Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14](C(O)=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=[C:53]([O:55]C)[N:52]=[C:51]([N+:57]2(C)[CH2:62][CH2:61]OCC2)[N:50]=1.S(O)(O)(=O)=O.N1C=CN=C1N>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:53]([NH:52][C:51]3[NH:50][CH:61]=[CH:62][N:57]=3)=[O:55])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ncc[nH]2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (121 mg, 0.225 mmol) in acetonitrile (4 mL) at 0° C. was added 4-methylmorpholine (0.087 mL, 0.788 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (DMTMM) (89 mg, 0.270 mmol). The solution was stirred for 15 min, and then 1H-imidazol-2-amine sulfate (38.7 mg, 0.293 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated and the residue was purified by RP-HPLC to provide phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(1H-imidazol-2-ylamino)carbonyl]-1-pyrazolidinecarboxylate as a colorless gum (39 mg, 29%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:42](/[CH:43]=[CH:44]/[C:45](O)=[O:46])=[CH:41][CH:40]=1>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:45](=[O:46])[CH:44]=[CH:43][C:42]1[CH:48]=[CH:49][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(OC)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 47.8 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-4-methoxy-cinnamic acid (17.6 mg, 0.099 mmol) gave 27.7 mg (48%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-methoxy-phenyl)-N-(4-pentyl-benzyl)-acrylamide. LC-MS: tR=1.00 min; [M+H]+=644.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:19])[CH2:10][C:11](=O)[CH2:12][C:13]([O:15]CC)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCO>[CH2:21]([N:28]1[C:13](=[O:15])[CH:12]=[C:11]([CH2:10][N:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:19])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)CC(=O)CN(C)c1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(Cc1cc(=O)n(Cc2ccccc2)[nH]1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 4-((3,5-dichlorophenyl)(methyl)amino)-3-oxobutanoate (304 mg, 1.0 mmol) and benzyl hydrazine chloride (388 mg, 2.0 mmol) in EtOH (5 mL) was added anhydrous triethylamine (570 uL, 4.0 mmol). The resulting solution was stirred at room temperature overnight. After evaporating the volatiles, the residue was purified on a silica gel column, eluting with a mixture of MeOH and dichloromethane (1% to 2% MeOH) to afford the product as a pale yellow solid (320 mg, 88%). The solid was then recrystallized in dichloromethane/hexane to give the product as a white solid. 1H NMR (DMSO-d6, 500 MHz): δ=11.00 (br s, 1H), 7.28 (t, J=7.0 Hz, 2H), 7.23 (d, J=7.0 Hz, 1H), 7.11 (d, J=7.0 Hz, 2H), 6.74 (d, J=1.5 Hz, 2H), 6.69 (s, 1H), 5.12 (s, 1H), 5.01 (s, 2H), 4.33 (s, 2H), 2.98 (s, 2H); 13C NMR (DMSO-d6, 125 MHz): δ=152.7, 151.0, 146.8, 138.0, 134.4X2, 128.4X2, 127.1, 127.0X2, 114.4, 110.6X2, 84.6, 50.3, 49.2, 38.9 ppm; MS (ESI): m/z 284.0 [M+H]+; CHN calculated for C18H17Cl2N3O: C, 59.68; H, 4.73; N, 11.60. found: C, 59.79; H, 4.68; N, 11.48.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CCCNC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCC(CO)C1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), piperidine-3-methanol (2.9 g), a 1.6M solution of butyllithium in hexane (31 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethyl acetate, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine-3-methanol (1 g), melting at 142° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(O)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2nccc(C(F)(F)F)n2)cc1=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyclopentyl-2-(4-hydroxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (3.0 g, 11.3 mmol) in N,N-dimethylformamide was treated with potassium carbonate (2.33 g, 16.9 mmol) and 2-chloro-4-trifluoromethyl-pyrimidine (3.1 g, 16.9 mmol). The reaction mixture was stirred at 110° C. for 1 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography afforded 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionic acid methyl ester as a light oil (4.0 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18]([S-:20])#[N:19].[K+].BrBr.O>CN(C=O)C>[NH2:19][C:18]1[S:20][C:3]2[CH:4]=[C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=4[N:12]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3ccc4nc(N)sc4c3)sc2c1
Reaction time: 20 h
Yield: 39.9 %

