Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2(O)[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.BrC1C=CC(C2CCN(C)CC=2)=CC=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([F:7])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: CN1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: CN1CC=C(c2ccc(Br)cc2)CC1
Solvent: ClCCl
Product: CN1CCC(F)(c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of DAST (0.50 g, 3.8 mmol) in CH2Cl2 was added a solution of 4-(4-bromophenyl)-1-methylpiperidin-4-ol (0.507 g, 1.88 mmol) in CH2Cl2 at −78° C. The resulting mixture was warmed to rt over a period of 3 h. The reaction was then allowed to cool to 0° C. and quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4 and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (95:5 EtOAc/NH3 to 10:8:2 CH2Cl2/MeOH/NH3) to yield an inseparable mixture of the title compound and 4-(4-bromophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (280 mg, used without further purification).
Reaction SMILES: [CH:1]1([C:5]([OH:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[CH2:16]1[CH2:26][CH2:25][N:24]2[C:19](=N[CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17]1.C(C=C)=O.[I-].[CH:32]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:36]C[CH2:34][CH2:33]1.C([Li])CCC>O1CCCC1.O.CCCCCC>[C:17]1(=[CH:16][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH:21]([O:7][C:6](=[O:8])[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)([OH:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:18][CH2:19]2)[CH2:34][CH2:33][CH2:32][CH2:36]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCC1
Reactant: C1CCC2=NCCCN2CC1
Agent: C=CC=O
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OC1CCN(CCC=C2CCCC2)CC1)C(O)(c1ccccc1)C1CCC1
Reaction time: 0.33 h

Procedure:
According to the method of A. Chesnyl et al. [Synthetic Communications, Vol. 20, pp. 3167-3180 (1990)], 50 mg of the 2-cyclobutyl-2-hydroxy-2-phenylacetic acid obtained in Step 1 of Example 1 and a catalytic amount of DBU were dissolved in 2 ml of tetrahydrofuran, and 15 μl of acrolein was added thereto at -15° C., followed by stirring for 20 minutes. The resulting solution was added at 0° C. to an ylide compound prepared from 156 mg of cyclopentyltriphenylphosphonium iodide and 200 μl of n-butyl lithium (as a 1.69M hexane solution), and this mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. After the addition of 20 ml of water, the reaction mixture was extracted with ethyl acetate (30 ml×3). The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by thin-layer chromatography [Kieselgel™ 60F254, Art 5744 (manufactured by E. Merck); developing solvent: hexane/ethyl acetate=1/2] to obtain 2.0 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[C:13]=2[CH3:14])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]1)#[N:25]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(F)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)c(F)c1
Yield: 32.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxylic acid (3 g) and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (3.7 g), the title compound (1.9 g) was obtained, melting point: 164–165° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]O)=[CH:22][N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([C:5]3[N:4]=[C:3]([C:2]([F:17])([F:1])[F:18])[O:7][N:6]=3)=[CH:9][C:10]=2[CH3:16])=[CH:22][N:21]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Reactant: OCCCc1ccc(Cl)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 78.3 %

Procedure:
To a suspension of 1.12 g (4.34 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.87 g (1.2 eq) of 2-chloro-5-(3-hydroxypropyl)-pyridine, 1.4 g (1.2 eq) of triphenylphosphine in 50 ml of methylene chloride under nitrogen at 0° C. was added dropwise a solution of 0.86 g (1.2 eq) of DEAD in 5 ml of methylene chloride. The mixture was stirred under nitrogen at room temperature for 60 h, concentrated in vacuo and the residue was triturated with hexane/ethyl acetate, filtered, and the filtrate was concentrated in vacuo to yield a dark brown oil. The brown oil was purified by MPLC (50 id, Kieselgel 60 column, hexane/ethyl acetate, 3:1) to afford 1.4 g (78%) of 2-chloro-5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine, as a white crystalline solid, m.p. 89°-91° C.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15](C2C=CC=CC=2C([O-])=O)=[CH:14][C:13]=1[N+:27]([O-:29])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C[O:33]CC1.Cl>CO.O>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:33])=[CH:14][C:13]=1[N+:27]([O-:29])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])c1ccccc1-c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(O)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 95 %

