Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)(=O)=O.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:9]1[CH:8]=[C:7]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)[CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[CH3:15]
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)cc(OC)c1C
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: COc1cc(-c2ccco2)cc(OC)c1C
Temperature: 80 °C
Yield: 76.8 %

Procedure:
To a solution of 3,5-dimethoxy-4-methylphenyl trifluoromethanesulfonate (0.50 g, 1.67 mmol) in DME (15 mL) was added 2-furylboronic acid (0.245 g, 2.2 mmol), LiCl (0.149 g, 3.5 mmol), 2 M aqueous Na2CO3 (1.8 mL, 3.6 mmol) and tetrakis(triphenylphosphine)palladium (0.098 g, 0.085 mmol) and the mixture was degassed as described previously. The reaction was heated at 80° C. under argon for 22 hrs. After cooling to room temperature, the reaction was diluted with H2O and extracted with EtOAc. The combined organics were washed with H2O, saturated aqueous NH4Cl, H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-25% Et2O-hexanes) gave 2-(3,5-dimethoxy-4-methylphenyl)furan as a white solid (0.28 g, 77% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:22](=[O:23])[CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCN)cc1C
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(CCNC(=O)CCc2ccc(Cl)cc2)cc1C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
Heat a solution of 2-(3-methyl-4-methoxyphenyl)ethylamine (64.4 g) and 3-(4-chlorophenyl)-propionic acid (70.2 g) in xylene (600 mL) at reflux over a Dean-Stark trap for 5.5 h. Pour the hot reaction mixture into water an allow to stand overnight. Filter to collect the solid and recrystallize from ethanol to give N-[2-(3-methyl-4-methoxyphenyl)ethyl]-3-(4-chlorophenyl)propionamide (101.1 g), mp=142°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O.COC1C=C2C(C3CCCCC=3C2)=CC=1>[Pd].CO.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14]([CH:12]3[CH:7]([CH2:6]2)[CH2:8][CH2:9][CH2:10][CH2:11]3)=[CH:15][CH:16]=1
Reactant: COc1cccc(CC2CCCCC2=O)c1
Agent: [Pd]
Agent: COc1ccc2c(c1)CC1=C2CCCC1
Solvent: CCO
Solvent: CO
Product: COc1ccc2c(c1)CC1CCCCC21

Procedure:
2-(3-Methoxy-benzyl)-cyclohexanone was converted to 7-methoxy-2,3,4,9-tetrahydro-1H-fluorene in accordance with the procedure of U.S. Pat. No. 3,743,663, followed by hydrogenation (Pd/C, MeOH/EtOH, H2, 1 atm) to obtain 7-methoxy-2,3,4,4a,9,9a-hexahydro-1H-fluorene.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[C:60]1([SH:66])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=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.[Pd].[Pd].O1CCOCC1>[C:60]1([S:66][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: Nc1ncccc1Br
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncccc1Sc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 3-bromopyridin-2-amine (167 mg, 0.966 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9=mg, 0.048 mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol), thiophenol (121 mg, 1.1 mmol), and dioxane (10 mL) was heated at 100° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The reaction mixture was purified by MPLC to afford 3-(phenylthio)pyridin-2-amine.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22](CC4C=CC=CC=4)[CH3:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2>CO.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=1)[CH2:2]2
Reactant: CN(Cc1ccccc1)c1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Yield: 13 %

Procedure:
The product of Example 8B (200 mg, 0.50 mmol) in methanol (10 mL) was treated with Pd/C (Aldrich, 10% wt., 50 mg) at 60° C. under H2 for 10 hours. The mixture was allowed to cool to room temperature and was filtered through a short column of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound (20 mg, yield, 13%). 1H NMR (MeOH-d4, 300 MHz) δ 1.43-1.56 (m, 1H), 1.62-1.88 (m, 2H), 1.99-2.12 (m, 1H), 2.14-2.21 (m, 1H), 2.79 (s, 3H) 2.90-3.03 (m, 5H), 3.27-3.38 (m, 1H), 4.49-4.56 (m, 1H), 6.67 (d, J=8.8, 2.7 Hz, 2H), 6.91 (d, J=8.8, 2.9 Hz, 2H), 7.35 (d, J=8.8, 2.7 Hz, 2H), 7.43 (d, J=9.2, 2.7 Hz, 2H) ppm. MS (DCl/NH3): m/z 309 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>O1CCCC1>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: CC(C)(N)CO
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: C1CCOC1
Product: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Yield: 65.5 %