Procedure:
2-(4-aminophenyl)-6-methyl-benzothiazole 1 (4.0 g, 16.6 mmol) and KSCN (2.6 g, 26.7 mmol) were dissolved in DMF (20 ml) and cooled in an ice-bath. Br2 (0.9 ml, 17 mmol) in DMF (15 ml) was added dropwise under 3 h. The mixture was stirred for another 20 h. Water was added and the precipitate formed was collected by filtration and dried. The crude product was triturated on the sinter with several portions of boiling dichloromethane to afford 2 as a light green-yellow solid (1.97 g, 40%). Mp 250-251° C.; 1H NMR (DMSO): δ 2.45 (3H, s, Ar—CH3), 7.34 (1H, d, J=8.4, ArH), 7.50 (1H, d, J=8.4, ArH), 7.89 (1H, d, J=8.4, ArH), 7.91 (1H, s, ArH), 7.99 (1H, d, J=8.4, ArH), 8.51 (1H, s, ArH), 8.56 (2H, s, NH2); 13C NMR (DMSO): δ 21.10, 116.7, 120.7, 121.8, 122.1, 125.6, 126.9, 128.1, 129.7, 133.3, 134.5, 135.0, 151.7, 165.9, 169.3; HR-FAB-MS m/z Found: 298.0521 C15H12N3S2 (M+H+): requires M, 298.0473.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][OH:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:22].[K+]>O>[CH2:1]([O:8][C:9]1[C:10]([C:17]([OH:22])=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccnc(CO)c1OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(C(=O)O)c1OCc1ccccc1
Yield: 83.9 %

Procedure:
3-Benzyloxy-2-hydroxymethyl-4-methoxypyridine (7.1 g) and 2.5 g of potassium hydroxide were suspended in 100 ml of water. While heating the suspension in a water bath, potassium permanganate (7.3 g) was added thereto, and the mixture was stirred. The precipitate was filtered, and was washed with 100 ml of methanol. The filtrate and the washings were combined, followed by concentration under the reduced pressure. The concentrate was adjusted to pH 1 by the addition of concentrated hydrochloric acid. The precipitate was filtered, washed with water, and then dried to give 6.3 g (yield 83.9%) of the title compound as colorless powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[CH2:33]O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>C(#N)C>[Br:20][CH2:33]/[CH:32]=[CH:31]/[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(/C=C/CBr)c1
Temperature: 25 °C

Procedure:
To a solution of triphenylphosphine (1.47 g, 5.6 mmol) in acetonitrile (35 ml) at 0° C. was added dropwise over 5 minutes a solution of bromine (0.88 g, 5.6 mmol) in acetonitrile (5 ml) at a rate such that the temperature was kept between 5° C. and 10° C. The mixture was then allowed to warm to room temperature, then to this was added dropwise a solution of (E)-3-(3-nitrophenyl)-2-propen-1-ol (Preparation 21, 1 g, 5.6 mmol) in acetonitrile (5 ml). The mixture was warmed to 65° C. for 40 min, cooled to room temperature, and poured onto diethyl ether (150 ml). The mixture was concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with hexane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, and the residue recrystallised from cyclohexane to give the title compound as a very pale yellow solid (0.82 g, 61%).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10](Cl)=[O:11].CO.[Cl-].[NH4+]>O1CCCC1.C1(S[Cu])C=CC=CC=1>[CH3:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: [Li]C(C)(C)C
Reactant: Cc1ccc(C(=O)Cl)cc1C
Agent: [Cu]Sc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C(C)(C)C)cc1C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
A suspension of 25.9 g. (0.15 mole) of phenyl thio copper in 1 liter dry tetrahydrofuran is cooled to -20° C. and treated by the dropwise addition of 120 ml. t-butyl lithium (0.149 mole, 1.24 M in pentane) for about 20 minutes maintaining the temperature at -20° C. The resulting green solution is stirred at -20° C. for 5 minutes and then cooled to -72° C. and treated by the dropwise addition of 17.8 g. (0.107 mole) 3,4-dimethyl-benzoyl chloride in 50 ml. tetrahydrofuran for about 20 minutes. The mixture is then stirred at -22° C. for 11/2 hours and then treated with 100 ml. methanol and allowed to warm to room temperature and then hydrolyzed by the addition of 250 ml. saturated ammonium chloride. The resulting solids are filtered and washed with tetrahydrofuran. The filtrate is dried over anhydrous magnesium sulfate, filtered and evaporated and the oil distilled to give 3',4' -dimethylpivalophenone; (b.p. 73°-76° C. at 0.1 mm).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C[O-].[Na+].CO>CO.O>[C:1]([NH:9][CH:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:31][OH:32])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(CCCCC(NC(=O)c1ccccc1)c1ccc2ccccc2c1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Ethyl 6-benzoylamino-6-(2-naphthyl)hexanoate (Reference Example 25) (0.8 g) and hydroxylamine hydrochloride (0.71 g) were suspended in methanol. To this suspension (4.2 ml) was added 4.9N sodium methoxide/methanol (4.9 ml) and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with water and the methanol was distilled off under reduced pressure. The residue was acidified with 3N HCl and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated and the crude residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:1) to provide the title compound (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.Cl[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[CH:8]=2)[N:3]=1
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Reactant: Oc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(CCOc3ccc4nc(Cl)cnc4c3)CC2)nn1
Yield: 61.5 %