Procedure:
Lithium hydroxide monohydrate (5.632 g, 134.2 mmol) was added to a stirred solution of compound 53 (2.343 g, 6.71 mmol) in 150 ml methanol and 50 ml water. THF (50 ml) was added after 20 minutes to increase solubility. The reaction mixture was stirred overnight and was then acidified with concentrated HCl. The reaction mixture was extracted five times with dichloromethane, and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified via flash chromatography over silica gel with gradual elutions from 80/10-50/50 (Hex/EtOAc). Evaporation of solvent yielded 1.567 g (95%) of a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:13][CH2:14][CH3:15])=[N:9][C:8](=S)[N:7]([CH2:17][CH3:18])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[OH-].[Na+].[Ni]>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][CH2:14][CH3:15])[N:9]=[CH:8][N:7]3[CH2:17][CH3:18])[CH2:3][CH2:2]1
Reactant: CCNc1nc(=S)n(CC)c2nc(C3CC3)[nH]c12
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CCNc1ncn(CC)c2nc(C3CC3)nc1-2
Temperature: 67.5 °C

Procedure:
The product of step (i) (11.85 g) was dissolved in 2N NaOH (270 ml) and 10N NaOH (27 ml) and heated to 65° C. Within 1.25 hours 50% Ni-Al alloy (518 mmoles of Ni and 1125 mmoles of Al) (60.8 g) was added under vigorous stirring at 65-70° C. After a further 0.75 hr at the same temperature the reaction mixture was cooled to room temperature and treated with chloroform (400 ml). The nickel was filtered off and washed with 350 ml of chloroform and 150 ml of water. The filtrate was separated and the chloroform layer evaporated to dryness. The residue (19.64 g) was dissolved in acetone (100 ml), treated with 2 portions of charcoal (0.15 g) filtered, and evaporated. The residue was treated with diethylether (100 ml) and crystals collected (6.10 g), mp 80-96° C. A second crop gave 1.25 g. A recrystallized sample from diisopropylether had mp 103-105° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:23])[CH2:3]1.N.[C:25](O)(=O)[CH3:26]>>[CH2:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:2]([CH3:1])[CH2:3][C:4](=[O:23])[NH:5][N:6]=3)=[CH:9][C:10]=2[N:22]=[C:25]1[CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1
Reactant: CC(=O)O
Agent: N
Product: Cc1nc2cc(C3=NNC(=O)CC3C)ccc2n1Cc1ccccc1

Procedure:
The product obtained according to (a) was taken up in 100 ml of glacial acetic acid and refluxed for 2.5 hours. The mixture was mixed with ice and made alkaline with ammonia, and the precipitated product was purified by chromatography on silicagel (eluting agent: at first pure methylene chloride, then increasing amounts of acetone up to a mixture ratio methylene chloride/acetone=10:3). After evaporation, the product was obtained in crystalline form by trituration with ether.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:23][CH3:24])=[O:8].[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28]>O1CCOCC1>[F:26][C:6]([F:5])([F:25])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:28][CH2:27][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:23][CH3:24])=[O:8]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(C2CCNCC2)c(C)cc1NC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1NC(=O)C(F)(F)F
Temperature: 90 °C
Yield: 28.4 %

Procedure:
To 2,2,2-trifluoro-N-[5-methyl-2-(methyloxy)-4-(4-piperidinyl)phenyl]acetamide acetate (1.5 g, 4.0 mmol) in 30 mL of dioxane was added, TEA (2 g, 20 mmol), and methyl vinyl sulfone (1.06 g, 10 mmol). The mixture was heated to 90° C. for 72 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give 480 mg of 2,2,2-trifluoro-N-(5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}phenyl)acetamide and the title compound of step D (0.40 g, 1.2 mmol, 31%). 1H NMR (400 MHz, CDCl3) δ ppm 6.62 (s, 1H), 6.51 (s, 1H), 5.22 (s, 2H), 3.80 (bs, 3H), 3.29 (t, J=6.87 Hz, 2H), 3.13 (d, J=11.17 Hz, 2H), 3.04 (s, 3H), 2.98 (t, J=6.96 Hz, 2H), 2.61-2.70 (m, 1H), 2.24-2.31 (m, 2H), 2.17 (s, 3H), 1.73-1.81 (m, 4H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:12](=O)[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)=O)C.CC[O-].[Na+].[NH2:25][C:26]([NH2:28])=[S:27].[CH3:29]I>CCO>[C:17]([O:16][C:14]([N:9]1[CH2:8][CH2:7][C:6]2[C:4]([OH:3])=[N:25][C:26]([S:27][CH3:29])=[N:28][C:12]=2[CH2:11][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CI
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CSc1nc(O)c2c(n1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To solution of 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10.5 g, 0.04 mol) in EtOH (168 mL) was added NaOEt (8.1 g, 0.12 mol) and thiourea (4.2 g, 0.06 mol). The mixture was heated at reflux for 12 h. The mixture was cooled, treated with MeI (3.0 mL, 0.05 mol) drop-wise, and stirred at rt for 1 h. The mixture was concentrated and the residue was dissolved in water and acidified to pH=7 with HOAc (a precipitate formed). The solid was filtered to give the title compound (8.4 g, 73%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH:17][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(NC(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (194 mg, 607 μmol) was dissolved in pyridine (2 mL) and to this was added 4-(dimethylamino)pyridine (7.8 mg, 64 μmol) and cooled to 0° C. To this was added phenylacetyl chloride (160 μL, 1.21 mmol) and stirred for 2 h after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and after collecting the precipitate by filtration using a Kiriyama funnel, the residue was dried in vacuo to give 5-(4-acetoxyphenyl)-3-benzyl-2-(phenylacetylamino)pyrazine (c-30) as a colorless solid (53.9 mg, 20.3%). Rf=0.24 (n-hexane/ethyl acetate=3/2). Mp. 228-231° C. UV (MeOH, 0.3% DMSO) λmax (log ε) 318 (4.19), 290 (4.17), 259 (4.24). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.68 (s, 2H), 4.07 (s, 2H), 7.01-7.08 (AA′BB′, 2H), 7.11-7.22 (m, 3H), 7.23-7.29 (m, 3H), 7.31-7.38 (m, 4H), 8.07-8.14 (AA′BB′, 2H), 8.93 (s, 1H), 10.57 (s, 1H). IR (KBr, cm−1) 706, 851, 918, 1157, 1206, 1223, 1346, 1366, 1410, 1449, 1495, 1543, 1576, 1670, 1755, 3248. HRMS (FAB+) m/z 438.1806 (M+H, C27H24N3O3 requires 438.1818).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][NH:11][C:10](Cl)([NH2:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1.C(N(CC)CC)C>C(#N)C.[OH-].[Na+]>[CH2:1]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][NH:11][C:10]([N:19]2[CH:23]=[N:22][N:21]=[N:20]2)([NH2:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(Cl)N=C(Cc2ccccc2)C([N+](=O)[O-])=CN1
Reactant: c1nnn[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC1(n2cnnn2)N=C(Cc2ccccc2)C([N+](=O)[O-])=CN1
Reaction time: 8 h

