Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)[O:10][C:9]2=[O:19])=[N:6][CH:7]=1.C[Sn](C)(C)[C:22]1[S:26][C:25]([C:27]2[CH2:31][CH:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:24][CH:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:33][CH2:32][CH:30]1[O:29][N:28]=[C:27]([C:25]2[S:26][C:22]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][C@H:11]([CH2:13][N:14]5[CH:18]=[CH:17][N:16]=[N:15]5)[O:10][C:9]4=[O:19])=[N:6][CH:7]=3)=[CH:23][CH:24]=2)[CH2:31]1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(Br)cn1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)s2)cn1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
(5R)-3-(5-Bromopyrid-2-yl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (187 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 5 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (99 mg).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.CCOC(C)=O>O1CCOCC1>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a flask containing Boc-Leu-Pro-OBn (113.8 g, 272 mmol) a solution of hydrogen chloride in dioxane (209 ml, 5.3 N) was added and the stirring was continued for 5 h or until total conversion by TLC (disappearance of starting material; Rf=0.47 (hex-EtOAc 2:1, silica). The solution was concentrated under reduced pressure and the resulting oil was chased with CHCl3 (3×50 ml), CHCl3-MTBE (30 ml-50 ml), MTBE (50 ml) and hex (50 ml). The residue was dried under vacuum (16 h) to remove residual HCl, to give the title compound as a white solid. A5 (96.4 g, 100%) was used directly without further purification in the next step. [α]D22−85.21 (c=1, CHCl3).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].C(N)(=[O:31])C>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:31])=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CC(N)=O
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C#N)cc3)CC2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Temperature: 25 °C

Procedure:
The product of step A (150 mg, 0.398 mmol), acetamide (101 mg, 1.71 mmol) and Pd(OAc)2 (13.4 mg, 0.02 mmol) in THF (4.5 mL) and H2O (1.5 mL) was heated at 65° C. for 24 h. The mixture was cooled to RT and diluted with H2O. The solution was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 20:1 DCM:MeOH) to yield the desired compound. MS (ESI) m/z 395 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:20][C:18]1[CH:17]=[C:4]([CH:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[C:25]#[N:26])[CH:3]=[C:2]([CH3:1])[CH:19]=1
Reactant: Cc1cc(C)cc(C=Nc2ccc(S(N)(=O)=O)cc2)c1
Reactant: C[Si](C)(C)C#N
Product: Cc1cc(C)cc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3,5-dimethylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 90%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])=[O:5].[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:8]1[CH2:15][CH2:16][O:17][C:7]1([CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1(CC(=O)OCC)OCCO1
Yield: 42 %

Procedure:
A solution of diethyl 1,3-acetonedicarboxylate (12 g, 59.3 mmol), ethyleneglycol (9.93 mL, 178 mmol), and p-toluenesulfonic acid monohydrate (564 mg, 2.97 mmol) in benzene (80 mL) was refluxed under heating removing water for 10 h by Dean-Stark trap. The benzene layer was washed with a saturated aqueous sodium bicarbonate solution and brine. The solvent was distilled away and the residue obtained was purified by flash chromatography (10 to 40% EtOAc in heptanes) yielding diethyl 2,2′-(1,3-dioxolane-2,2-diyl)diacetate (42%). LCMS (m/z): 247.2 (MH+), 0.65 min; 1H NMR (400 MHz, CDCl3) δ ppm 4.17 (q, J=7.04 Hz, 4H) 4.03 (s, 4H) 2.95 (s, 4H) 1.27 (t, J=7.24 Hz, 6H).
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH3:9]
Reactant: O=CO
Reactant: CCCCCCC
Product: CCC=CCCCCCCCCCC=O
Yield: 67 %