Procedure:
The product from step (c) (0.6 g) and 2-amino-2-methylpropanol (1.1 g) in tetrahydrofuran (10 ml) was heated in a sealed vessel at 100° C. for 18 hours. The mixture was evaporated to dryness and purified (SiO2, ethyl acetate as eluant) to give the subtitle compound (0.46 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: CC1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: CO
Product: CC1CNCCN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 116.9 %

Procedure:
4-Benzyl 1-tert-butyl 2-methylpiperazine-1,4-dicarboxylate (3.0 g, 8.97 mmol) was dissolved in MeOH (30 mL) and purged with nitrogen for 5 min. 10% palladium on charcoal (300 mg) was added, and the reaction mixture was hydrogenated at room temperature for 2 h. The mixture was then filtered through Celite and the clear filtrate was concentrated under reduced pressure to obtain tert-butyl 2-methylpiperazine-1-carboxylate (2.1 g, crude), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 4.23-4.15 (m, 1H), 3.82-3.77 (m, 1H), 3.01-2.88 (m, 3H), 2.78-2.75 (m, 1H), 2.71-2.63 (m, 1H), 1.47 (s, 9H), 1.22-1.21 (m, 3H). MS (ESI) m/z: Calculated for C10H20N2O2: 200.15. found: 201.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[NH2:18][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:35])=[O:17]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting D-alanine amide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.54 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/z 477.1104 (M+H calculated for C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]1[S:12][C:13]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:14]=2[N:15]=1)[CH3:7])C.[OH-].[Na+]>CO.O>[F:22][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][CH2:9][C:8]([N:6]([CH3:7])[CH2:5][C:4]([OH:24])=[O:3])=[O:23])[S:12][C:13]=2[C:19]([F:20])=[CH:18][C:17]=1[F:21]
Reactant: CCOC(=O)CN(C)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC(=O)O)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine ethyl ester (290 mg, 0.8 mmol) in methanol (2 ml) was added 2N sodium hydroxide (0.5 ml, 1 mmol) and the mixture was stirred for 30 min. at room temperature. The reaction mixture was diluted with water and then washed with ether. The aqueous layer was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, then dried and evaporated to yield a residue, which was recrystallized from ethanol-isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine (185 mg, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:14]2[N:22](S(C3C=CC=CC=3)(=O)=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1.[OH-].[Na+]>C(O)C.O1CCCC1.O>[CH3:32][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)C=C(c1cccc(N(C)C)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C=C(c1cccc(N(C)C)c1)c1cc2cccnc2[nH]1
Temperature: 70 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
A solution of N,N-dimethyl-3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)but-1-enyl)benzenamine (3.0 g, 6.7 mmol) in ethanol (60 mL) and tetrahydrofuran (120 mL) was treated with an aqueous sodium hydroxide solution (10%, 23 mL). The reaction was stirred at 70° C. for 18 h. At this time, the reaction was cooled to 25° C., diluted with water (200 mL) and then extracted with ethyl acetate (2×100 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (50 g, petroleum ether/ethyl acetate 10:1) afforded N,N-dimethyl-3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)benzenamine (1.6 g, 76%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.46 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 7.86 (dd, 1H, J1=7.8 Hz, J2=1.8 Hz), 7.65 (d, 2H, J=7.8 Hz), 7.37 (d, 1H, J=7.5 Hz), 7.24-7.15 (m, 2H), 6.51 (s, 1H), 6.13 (d, 1H, J=10.2 Hz), 2.78 (s, 6H), 2.71-2.64 (m, 1H), 1.28 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)([O:3][CH2:4][CH3:5])=[O:2].[N-:18]=[N+:19]=[N-:20].[Na+]>O>[N:18]([C:15]1[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[N+:19]=[N-:20]
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnc2nc(C)ccc2c1N=[N+]=[N-]
Reaction time: 20 h