Procedure:
4.0 g of 4N-benzyl-2-chloro-5-nitropyrimidineamine (Reference Example 2) is added to a solution of 3.0 g of 1H-tetrazol in 120 ml of acetonitrile. A mixture of 2.5 ml of triethylamine and 45 ml of acetonitrile is added dropwise to the solution. The reaction solution is stirred overnight and is concentrated under reduced pressure to obtain solid. The resulting solid is suspended in 3N sodium hydroxide solution for 1 hour, filtered and dried to obtain 3.80 g of the title compound.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C([NH:32][C@@H:33]([C:42]([OH:44])=O)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)(OC(C)(C)C)=O.[N:45]1([C:51]2[CH:56]=[CH:55][N:54]=[C:53]3[NH:57][CH:58]=[CH:59][C:52]=23)[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[ClH:41].[ClH:41].[NH2:32][C@H:33]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:42]([N:48]1[CH2:49][CH2:50][N:45]([C:51]2[CH:56]=[CH:55][N:54]=[C:53]3[NH:57][CH:58]=[CH:59][C:52]=23)[CH2:46][CH2:47]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.5 %

Procedure:
PyBrop (407 mg, 0.87 mmol) was added in a single portion to a solution of (R)—N-Boc-4-chlorophenylalanine (458 mg, 1.53 mmol) and 4-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.73 mmol) in DCM (5 mL) cooled in an ice bath. DIEA (0.66 mL, 3.78 mmol) was then dropped in, the ice bath was removed, and the mixture was stirred for 12 hours at ambient temperature. The mixture was diluted with DCM and washed with 0.1N HCl. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. This material was dissolved in MeOH (4 mL) followed by the addition of LiOH monohydrate (122 mg, 2.91 mmol) in H2O (2 mL) and stirred for 12 hours. The mixture was concentrated in vacuo and chromatographed (SiO2) using 2% MeOH/DCM followed by 5% MeOH/DCM as eluent. The resulting material was dissolved in DCM (4 mL) and 2.0 M HCl in Et2O (2 mL), and then stirred for 12 hours. The mixture was concentrated in vacuo and chromatographed (SiO2) using 10% MeOH/DCM followed by 10% (7N NH3 in MeOH)/DCM as eluent. The purified material was dissolved in MeOH followed by the addition of 2.0N HCl in Et2O, and then concentrated in vacuo. The resulting glass was suspended in Et2O and concentrated in vacuo (repeat twice) to give 2-(R)-amino-3-(4-chlorophenyl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride as an off-white powder (50 mg). 1H NMR (DMSO-d6, 400 MHz) δ 12.6 (s, 1H), 8.56 (bs, 3H), 8.03 (d, J=7.1 Hz, 1H), 7.38 (m, 3H), 7.32 (m, 2H), 6.84 (s, 1H), 6.69 (d, J=7.1 Hz, 1H), 4.63 (bs, 1H), 3.88-3.58 (m, 7H), 3.33 (m, 1H), 3.14 (m, 1H), 3.05 (m, 1H). LCMS (APCI+) m/z 384, 386 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[S:8]([CH3:11])(=O)=O)#[N:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21](CS)=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[S:8][CH2:11][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Reactant: COc1ccc(CS)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#N)c(SCc2ccc(OC)cc2)s1

