Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([CH2:20][CH2:21][NH:22][C@@H:23]([CH3:33])[C@H:24]([OH:32])[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C:13]([OH:15])=[O:14])C1C=CC=CC=1>C(O)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:19]=[C:18]([CH2:20][CH2:21][NH:22][C@@H:23]([CH3:33])[C@H:24]([OH:32])[C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: C[C@H](NCCc1ccc(OCC(=O)O)c(OCc2ccccc2)c1)[C@H](O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@H](NCCc1ccc(OCC(=O)O)c(O)c1)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 99.2 %

Procedure:
To a solution of 2-[2-benzyloxy-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (97 mg) in acetic acid (4 ml) was added 10% palladium carbon (wet, 50% water) (30 mg), and the mixture was stirred for 50 minutes at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the solvent was removed under reduced pressure. After addition of ethyl acetate to the residue, collection of the resulting insoluble material by filtration gave 2-[2-hydroxy-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (77 mg).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:5]2=[C:4]([C:19](O)=[O:20])[N:3]=1.[CH3:22][NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:11][C:5]2=[C:4]([C:19](=[O:20])[NH:26][C@@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24]([NH:23][CH3:22])=[O:31])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(Br)nc(C(=O)O)c2C1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CCC2
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 3-bromo-8-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxylic acid (33E) (1.08 g, 3.0 mmol), H-Leu-NHMe (20B) (0.62 g, 4.30 mmol) and DIEA (0.52 mL, 3.0 mmol) in DMF (25 mL) was added TBTU (1.46 g, 4.55 mmol) in two batches over 10 min at 0° C. After stirring from 0° C. to room temperature overnight, the reaction was quenched with water and evaporated under vacuum. The residue was extracted between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography with 60% to 100% EtOAc/Hex to give an oily product 55A at 51% yield. LCMS (+ESI) m/z 486.1, 489.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]([N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]3=[O:19])[CH:10]=[N:11][CH:12]=2)=[CH:5][N:6]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27]>CC(O)C>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([NH:27][C:2]2[O:3][C:4]([C:7]3[CH:8]=[C:9]([N:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]4=[O:19])[CH:10]=[N:11][CH:12]=3)=[CH:5][N:6]=2)[CH:28]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: O=c1ccccn1-c1cncc(-c2cnc(Cl)o2)c1
Solvent: CC(C)O
Product: COc1ccc(C)c(Nc2ncc(-c3cncc(-n4ccccc4=O)c3)o2)c1

Procedure:
5′-[2-(5-Methoxy-2-methyl-phenylamino)-oxazol-5-yl]-[1,3′]bipyridinyl-2-one 221 was prepared as described for I-f above from 5′-(2-Chloro-oxazol-5-yl)-[1,3′]bipyridinyl-2-one VIII-c (68 mg, 0.250 mmol), and 5-methoxy-2-methylaniline (35 mg, 0.250 mmol) in iPrOH (3 mL) to afford the title compound 221 after column chromatography (SiO2; eluting with 2% to 5% EtOH in DCM) as an orange solid (28 mg, 30%). (300 MHz, CDCl3) δ 8.83 (d, J=1.9 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.93 (t, J=2.1 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 7.30 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.78 (s, 1H), 6.68 (d, J=9.3 Hz, 1H), 6.55 (dd, J=8.3, 2.5 Hz, 1H), 6.30 (t, J=5.6 Hz, 1H), 3.81 (s, 3H), 2.25 (s, 3H). ESL MS m/z 375 (M+H)+. Retention time=2.99 min (method 1).
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1>C(OCC)C>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[NH:5][S:2]([Cl:1])(=[O:4])=[O:3])=[CH:10][CH:11]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)NS(=O)(=O)Cl)cc1
Temperature: -40 °C
Yield: 80 %

Procedure:
This compound was prepared according to J. Med. Chem. 1996, 39, 1243-1252. Briefly, a solution of chlorosulfonylisocyanate (1.62 g, 11.5 mmol, 1 eq.) was diluted in dry diethylether and the resulting solution was cooled at −50° C.<T<−40° C. To this solution, p-toluidine (1.23 g, 11.5 mmol, 1 eq.) was added. The solution was stirred at −35° C. for 10′ and a suspension was obtained. The solid was filtered and washed with diethyl ether. Yield 80%, 2.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)OC(C)(C)c2cc(Nc3cccc(Cl)c3Cl)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 2,3-dichlorophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 351/353/355 ([M+H]+); MS (ESI) m/z 349/351/353 ([M−H]−); Anal. calcd for C17H16Cl2N2O2: C, 58.13; H, 4.59; N, 7.98. Found: C, 58.59; H, 4.61; N, 7.36.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:26][O:27][CH3:28])=[C:10](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>CCO.[Pt]=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:26][O:27][CH3:28])=[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(COC)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CCc1c(COC)nc2c(cnn2CC)c1-c1cncc(C)c1
Yield: 57.7 %

