°-193° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]([CH2:15][OH:16])[CH2:20][OH:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCOCCOCc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: OCC(CO)CCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C6H5—CH2O—CH2CH2OCH2CH2—CH(COOC2H5)2 (5 g) from Step B was dissolved in 200 ml of toluene and 29.5 ml of LiA1H4 (1 M in THF) was added at 0-5° C. After stirring overnight at room temperature, 1 ml of water was added followed by 1.0 ml of 15% NaOH and 3.0 ml of water. The insoluble material was filtered and the filtrate was evaporated to dryness. The product was purified by flash chromatography on a silica gel column eluted with ethyl acetate. Combined fractions were evaporated to dryness. The final product was dried under vacuum overnight.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[C:13]([CH3:20])=[CH:12][S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: N#Cc1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1csc2nc(-c3ccccn3)nc(Cl)c12

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-4-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[Cl:24][C:25]1[C:30](C=O)=[C:29](Cl)[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]2[N:9]([C@H:10]3[CH2:11][CH2:12][C@@H:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:22])[CH3:23])[N:17]=4)[CH2:14][CH2:15]3)[N:8]=[CH:6][C:30]=12
Reactant: CC(C)c1noc([C@H]2CC[C@@H](NNC(=O)OC(C)(C)C)CC2)n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc([C@H]2CC[C@@H](n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (Intermediate 13; 309 mg, 2.03 mmol) in tetrahydrofuran (3 mL) was added to a cooled (0° C.) solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 169 mg, 0.95 mmol) and diisopropylethylamine (337 μL, 1.9 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h. The mixture was filtered, and the filtrate was washed with brine. The aqueous layer was extracted with methyl tert-butyl ether and the organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, evaporated, and held under high vacuum. Toluene (10 mL) was added and the mixture was held at 110° C. overnight. The solvent was evaporated and the residue was purified on a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (211 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:12]
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
A solution of (3-bromo-phenyl)-acetic acid methyl ester (0.6 g, 2.62 mmol) in dry N,N′-dimethylformamide is added to a stirred suspension of sodium hydride (60% in mineral oil, 0.26 g, 6.55 mmol) in dry N,N′-dimethylformamide at 0° C. and stirring is continued for 20 minutes. A solution of bis(2-bromoethyl) ether (0.39 mL, 3.14 mmol) in N,N-dimethylformamide is added drop-wise and the reaction mixture is stirred overnight, while warming to room temperature. The reaction is quenched with water, extracted twice with ethyl acetate, the combined extracts is washed with brine and water, dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (610 mg) used in the next step without further purification. LCMS: RT=2.81 minutes; MS: 299, 301 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2[nH]1)OCC(Cl)(Cl)Cl
Yield: 54.8 %

Procedure:
To a solution of 2-aminobenzimidazole (1.00 g, 7.51 mmol) and pyridine (0.714 ml, 9.01 mmol) in tetrahydrofuran (25 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.25 ml, 9.01 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and 1.27 g (54.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:10]1[N:14]([CH2:15][CH3:16])[C:13](SC)=[N:12][N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[O-:20][S:21]([O-:24])(=S)=O.[Na+].[Na+].[OH-].[Na+].[CH:29](Cl)(Cl)Cl>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:10]1[N:14]([CH2:15][CH3:16])[C:13]([S:21]([CH3:29])(=[O:24])=[O:20])=[N:12][N:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClC(Cl)Cl
Reactant: O=S([O-])([O-])=S
Reactant: CCn1c(SC)nnc1[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCn1c([C@@H](C)NC(=O)OC(C)(C)C)nnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a chloroform (293 ml) solution of the [(R)-1-(4-ethyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester (21.0 g) obtained in Example 8-(4), m-perchlorobenzoic acid (43.0 g) was added in four portions while being cooled with ice. The mixture was stirred for 3 hours at room temperature, and then stirred for 1 hour at 40° C. To the reaction mixture, Na2S2O3 (12.9 g) and an aqueous solution (300 ml) of sodium hydroxide (1 mol/liter) were added. The organic layer was separated, and washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a solvent mixture of hexane and ethyl acetate. Then, the purified substance was recrystallized using hexane and chloroform to obtain [(R)-1-(4-ethyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)ethyl]-carbamic acid t-butyl ester as a white powder (17.2 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([C:14]#[C:15][Si](C)(C)C)=[CH:11][CH:12]=3)[C:7]([CH3:21])([CH3:20])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CO.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCCCC>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=3)[C:7]([CH3:21])([CH3:20])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CC1(C)CCN(C2CC2)c2ccc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1)C(C)(C)CCN2C1CC1