Procedure:
A mixture of 2-chloro-6-hydroxyquinoxaline (52 mg, 288 μmol), 3-[-4-(2-chloroethyl)-1-piperidinyl]-6-methyl pyridazine (76 mg, 317 μmol), potassium iodide (53 mg, 317 μmol) and potassium carbonate (199 mg, 1.44 mmol) in anhydrous dimethylformamide (2 ml) was heated at 90° under an Argon atmosphere for 2 days. Tlc (silica; ethyl acetate) showed new polar material. Removal of the solvent under high vacuum and then chromatography on silica (5 g; eluent: 30% hexane in ethyl acetate) gave the product as a white solid 68 mg (61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([O:28][CH3:29])[C:4]=1B(O)O.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:47])[CH3:34].C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:6][C:5]=2[O:28][CH3:29])=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=1[Cl:46])[CH3:34]
Reactant: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]benzeneboronic acid (5.2 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (1.71 g), Pd(Ph3)4 (0.44 g) and K2CO3 (1.59 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 24 h under N2. The mixture was worked up and purified in a similar procedure as described in Example 8-3) to yield 2.9 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 770 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:16]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cccc(-c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2cccc(-c3ccccc3)c2)n1
Yield: 98 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 3-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (370 mg). Yield: 98%. 1H NMR (250 MHz, DMSO-d6) δ 7.35-7.72 (m, 9H, Harom), 8.53 (s, 1H, HPz 5), 8.59 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:5][C:4]([C:14]([F:17])([F:16])[F:15])=[N:3]1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:12][C:10]3[S:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:5]=4)=[CH:8][CH:9]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C=O)s1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cc(C(F)(F)F)nn4C)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 491.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.C(O)C>[C:16]([NH:24][NH:25][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Solvent: CCCCCC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Yield: 54.1 %

Procedure:
The procedure of Reference Example 2 was repeated except that 1.3 g of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and 1.0 g of benzoylhydrazine was used, and 1.18 g of trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol was obtained as white crystals, m.p. 197°-199° C. (recrystallized from hexane-ethanol).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>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>[F:1][C:2]1[CH:8]=[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Sc1ccccc1
Reactant: Nc1ccc(I)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccccc2)cc1F
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.578 g) was added to a deoxygenated mixture of 2-fluoro-4-iodoaniline (2.37 g), thiophenol (1.07 ml) and sodium methoxide (1.13 g) in ethanol (80 ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stirring under argon for 18 hours, cooled and filtered. The filter was washed with ether (3×20 ml) and the filtrates were combined and volatile material was removed by evaporation. The residue was treated with dichloromethane (50 ml), filtered and reconcentrated. This crude product was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50-70% dichloromethane/hexane to give the title compound (1.851 g) as a solid. M.p. 48-49° C.; NMR: 5.5 (s, 2H), 6.8 (t, 1H), 7.0-7.1 (m, 5H), 7.25 (t, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:30][C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:32][C:33](O)=[O:34])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)CCl.CI>>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:33](=[O:34])[CH2:32][C@H:31]([O:30][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: CI
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 94.1 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (0.212 g, 1.08 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (0.541 g, 1.19 mmol) in the presence of EDC·MeI (0.353 g, 1.19 mmol) to give 0.642 g (94%) of N-[(R)-3-tetradecanoyloxytetradecanoyl]-L-serine benzyl ester as a waxy solid: mp 56-61° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=˜7 Hz), 1.1-1.7 (m, 42H), 2.29 (t, 2H, J=7.5 Hz), 2.50 (m, 2H), 3.87 (br t, 1H), 3.95 (m, 2H), 4.65 (m, 1H), 5.1-5.25 (m, 3H), 6.69 (d, 1H, J=7 Hz), 7.34 (br s, 5H).
Reaction SMILES: BrC1C=[C:4]2[CH:10]=[N:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=NC=1.[Br:18][C:19]1[CH:20]=C2NN=CC2=[N:23][CH:24]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(CC)CC>CN(C)C1C=CN=CC=1.C(#N)C>[Br:18][C:19]1[CH:20]=[C:5]2[N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[N:9]=[CH:10][C:4]2=[N:23][CH:24]=1
Reactant: Brc1cnc2cn[nH]c2c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)cnc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc2ncc(Br)cc21
Yield: 93 %

Procedure:
Analogous to the preparation of tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate, 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.0 g, 10.10 mmol) was reacted with di-tert-butyl dicarbonate (2.8 g, 13.10 mmol), NEt3 (1.44 g, 2.0 mL, 14 mmol) and 4-(dimethylamino)pyridine in acetonitrile (20 mL) for 3 h. Work-up as discussed previously in the preparation of tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate provided desired product of tert-butyl 6-bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate as a brown solid (2.8 g, 93%).