Procedure:
3-Carbethoxy-4-chloro-7-methyl-1,8-naphthyridine (0.8 g; 0.03 M) was dissolved in dry D.M.F. (5 ml) at ambient temperatures and NaN3 (0.5 g; 0.007 M) added. This mixture was stirred for 20 hr. at ambient temperatures and then poured into a large volume (1 l) of H2O. The product (0.64 g; 83%), m.p. 114°-115° C. (dec.), was filtered off, washed with H2O and dried over P2O5 in vacuo (Found: N, 27.49; C, 55.59; H, 4.50%. C12H11N5O2 requires: N, 27.24; C, 56.03; H, 4.28%), νmax (KBr) 3080, 2900, 2142, 1708, 1600, 1550, 1472, 1375, 1268, 1210, 1194, 1050, 1038, 806 cm-1, δ [(CD3)2SO] 1.38 (t), 4.40 (q), (CH3CH2), 2.68 (s), (CH3), 7.5 (d), 8.5 (d), 9.14 (s) (heterocyclic protons), m/e 257 (M+ ; 65%) 229 (M+ --N2 ; 32%), 212 (M+ --OC2H5 ; 15%), 201 (52%), 133 (100%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[N:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=1[F:25].C1(C)C=CC=CC=1.C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)=[CH:20][C:19]=1[F:25]
Reactant: OB(O)c1ccncc1
Reactant: Fc1cc(I)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccncc2)ccc1Br

Procedure:
Sodium carbonate (0.86 g, 0.0081 mol) in water (3.0 mL, 0.17 mol) was added to a mixture of 4-pyridinylboronic acid (0.5 g, 0.004 mol), 1-bromo-2-fluoro-4-iodobenzene (1.5 g, 0.0049 mol), and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol) in toluene (6.0 mL, 0.056 mol) and ethanol (3.0 mL, 0.051 mol). The resulting mixture was irradiated by microwave at 120° C. for 30 min. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and concented in-vacuo. The residue was purified by CombiFlash (EtOAc in hexanes: 40%) to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(NC(=O)C(Cl)c3ccccc3)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 16 (0.10 g, 0.42 mmol) in THF (10 mL), was added triethylamine (0.064 g, 0.63 mmol) and 2-chloro-2-phenyl acetyl chloride (0.119 g, 0.63 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [CH2:1]([C:24]([OH:26])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O.[CH3:27][Li]>C1COCC1.CCOCC>[O:23]=[C:21]([CH3:27])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[C:11][C:10]#[C:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:24]([OH:26])=[O:25]
Reactant: O=C(O)CCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)CCCCCCCCC#CC#CCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.08 g (3mmol) Icosa-9,11-diyne-1,20-dicarboxylic acid was suspended in 55 mL anhydrous THF and dissolved with slight warming. To this solution, 11.2 mL, 1.4 M methyl lithium in ether (8 mmol) was slowly added with the aid of syringe. A total of 2 mol equivalent of methyl lithium in ether were used per carboxylic acid to convert acid into ketone. The reaction turned into a viscous slurry from a free flowing suspension. The reaction was left stirring at room temperature overnight. The purplish colored suspension was treated with ice to quench the reaction. The product was extracted with ether, after acidifying the solution. The yellowish waxy product was characterized by NMR and found to contain the desired product as well as one byproduct tertiary alcohol due to additional reaction of methyl lithium present in the reaction mixture at the time of quenching. This problem was alleviated by addition of trimethyl silyl chloride in an amount enough to react with excess methyl lithium. This step provided clean reaction product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][C:9]([O:11]CC)=[O:10].CC(CC1C=CC=CC=1)=CC(OCC)=O.[OH-].[K+]>O.CO.N1C=CC=CC=1>[CH3:6][C:7](=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(C)=Cc1ccccc1
Agent: CCOC(=O)C=C(C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CC(=Cc1ccccc1)CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To mixture of the above hydroxy-ester (3.06 g, 13.76 mmole) and pyridine (10 ml), cooled to 0° C., is slowly added phosphorus oxychloride (3.59 g, 23.39 mmole). The reaction mixture is stirred for about 2 hrs and then heated to 100° for 1.5 hours. The reaction is worked up by pouring into ice and extracting with water-hexane. The aqueous layer is back-extracted with hexane. The organic phases are combined, washed with 2 N hydrochloric acid, water and brine, dried over sodium sulfate and rotoevaporated to yield a mixture of esters--ethyl 3-methyl-4-phenyl-3- butenoate and ethyl 3-methyl-4-phenyl-2-butenoate. The mixture of esters is hydrolyzed using potassium hydroxide, water/methanol at 40° for about 20 hrs to yield the acids, 3-methyl-4-phenyl-3-butenoic acid and some 3-methyl-4-phenyl-2-butenoic acid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)#[N:2]>C(O)C.O.N.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: N#CCCC1CN(Cc2ccccc2)CCO1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: NCCCC1CN(Cc2ccccc2)CCO1
Yield: 86 %

