Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=O)[C:12]([OH:14])=[O:13])=[CH:2]1.CC1C(O)=C(CN)C(COP(O)(O)=O)=C[N:18]=1.P([O-])([O-])([O-])=O>O>[NH2:18][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Reactant: Cc1ncc(COP(=O)(O)O)c(CN)c1O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 37 °C
Reaction time: 2 h

Procedure:
To a solution containing 20.3 g (100mmol) of indole-3-pyruvic acid and 26.5 g (100 mmol) of pyridoxamine-5-phosphate in 1000 ml of distilled water buffered at pH 6.5 with 0.5M phosphate buffer and maintained at 37° C. is added 50 mg of the monoclonal antibodies prepared according to Example 15. The reaction mixture is gently agitated for 2 hours. The monoclonal antibodies are then recovered by ultrafiltration. Dialysis of the reaction mixture followed by lyophilization yields the product L-tryptophan.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][O-:10].[Na+].CO>>[CH3:9][O:10][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Nc1cnc(Br)cn1
Agent: [Na+]
Solvent: CO
Product: COc1cnc(N)cn1
Temperature: 140 °C
Yield: 31.7 %

Procedure:
5-Bromopyrazin-2-amine (0.11 g, 0.63 mmol) was dissolved in NaOMe/MeOH (0.23 g Na metal in 10 mL MeOH) and heated by microwave irradiation at 140° C. for 7 hours. After evaporation of the solvent, the residue was purified by preparative TLC, eluting with 30% ethyl acetate-n-hexane, to give 5-methoxypyrazin-2-amine (25 mg, 32%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH3:13])[C:7](=[O:21])[C@@H:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.[NH:26]1[C:34]2[C:29](=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[C:7](=[O:21])[CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]3[N:3]=[C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:29]=4[CH:28]=[CH:27][NH:26]5)[N:11]=[CH:10][C:9]2=3)[CH3:13])=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: C[C@@H](c1ccc(Cl)cc1)N1C(=O)[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C[C@@H](c1ccc(Cl)cc1)N1C(=O)C2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Yield: 44.3 %

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 85 using (S)-2-chloro-5-((S)-1-(4-chlorophenyl)ethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (43 mg, 0.113 mmol), 1H-indol-4-ylboronic acid (36.5 mg, 0.227 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (4.66 mg, 5.67 μmol). The crude product was purified by preparatory HPLC using a gradient of 35-50% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). Lyophilization of the collected fractions gave a diastereomeric mixture of title compound (TFA salt) as a yellow powder (23 mg, 44.1%). 1H NMR (400 MHz, DMSO-d6) δ 1.74-1.81 (m, 2H), 1.82-1.89 (m, 1H), 11.20-11.34 (m, 1H), 3.07-3.18 (m, 1H), 3.58-3.77 (m, 3H), 4.03-4.12 (m, 2H), 4.23-4.31 (m, 2H), 4.41-4.60 (m, 3H), 6.32-6.08 (m, 1H), 7.12-7.19 (m, 1H), 7.22-7.30 (m, 1H), 7.35-7.55 (m, 6H), 7.81-7.73 (m, 1H), 7.91-8.01 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H22ClN5O2, 460.15. found 460.4.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:15]=2)[N:10]=1)([CH3:8])[C:3](OCC)=[O:4].CO.O1CCCC1.[BH4-].[Na+]>>[NH2:1][C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:15]=2)[N:10]=1)([CH3:8])[CH2:3][OH:4]
Reactant: CCCCCCCOc1ccc2nc(C(C)(N)C(=O)OCC)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCOc1ccc2nc(C(C)(N)CO)ccc2c1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Ethyl 2-amino-2-(6-heptyloxyquinolin-2-yl)propanoate (7, 5.0 mg, 0.000014 mol) was dissolved in a mixture of methanol (1.0 mL, 0.025 mol) and tetrahydrofuran (1.0 mL, 0.012 mol), followed by sodium tetrahydroborate (1.06 mg, 0.0000279 mol) in small portions at 23° C. The reaction mixture was then allowed to stir for 2 hours. The reaction mixture was quenched with NH4Cl (sat), and solvents were removed under vacuum. The solid residue was then treated with MeOH/DCM, and the crude product was purified via HPLC to give pure product (4 mg, 70%). 1H NMR (CHLOROFORM-d) δ: 8.22 (d, J=8.5 Hz, 1H), 7.97 (d, J=9.3 Hz, 1H), 7.39-7.51 (m, 2H), 7.10 (d, J=2.5 Hz, 1H), 4.14 (br. s., 2H), 4.08 (t, J=6.5 Hz, 2H), 1.81-1.93 (m, 2H), 1.77 (s, 3H), 1.50 (d, J=8.0 Hz, 2H), 1.21-1.44 (m, 6H), 0.81-0.99 (m, 3H). MS (ES, M+1): 317.30.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
(193) A solution of 2-(oxazol-5-yl)pyridine (98 mg, 0.67 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.74 mmol, 0.3 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.34 mmol, 2.7 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.67 mmol, 128 mg) was added, and the solution was stirred for 10 min at 0° C. Butyryl chloride (2.0 equiv, 1.34 mmol, 143 mg, 0.14 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)butan-1-one (193) (68 mg, 0.31 mmol, 46% yield) as a light brown powder: mp 54-55° C; 1H NMR (CDCl3, 250 MHz) d 8.65-8.62 (m, 1H), 7.85-7.78 (m, 3H), 7.31-7.26 (m, 1H), 3.07 (t, J=7.3 Hz, 2H), 1.87-1.72 (m, 2H), 1.00 (t, J=7.7 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz)d 188.4, 162.0, 157.3, 150.1, 146.3, 136.9, 126.8, 124.1, 120.3, 40.9, 17.5, 13.5; IR (KBr) umax 2963, 2933, 2872, 1675, 1469, 1426, 1387, 1227 cm−1; MALDI-FTMS (DHB) m/z 217.0968 (C12H12N2O2+H+ requires 217.0971).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=12.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN1C(=O)CCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=23)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1c[nH]c2nccc(F)c12
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12
Temperature: 80 °C
Yield: 75.9 %