Procedure:
The Grignard solution is then added to a mixture of 1-penten-3-yl isobutyrate ester (84 g, 0.538 mol) and LiCuBr2 reagent (1 M/THF, 63 mL) at a rate that maintains the reaction temperature between 25-30° C., with cooling as necessary. The mixture is stirred for 15 minutes then quenched with aqueous citric acid solution (1 L). The layers are separated and the organic portion is washed with water (2×) and dilute sodium hydroxide solution (until pH basic). The crude organic portion is then stripped of solvent and distilled to afford 98.1 g of the 11E-tetradecenal DEA product (b.p. 150° C., 0.1 mm Hg, Yld. 64%, m/z 284), which is subsequently deprotected using formic acid in heptane at room temperature to give 11-tetradecenal (67.3 g, Yld. 67%, E/Z 83:17).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][SH:16]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]2[NH:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][S:16]2)[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Product: O=C(O)C1CSC(c2cnc3ccccc3c2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Quinoline-3-carbaldehyde (1.57 g ) and 1.21 g of L-cysteine were dissolved in 50 ml of 50% ethanol, and the solution was stirred at room temperature for 1 hour. The resultant crystalline precipitate was collected by suction filtration, washed with 50% ethanol and dried to give 1.95 g of 2-(3-quinolyl)thiazolidine-4-carboxylic acid. Melting point 173°-175° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:20])[N:8]([C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>C(O)(C)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:20])[N:8]([C:12]3[CH:17]=[C:16]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[N:15]=[C:14]([NH2:19])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(Cl)nc(N)n1
Solvent: O
Solvent: CC(C)(C)O
Product: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-chloropyrimidin-2-amine (2.3 g, 6.5 mmol) and 1-methyl piperazine (3.61 mL, 32.6 mmol) in tert-butyl alcohol (10 mL) and was heated at 120° C. for 20 h. The reaction mixture was cooled to r.t., poured into water, extracted with AcOEt, washed with sat'd NaHCO3 aqueous solution and brine, dried with MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 10% methanol in methylene chloride to afford the desired compound. LCMS (M+H)+: m/z=417.1.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)=[C:11]3[N:10]=[C:9](SC)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([NH:36][C:9]2[N:8]=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH:17]=4)=[C:11]3[N:10]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCCC1
Reactant: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(-c3ccnc(F)c3)c2n1
Product: c1ccc(-c2nn3c(NC4CCCC4)nc(NC4CCCC4)nc3c2-c2ccnc(NC3CCCC3)c2)cc1
Temperature: 160 °C
Yield: 34 %

Procedure:
N-Cyclopentyl-8-(2-fluoro-4-pyridiny)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin -4amine 60 mg, 0.14 mmol) was dissolved in cyclopentylamine and heated at 160° C. in a glass pressure vessel for 24 hours. The resulting solution was concentrated in vacuo to give a residue that was purified by silica gel chromatography (ethyl acetate:hexane 1:1 to ethyl acetate) to yield 25 mg (34%) of N2,N4-dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine as a foam. 1H-NMR (CDCl3): δ 7.94 (d, 1H), 7.60 (m, 2H), 7.45 (m, 3H), 6.81 (d, 1H), 6.36 (m, 1H), 5.13 (d, 1H), 4.60 (m, 1H), 4.44 (m, 2H), 3.74 (m, 1H), 2.1–1.4 (m, 24H); MS m/z 523 (M+1).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH:15][CH2:16][CH2:17][NH:18][CH3:19]>C1COCC1>[CH3:14][N:15]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1)[CH2:16][CH2:17][NH:18][CH3:19]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: CNCCNC
Solvent: C1CCOC1
Product: CNCCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Yield: 18 %