Procedure:
A solution of 2-(2-cyanoethyl)-4-benzylmorpholine (8 g) in a mixture of ethanol (60 ml) and 28% ammonia water (4 ml) is hydrogenated over Raney nickel at 25° C. After the calculated amount of hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound (7 g) as an oil.
Reaction SMILES: Cl.C(OC([N:9](C(OC(C)(C)C)=O)[C:10]1[C:19]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>CO>[NH2:9][C:10]1[C:19]([NH:20][C:21]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccc(NC(=O)c2cnccn2)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(NC(=O)c2cnccn2)c1N
Yield: 85.3 %

Procedure:
HCl gas was bubbled through a solution of methyl 2-(bis-(tert-butoxycarbonyl)amino)-3-(pyrazine-2-carboxamido)benzoate 14 (2.8 g, 5.9 mmol) in MeOH (50 ml) for 2 h. The volatiles were removed in vacuo and H2O (20 mL) was added. The pH was adjusted to 7 using aq NaOH and the resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 15 (1.37 g, 85% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([N:28]1[CH:31]([S:32][CH2:33][C:34]#[C:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH:30]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:29]1=[O:63])=[P:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.C(OCC)(=[O:72])C>>[C:1]([O:5][C:6]([C:8]([N:28]1[CH:31]([S:32][CH2:33][C:34](=[O:72])[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH:30]([NH:43][C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:29]1=[O:63])=[P:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC(=O)Cc1ccc(F)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1-(1-t-Butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (370mg) was refluxed is piperidine (25ml) under nitrogen for 6 hours. The mixture was cooled, diluted with ethyl acetate and the organic layer washed with N-hydrochloric acid and brine, dried and evaporated to an amorphous solid. Chromatography on silica gave 1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenyl-2-oxopropylthio)azetidin-2-one as an amorphous solid (330mg).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[N:16]2[N:17]=[C:18]([NH2:20])[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH:1]1([O:7][C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: Nc1nc2cccc(Cl)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2cccc(OC3CCCCC3)n2n1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
Cyclohexanol (1.68 mL; 15.84 mmol; 5.0 eq.) was added to a suspension of NaH (152 mg; 3.80 mmol; 1.2 eq.) in THF (6.0 mL) and maintained under inert atmosphere at 0° C. The reaction mixture was brought back to rt and stirred for 1 h before the addition of 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 534 mg; 3.17 mmol; 1.0 eq.). Reaction mixture was then heated at reflux for 3 h after which time it was quenched by addition of water. It was then extracted with EtOAc, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (DCM/MeOH, 95:5 to 10:90) gave the title compound as a white solid (590 mg, 80%). HPLC, Rt: 2.18 min. (purity 90.1%). LC/MS, M+(ESI): 233.0.