Procedure:
4-Fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.300 g, 1.66 mmol) and 1-benzylpiperazine (0.350 g, 1.99 mmol) were placed in NMP (3 mL) and heated to 80° C. in a microwave for 30 minutes. The reaction was then poured into water and extracted with MTBE. The organic fractions were dried, filtered, and concentrated. The crude residue was slurried in minimal DCM, and then triturated with hexane to give 4-(4-benzylpiperazin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.425 g, 76.1% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)(C)C>[CH:8]1[N:9]([C@H:20]2[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]2)[C:10]2[N:11]=[C:12]([NH2:14])[N:13]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:6]=2[N:7]=1
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 87.3 %

Procedure:
A mixture of N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (10 g, 28 mmol), isopropanol (100 ml) and 10% solution of NaOH (16.8 ml, 42 mmol) was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and washed several times with 25% solution of NaOH (10 ml). The wet organic layer was neutralized to pH 7.0-7.5 with 17% hydrochloric acid and it was concentrated to dryness under vacuum. The residue was crystallized in acetone (300 ml) to afford abacavir (7.0 g, 88%).
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](I)=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1COCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[N:28][CH:29]=1
Reactant: Brc1ccc(I)nc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
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: C1CCOC1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)nc1
Temperature: 80 °C
Yield: 98.2 %

Procedure:
A mixture of 4-(diphenylamino)phenylboronic acid (7.00 g, 24.2 mmol), 5-bromo-2-iodopyridine (7.56 g, 26.6 mmol), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 1.21 mmol), Na2CO3 (9.18 g, 86.6 mmol), H2O (84 mL) and THF (140 mL) was degassed with argon for about 1.5 hours (h) while stirring. The stirring reaction mixture was then maintained under argon at 80° C. for about 19 h. Upon confirming consumption of the starting material by thin layer chromatography (TLC) (SiO2, 19:1 hexanes-EtOAc), the reaction was cooled to room temperature (RT) and poured over EtOAc (500 mL). The organics were then washed with sat. NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. The crude product was then purified via flash chromatography (SiO2, 2:1 hexanes-dichloromethane) to afford compound 1 (9.54 g, 98% yield) as a light yellow, crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>>[CH:30]1([C:34]([N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]3[S:11][C:7]4[C:6]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[N:9]=3)=[O:23])=[CH:19][CH:18]=2)[CH3:22])=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CCC1
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)C4CCC4)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and cyclobutanecarbonyl chloride, the title compound was prepared as light yellow crystals (59% yield). MS: m/e=495(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCc1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3)cc2OC1C(F)(F)F
Temperature: 100 °C