Procedure:
Dissolve 2-chloro-6-nitro-benzothiazole (2.20 g, 10.3 mmol) in THF (50 mL). Add N,N′-dimethyl-ethane-1,2-diamine (10.0 mL) and stir overnight at room temperature. Concentrate the reaction mixture in vacuo (adsorbing onto silica gel). Subject the mixture to silica gel flash column chromatography (120 g column, eluting with 10% 2N NH3 in MeOH/CH2Cl2) to yield the desired product (0.500 g, 18%). mass spectrum (m/e): 267.3 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]1[C:14]([S:15](Cl)(=[O:17])=[O:16])=[C:13]([F:19])[C:12]([F:20])=[C:11]([F:21])[C:10]=1[F:22].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[C:12]([F:20])=[C:13]([F:19])[C:14]=1[S:15]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: COC(C)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
To a solution of 3-methoxybutane-1-ol (0.78 g, 7.5 mmol) and TEA (0.388 g, 3.8 mmol), in CH2Cl2 (15 mL) was added pentafluorobenzenesulfonyl chloride (0.79 g, 3.0 mmol). The solution was stirred at rt for 4 h. Saturated aqueous NaHCO3 (10 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (30 mL) and washed with 0.5 M HCl (2×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography (15% ethyl acetate in hexanes) yielded the desired product (0.39 g, 36%). 1H NMR (400 MHz CDCl3) δ 4.40 (m, 2H), 3.45 (m, 1H), 3.26 (s, 3H), 1.87 (m, 2H), 1.15 (d, 3H, J=6.1 Hz). Anal. Calcd. For C11H11F5O4S: C, 39.53; H, 3.32. Found: C, 39.83; H, 3.45.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:32])[CH:19]([C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[C:26](O)[CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:32])[CH:19]([C:24]1[CH:29]=[C:28]([O:30][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])[CH:27]=[C:26]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Trifluoromethanesulfonic anhydride (208 μL, 1.26 mmol) was added dropwise to a stirred solution of 2-(3,5-dihydroxy-phenyl)-4-methyl-pentanoic acid methyl ester (50 mg, 0.21 mmol) and pyridine (195 μL, 2.52 mmol) in DCM (5 mL) at 0° C. then warmed to room temperature. After 1 h, the mixture washed with 1M HCl (2 mL), dried (MgSO4) and concentrated in vacuo to afford the title product as an orange oil (104 mg, 99%). The product was used without further purification in the next step
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:13]([NH:21][C:22]([NH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cnc2c(c1)CCCC2N
Solvent: CC(C)=O
Product: Cc1cnc2c(c1)CCCC2NC(=S)NC(=O)c1ccccc1
Yield: 60.2 %