Procedure:
Following general procedure E and using 1-cyclopropyl-6-trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (Intermediate 52, 0.40 g, 1.34 mmol), methanol and potassium carbonate (0.2 g, 1.47 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.17 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:5][C:6](=[O:27])[C@H:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:5][C:6](=[O:27])[C@H:7]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:8][C@H:9]([C:10]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Nc1ccccn1

Procedure:
A solution of 2.1 g of N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-S-benzyl-(L)-cysteine methyl ester, 0.60 g of 2-aminopyridine and 1.2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 25 ml of methylene chloride is stirred at room temperature overnight. The mixture is concentrated, ethyl acetate is added and washed with water, sodium bicarbonate, dried (Na2SO4), filtered and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetatemethylene chloride (1:9) to give N-[4-(2-pyridylamino-carbonyl)-(S,S)-2,4-dibenzylbutyryl]-S-benzyl-(L)-cysteine methyl ester (oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=C(C=C(Cl)C=1)N.N1C=CC=CC=1C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[C:6]([Cl:19])[CH:7]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: O=Cc1ccccn1
Product: Clc1cc(Cl)cc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-dichloroaniline (48.6 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3,5-dichlorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: C1C(=O)N(OC(CCCCCNC([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]2[S:35][CH2:34][C@@H:33]3[NH:36][C:37]([NH:39][C@H:32]23)=[O:38])=[O:26])=O)=O)C(=O)C1.C1(=O)[NH:44]C(=O)C=C1.[OH:47][C:48](CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=[O:49]>>[C:25]([NH:24][C@H:23]([C:48]([OH:49])=[O:47])[CH2:22][CH2:21][CH2:20][CH2:19][NH2:44])(=[O:26])[CH2:27][CH2:28][CH2:29][CH2:30][C@H:31]1[C@@H:32]2[C@@H:33]([NH:36][C:37]([NH:39]2)=[O:38])[CH2:34][S:35]1
Reactant: O=C1C=CC(=O)N1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C(CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Product: NCCCC[C@H](NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
and 6-(biotinamidocaproylamido) caproic acid N-hydroxysuccinimide ester (Sigma-Aldrich, product B3295), biotinamidocaproate-N-hydroxysuccinimide ester (Sigma-Aldrich, product B2643), biotinamidocaproic acid 3-sulfo-N-hydroxysuccinimide ester (Sigma-Aldrich, product B1022) and biotin-maleimide (Sigma-Aldrich, product B1267).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[OH:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[NH2:21][C:19]1[CH2:18][O:17][CH2:16][C@:15]2([C:14]3[CH:13]=[C:12]([O:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[N:11]=[CH:10][C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=2)=[CH:7][CH:6]=3)[N:20]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C#N)CO
Product: CC(C)(C#N)COc1cc2c(cn1)Oc1ccc(-c3cccc(F)c3)cc1[C@@]21COCC(N)=N1

Procedure:
The title compound was synthesized by steps analogous to those described in Method A4, but using Intermediate 10B, 3-hydroxy-2,2-dimethylpropanenitrile, and 3-fluorophenylboronic acid. MS m/z=459.3 [M+H]+. Calculated for C26H23FN4O3: 458.18.
Reaction SMILES: CN1CCOCC1.N#N.[C:10]([NH:13][C@H:14]([C:30]([OH:32])=O)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:12])[CH3:11].C(N=C=NCCCN(C)C)C.[C:44]([O:48][C:49](=[O:73])[CH:50]([CH2:71][NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:64][CH2:63][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:61][CH2:60]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:47])([CH3:46])[CH3:45]>ClCCl>[C:44]([O:48][C:49](=[O:73])[CH:50]([CH:71]([C:30](=[O:32])[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[NH:13][C:10](=[O:12])[CH3:11])[NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:60][CH2:61][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:63][CH2:64]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:46])([CH3:45])[CH3:47]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N#N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-Hydrobenztriazole (207 mg, 1.53 mmole) and N-methylmorpholine (235 mg, 2.36 mmole) were added to a stirred solution of N2 -acetyl-N6 -benzyloxycarbonyl-L-lysine (456 mg, 1.41 mmole) in dry dichloromethane at 0° C., followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (361 mg). The solution was stirred at 0° C. for 20 minutes and 3-{1-[(cis-4-ethoxycarbonylcyclohexyl)-carbamoyl]cyclopentyl}-2-(aminomethyl)propanoic acid t-butyl ester (500 mg, 1.18 mmole) in dichloromethane (10 ml) was added in one portion and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated under vacuum to a volume of 10 ml and partitioned between ethyl acetate and water. The organic phase was washed with water (2×50 ml), 2M hydrochloric acid (50 ml, 2×25 ml), sodium bicarbonate solution (2×25 ml) and brine and then dried (MgSO4) and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the title compound (610 g, 71%). Found: C, 63.34; H, 8.61; N, 7.45. C39H60N4O9 (0.25 H2O) requires C, 63.48; H, 8.33; N, 7.59%.