Procedure:
To 4.05 g (12.5 mmole) of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 30 mL of DMF was added 1.86 g (15.2 mmole) of 4-ethylphenol and 2.42 g (17.5 mmole) of potassium carbonate. The stirred mixture was heated to 100° C. for 8 h, allowed to cool and treated with 100 mL of water. The mixture was extracted three times with diethyl ether, the combined filtrates filtered through 30 g of silica and the filtrates concd in vacuo to afford a crude product. Recrystallization from methanol-water afforded 4.43 g (83%) of a yellow, crystalline solid: mp 109-110° C.; 1H NMR (d6-acetone/400 MHz) 1.22 (t, 3H, J=7.5 Hz), 1.30 (t, 3H, J=7.1 Hz), 2.66 (q, 2H, J=7.6 Hz), 4.28 (m, 2H), 5.81 (q, 1H, J=7.0 Hz), 6.44 (s, 1H), 7.04 (d, 2H, J=8.8 Hz), 7.31 (d, 2H, J=8.6 Hz), 7.67 (s, 1H), 7.86 (s, 1H); 19F NMR (d6-acetone/400 MHz) −79.5 (d, 3F, J=6.8 Hz); 13C NMR (d6-acetone/100 MHz) 13.8, 15.4, 61.3, 70.8 (q, J=32.8 Hz), 105.5, 115.2, 115.9, 117.5, 119.9, 123.8 (q, J=287.1 Hz), 129.8, 131.2, 135.5, 141.5, 153.1, 153.2, 157.4, 163.4; MS (ES+) 427 (M+1, 100); HRMS (ES+) m/z calcd for (C21H18O4ClF3) 427.0918, found 427.0921.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](N)=[N:8][CH:7]=1)=[O:5])[CH3:2].[N+]([O-])(O)=O.N([O-])=O.[Na+].[BrH:20]>P(=O)(O)(O)O.O.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:20])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: Br
Agent: [Cu]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1cnc(Br)s1
Temperature: -10 °C
Reaction time: 0.58 h
Yield: 52 %

Procedure:
The starting material can be prepared as follows: To a 500 mL 24/40 3-neck round bottom flask equiped with a mechanical stirrer, was charged 3.4 g (19.7 mmol) of 2-amino-5-thiazolecarboxylic acid ethyl ester (Ber., 1888, 21, 938), partially dissolved in 30 mL of concentrated phosphoric acid. The stirring mixture was cooled in an ice bath and then 9 mL of concentrated nitric acid was added slowly, followed by the dropwise addition of 2.85 g (41.3 mmol) of sodium nitrite in 5 mL of water. The mixture was stirred in the cold for 35 minutes, and then added dropwise was 3.0 g (47.2 mmol) of copper powder in 75 mL of 48% hydrobromic acid cooled to -10° C. After the evolution of nitrogen gas ceased, the thick reaction mixture was removed from the ice bath and neutralized to pH 8, first using 5N sodium hydroxide and then sodium carbonate. The aqueous was then extracted with 400 mL ether. The insoluble material was filtered away and the filtrate was washed with 5% sodium bicarbonate, water, dried over sodium sulfate, and removed in vacuo. The crude residue was then purified using silica gel flash chromatography eluting with 1:1 ether/hexanes to give 2.4 g (52%) of 2-bromo-5-thiazolecarboxylic acid ethyl ester as a yellow oil. Rf =0.62 (1:1 ether/hexanes). 1H NMR (300 MHz, DMSO d6) δ 1.26 (t, J=7.0 Hz, 3H), 4.29 (q, J=7.1 Hz, 2H), 8.28 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)([CH2:13][CH:14]=[CH2:15])[CH2:9][S:10]2)=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)([CH2:13][CH2:14][CH3:15])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.6 %