Procedure:
A solution of 8-amino-3-methyl-5,6,7,8-tetrahydroquinoline (6 g.) in acetone (48 ml.) was treated with benzoylisothiocyanate (6 g.) and the mixture heated at reflux for 45 minutes. The solvent was removed in vacuo and the residual solid recrystallised from ethanol-ether to give the title compound as colourless needles (7.2 g.) m.p. 168° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]#[C:8][C:9]([OH:11])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:47][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:9](=[O:11])[C:8]#[C:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][CH:44]=1
Reactant: COCCOCC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
To a solution of 0.56 g (3.54 mmol) of 4-(2-methoxy-ethoxy)-but-2-ynoic acid and 0.46 g (3.4 mmol) of isobutyl chloroformate in 12 ml of tetrahydrofuran was added at 0° C. with stirring 0.36 g (3.54 mmol) of N-methylmorpholine. After 15 min, 1.0 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile was added. After stirring 3 hr at 0° C. and 17 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dries over magnesium sulfate. The solvent was remove and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.53 g of 4-(2-Methoxy-ethoxy)-but-2-ynoic acid[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow powder: mass spectrum (electrospray, m/e,): M+H 480.9.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C:10]([NH:28][C@H:29]([C:37]([CH:39]1[CH:46]2[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:48][C:40]1([NH2:49])[CH2:41]3)[CH2:45]2)=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.42 g of Boc-glycine and 0.90 ml of N-methylmorpholine in 10 ml of dry methylene chloride under nitrogen is allowed to react with 1.05 ml of isobutylchloroformate at -45° C. The reaction mixture is allowed to warm to -20° C. then recooled to -40° C. To this solution is added 2.38 g of L-phenylalanyl-1-aminoadamantane. The cooling bath is removed and the reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is filtered, diluted with 20 ml of methylene chloride and washed with 10 ml of cold 1 M potassium bisulfate solution followed by washing with 10 ml of cold 2 M potassium carbonate solution and 10 ml of saturated sodium chloride solution. The reaction mixture is dried over sodium sulfate, filtered and concentrated. The product separates as crystals upon addition of ether. The crystalline material is collected to give Boc-glycyl-L-phenylalanyl-1-aminoadamantane. A dry solution of 2.8 g of Boc-glycol-L-phenylalanyl-1-aminoadamantane in 15 ml of methylene chloride under a nitrogen atmosphere at 5° C. is allowed to react with 10 ml of trifluoroacetic acid. The reaction mixture is allowed to stand for 30 minutes at room temperature. The solution is concentrated under reduced pressure then diluted with 10 ml of 5 M potassium carbonate solution and extracted with methylene chloride. The reaction mixture is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give glycyl-L-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR37##
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[CH3:8][N:9]1[CH2:14][CH:13]([C:15](OC)=O)[CH2:12][N:11]=[CH:10]1.C(O)C>C1COCC1>[CH3:8][N:9]1[CH2:14][CH:13]([C:15]2[O:7][N:6]=[C:3]([CH3:4])[N:5]=2)[CH2:12][N:11]=[CH:10]1
Reactant: CC(N)=NO
Reactant: COC(=O)C1CN=CN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(C2CN=CN(C)C2)n1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Sodium hydride (60% dispersion in mineral oil 112 mg, 2.8 mmol) and acetamidoxime (207 mg, 2.8 mmol) are suspended in dry THF (16 ml) in an oven dried round bottom flask under nitrogen with stirring at 0° C. After 10 minutes the grey suspension is refluxed for 30 minutes giving a white suspension. 1-Methyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (593 mg, 2.8 mmol) dissolved in dry THF (4 ml) and anhydrous ethanol (1 ml) is added via syringe and reflux continued 15 hours. The suspension is evaporated in vacuo to a yellow gum and chromatographed (silica, chloroform/methanol, 9:1) to yield 24 mg (rf=0.07, 4%) solids identified by 300 MHz nmr and ms m/z=180.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:14]2[S:13][C:12]([Cl:15])=[N:11][C:10]=2[C:9]([Cl:16])=[CH:8][C:7]=1[Cl:17]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:15][C:12]1[S:13][C:14]2[C:6]([N:5]=[C:1]=[O:2])=[C:7]([Cl:17])[CH:8]=[C:9]([Cl:16])[C:10]=2[N:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C=Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under a nitrogen atmosphere 25 mL of ethyl acetate was stirred and cooled in an ice bath. To this was added via syringe 9.5 mL (18 mmole) of 1.9M phosgene in toluene. During 25 minutes, a solution of 3.0 grams (11.8 mmole) of 7-amino-2,4,6-trichlorobenzothiazole in 75 mL of ethyl acetate was added dropwise. Upon completion of the addition the reaction mixture was warmed to ambient temperature and then gently heated at reflux for 2.5 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding (2,4,6-trichlorobenzothiazol-7-yl)isocyanate, which was stored in a refrigerator.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:23]=[N:22][C:21]([O:24][CH3:25])=[N:20][CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:3]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cn1
Product: COc1ncc(C2(c3cccc(-c4cccc(OC)c4F)c3)N=C(N)c3ccccc32)cn1
Yield: 27 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyrimidin-5-yl)-1H-isoindol-3-amine (Example 106) as described in Example 67 Scheme #10, D in 27% yield using 2-fluoro-3-methoxyphenylboronic acid. 1H NMR (DMSO-d6) δ 8.55 (s, 2H), 7.96-7.79 (m, 2 H), 7.58-7.43 (m, 3 H), 7.43-7.34 (m, 3 H), 7.24-7.12 (m, 2 H), 7.08-6.83 (m, 3 H), 3.88 (s, 3 H), 3.86 (s, 3 H); MS (ESI) m/z 441 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10](OC(=O)C)(=[O:14])[C:11]([CH3:13])=[CH2:12]>>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OC(C)=O
Reactant: NCCCCCC(=O)O
Product: C=C(C)C(=O)NCCCCCC(=O)O
Reaction time: 12 h
Yield: 86.9 %

Procedure:
To a solution of 6-aminocaproic acid (6.55 g), 50 mmol) in 150 ml of glacial acetic acid methacrylic anhydride (8.7 ml, 55 mmol) were added at room temperature, and resulting mixture was stirred for 12 hours. All volatiles were removed under reduced pressure. Crude material was submitted to column chromatography on silica gel, which was performed in chloroform with applying gradient of methanol (0-7.5%) and gave 8.65 g (87%) of N-methacryloyl-6-aminocaproic acid as white solid. MALDI MS: found 200.06 (M+H)+, C10H17NO3; calc. 199.07.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24]Br>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Clc1cc(Cl)cc(CBr)c1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(Cl)cc(Cl)c2)c(=O)[nH]c1=O
Yield: 67.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (292 mg, yield: 67.1%).