Procedure:
To a stirred solution of 2.5 g (10 mmol) of methyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (Example 139, step (a)) in dry methanol (15 mL) was added p-methoxybenzylmercaptan (3.8 mL, 28 mmol) and triethylamine (1.4 mL, 10 mmol). This solution was refluxed for 15 min and cooled. The resulting solid was collected on a buchner funnel and washed with methanol (2×25 mL) to methyl 4-cyano-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylate (2.84 g, 89%) as a solid.
Reaction SMILES: CO[CH:3]1[O:8][CH:7]([CH3:9])[C:6](=[O:10])[CH:5]=[CH:4]1.ClCl.[OH-:13].[Na+]>C(O)(=O)C.O>[CH3:9][C:7]1[O:8][CH:3]=[CH:4][C:5](=[O:13])[C:6]=1[OH:10]
Reactant: COC1C=CC(=O)C(C)O1
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1occc(=O)c1O
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-2-methyl-2H-pyran-3(6H)-one (0.01 mole) in 20 ml of acetic acid was treated with gaseous chlorine (0.01 mole) at room temperature. The reaction mixture was then heated to reflux for about one hour, cooled to room temperature, diluted with 20 ml of water, the pH adjusted with 50% NaOH solution to 7.0 and the reaction mixture extracted with chloroform. The chloroform extract was concentrated to yield maltol which was recrystallized from methanol to give the pure product (56%), mp 159.5°-160.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
(S)-4-Methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) was dissolved in ethyl acetate (23 mL), followed by the addition of benzoyl chloride (365 mg, 2.6 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (318 mg, 2.6 mmol) in ethyl acetate (11 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 3 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (351 mg, 80%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[OH-:11].[Na+]>>[C:3]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: [OH-]
Agent: [Na+]
Product: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1

Procedure:
The hydrolysis of an indolin-2-one (II) is carried out in dilute aqueous base as, for example, 3 N sodium hydroxide solution, for a period of from about 0.5 hour to about 1.0 hour. The hydrolysis may be run in an inert atmosphere using nitrogen. The hydrolysis mixture may be filtered to remove base-insoluble materials and the pH of the basic solution is adjusted to pH 6-pH 7 by the addition of a weak organic acid such as glacial acetic acid or a dilute mineral acid such as hydrochloric acid. When (I) is a 2-amino-5-benzoylphenylacetic acid or a 2-amino-6-benzoylphenylacetic acid the product can be readily recrystallized from a suitable solvent. When (I) is a 2-amino-3-benzoylphenylacetic acid, recrystallization may result in partial cyclization to the precursor 7-benzoylindolin-2-one (II). Therefore, in the preparation of a 2-amino-3-benzoylphenylacetic acid (I) the product is preferably not recrystallized and is isolated by careful acidification of the filtered basic hydrolysis mixture.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:19][C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][CH:25]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:28]1[C:21]2[C:20]([NH:19][C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=3[F:9])=[CH:25][CH:24]=[N:23][C:22]=2[NH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]cc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
108 mg (810 μmol) of N-chlorosuccinimide are added to a solution of 200 mg (730 μmol) of N-(2-fluoro-4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 5 ml of THF, and the mixture is stirred at RT overnight. To bring the reaction to completion, another 49 mg (365 μmol) of N-chlorosuccinimide are added, and the mixture is stirred for another night. Saturated sodium bicarbonate solution is then added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and then dried with magnesium sulfate, and the solvent is removed under reduced pressure. Purification by column chromatography on silica gel (mobile phase: gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate 100%) and preparative RP-HPLC affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.[CH2:14]([Mg]Br)[CH:15]([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:11])[CH2:14][CH:15]([CH3:17])[CH3:16])=[C:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC(C)C[Mg]Br
Reactant: Cc1c(C=O)oc2ccc(Cl)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(O)CC(C)C)oc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution (20 mL) of 5-chloro-3-methyl-1-benzofuran-2-carbaldehyde (1.00 g) synthesized in Example A88(2) in tetrahydrofuran was added a 1.0M solution (10.3 mL) of isobutylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (650 mg, 50%) as a colorless oil.