Procedure:
10% Pd/C (580 mg) was added to a solution of 7-methoxy-3-(4-methoxyphenyl)-3-(2-propenyl)thiochroman-4-one (1.75 g, 5.14 mmol) in ethyl acetate (20 ml) followed by stirring for 15 hours at room temperature under a hydrogen stream. Pd/C was removed by filtration through cellite and the resulting filtrate was concentrated under reduced pressure to give 7-methoxy-3-(4-methoxyphenyl)-3-propylthiochroman-4-one (1.7 g, Yield 96%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][N:43]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 72.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (644 mg, 1.33 mmol, 72%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: COc1ccccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol) was dissolved in 3-amino-1-propanol(6 ml) in the pressure tube, and reacted at the same condition of Step 3 in the Example 12 to obtain 570 mg of desired compound as solid in 88% of yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22]#[N:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1.C1COCC1>[ClH:24].[ClH:24].[NH2:21][C:19]1[C:18]([C:22]#[N:23])=[CH:17][N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C#N)c(N)n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1cnc(NC2CCNCC2)nc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(4-amino-5-cyano-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.02 g, 9.49 mmol) in dioxane (10 mL) and THF (10 mL) was added 4 M HCl in dioxane (50 mL) and the reaction mixture stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 219.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[O:13][C:14](=O)[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:3]1.[NH3:25]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:25][C:14](=[O:13])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:3]1
Reactant: N
Reactant: Cc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c1
Solvent: CN(C)C=O
Product: Cc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c1
Temperature: 150 °C

Procedure:
0.30 g of 3-(1-methyl-3-indolyl)-4-(3-methylphenyl) furan-2,5-dione was treated with 8 ml of DMF and 60 ml of 33% aqueous ammonia and heated at 150° C. for 5 hours and then allowed to cool. The formed precipitate was filtered off, washed with water and dried to give 162 mg of 3-(1-methyl-3-indolyl)-4-(3-methylphenyl)-1H-pyrrole-2,5-dione, m.p. 243° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([C:11]([Br:14])=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[CH3:18][Si](C=[N+]=[N-])(C)C.CCCCCC>C1COCC1.CO>[CH3:18][O:9][C:8](=[O:10])[C:7]1[C:11]([Br:14])=[CH:12][CH:13]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)c1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 3-acetylamino-6-bromo-2-nitro-benzoic acid (3.86 g, 14.96 mmol) in dry THF (42 mL) and dry methanol (18 mL) was added a solution of (trimethylsilyl)diazomethane in hexane (2M, 24 mL, 48 mmol). The solution was stirred at room temperature for 3 h and evaporated. The residue was purified by flash chromatography in hexanes/ethyl acetate (6:1) to give 3-acetylamino-6-bromo-2-nitrobenzoic acid methyl ester (2.45 g, 52%).
Reaction SMILES: [CH3:1][C:2]([O:5][C@@H:6]([C:9]1[N:10]([CH3:28])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][OH:8])([CH3:4])[CH3:3].[O:29]1CCCC1.CC(=C(C)C)C.[O-]Cl=O.[Na+]>CS(C)=O.O>[C:2]([O:5][C@@H:6]([C:9]1[N:10]([CH3:28])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([OH:29])=[O:8])([CH3:1])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2c([C@@H](CO)OC(C)(C)C)n(C)c(=O)c3ccccc23)cc1C
Agent: CC(C)=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2c([C@H](OC(C)(C)C)C(=O)O)n(C)c(=O)c3ccccc23)cc1C
Reaction time: 18 h

Procedure:
A solution of 3-{(1S)-1-[(1,1-dimethylethyl)oxy]-2-hydroxyethyl}-4-(3,4-dimethylphenyl)-2-methyl-1(2H)-isoquinolinone (4 mg, 10.54 μmol) in DMSO is treated with DMP (13 mg, 0.032 mmol). After 18 h, the reaction mixture was filtered through a pad of silica gel and washed with 1:1 EtOAc-hexanes. The filtrate was concentrated, dissolved in EtOAc and washed with H2O (3×), brine, dried (Na2SO4), filtered and concentrated. The residue was then dissolved in tert-Butanol (51.5 μl) and Tetrahydrofuran (THF) (51 μl) and treated with 2,3-dimethyl-2-butene (3 μl, 0.02 mmol) and a solution of NaClO2 (1.787 mg, 0.016 mmol) and NaH2PO4 (1.2 mg, 10.5 μmol) in water (100 uL). The crude reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in DMF (250 uL) and purified by Gilson to afford the title compound: Rt=0.95, 0.97 (atropisomers), ES+ MS: 394 (M+1). The chirality of the above compound was established by comparison to authentic material of (R)- and (S)-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid using a Chiral SFC 20% MeOH/80% CO2; 4.6×250 mm IC column; Rt (R)=1 min; (S)=7.22 min.