Procedure:
A mixture of ethyl (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylate (50 mg) in EtOH (3 ml) was hydrogenated (3 atm) over platinum oxide (25 mg) at room temperature for 7 hours. The catalyst was filtered off through celite pad and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography-on silica gel eluting with a mixture of EtOAc and n-hexane (1:1) then a mixture of MeOH and CHCl3 (1:40) to give ethyl 3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (29 mg) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[Cl-].C[Al+]C.Cl[C:23](=[O:32])[CH2:24][C@@H:25]([CH3:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Cl-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][C@H:25]([CH3:31])[CH2:24][C:23]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([CH3:11])[C:6]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:32]
Reactant: CCCCCCc1cc2cc(Cl)ccc2n1C
Reactant: COC(=O)C[C@H](C)CC(=O)Cl
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)OC)c2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the cold solution of 5-Chloro-2-hexyl-1-methyl-1H-indole in methylene chloride was added dimethyl aluminum chloride solution and was stirred for 30 minutes. Then (S)-methyl 5-chloro-3-methyl-5-oxopentanoate in methylene chloride was added to the reaction mixture and was stirred for 3 hours. The reaction mixture was then treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][N:3]1[CH2:29][C:30]1[CH:42]=[CH:41][CH:40]=[CH:39][C:31]=1[C:32]([O:34]C(C)(C)C)=[O:33]>Cl.O1CCOCC1>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:11]2)[N:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][N:3]1[CH2:29][C:30]1[CH:42]=[CH:41][CH:40]=[CH:39][C:31]=1[C:32]([OH:34])=[O:33]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCCN1CCC2(CC1)C(=O)N(Cc1ccccc1C(=O)O)CN2c1ccccc1)c1ccccc1
Yield: 33.1 %

Procedure:
A solution of tert-butyl 2-((4-oxo-8-(4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (268 mg, 0.472 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 7% methanol in dichloromethane. The pure extract was treated with 4M hydrogen chloride solution in dioxane to afford the hydrogen chloride salt of the title compound as a white powder (80 mg, 30%); 1H NMR (400 MHz, DMSO-d6): δ 2.01 (d, 2H, J=14.4 Hz); 2.09 (t, 2H, J=7.2 and 7.6 Hz); 3.02 (t, 2H, J=12.4 and 10.4 Hz); 3.18 (bs, 2H); 3.23 (t, 2H, J=7.2 and 6.8 Hz); 3.65-3.7 (m, 4H); 4.69 (s, 2H); 4.94 (s, 2H); 6.81 (t, 1H, J=7.2 and 7.6 Hz); 7.04 (d, 2H, J=8.4 Hz); 7.24 (t, 2H, J=7.6 and 8 Hz); 7.33 (d, 1H, J=8 Hz); 7.43 (t, 2H, J=7.6 Hz); 7.53-7.61 (m, 3H); 7.66 (t, 1H, J=7.6 Hz); 7.93 (dd, 1H, J=1.2 and 1.6 Hz); 7.99-8.01 (m, 2H); 10.5 (bs, 1H); 13.2 (bs, 1H); MS for C31H33N3O4 m/z 512.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)no1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Methoxy-phenyl)-isoxazole-5-carboxylic acid ethyl ester (available from ChemDiv Inc., 6605 Nancy Ridge Dr, San Diego, Calif., 92121, USA; 15 g, 60.1 mmol) was taken up in CH2Cl2 (30 mL) and 1 M BBr3 (400 mL, 400 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was added to a beaker of ice-water and the solid was collected by filtration. The solid was taken up in EtOAc and the solution was washed with water to remove most of the undesired carboxylic acid side product. Yield: 1.9 g (14%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[O:21][C:20]([C:22]#[N:23])=[CH:19][CH:18]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[O:21][C:20]([C:22]#[N:23])=[CH:19][CH:18]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)o1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(C#N)o2)C1=O
Reaction time: 5 h
Yield: 100 %

Procedure:
A solution of (2-oxopyrrolidin-3-(S)-yl)carbamic acid tert-butyl ester (1.56 g, 7.8 mmol) in 80 mL of THF:DMF (5:1) is treated with 5-bromomethylfuran-2-carbo-nitrile (3.23 g, 16 mmol) and sodium hydride (60%) (0.32 g, 8 mmol) as described in EXAMPLE 122, Part F. After addition, the solution is allowed to warm to ambient temperatures. After 5 hours, the solution is quenched by the addition of sat. NH4Cl. The solution is diluted with EtOAc and washed with H2O (3x) and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 80% EtOAc/hexanes to afford [1-(5-cyanofuran-2-ylmethyl)-2-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester (2.38 g, 7.8 mmol) as a white solid. A portion of this material (1.28 g, 4.2 mmol) is treated as described in EXAMPLE 122, Part G to yield the title compound (1.1 g, 4.55 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl>>[S:13]1[CH2:14][CH2:10][N:11]=[C:12]1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: Cl
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCS3)cc2)cs1
Temperature: 120 °C
Reaction time: 10 h
Yield: 40.6 %

Procedure:
N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (1.8 g) prepared in a similar manner according to Step 6 of Production Example 1,2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (918 mg), hydrochloric acid concentrate (0.57 ml) and 2-methoxyethanol (28 ml) were combined under nitrogen atmosphere, and stirred at 120° C. for 10 hours. After cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in tetrahydrofuran/water, and made basic with aqueous potassium carbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (30:1→20:1) as an eluent, and triturated with ethyl acetate to give N-(4-(2-(4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide (484.7 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:19]1[CH2:23][CH2:22][CH2:21][C:20]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:39])[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33](Br)[CH:32]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:39])[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:32]=1)[CH3:28]
Reactant: OB(O)C1=C(c2cc(C(F)(F)F)ccc2OCc2ccccc2)CCC1
Reactant: CCOC(=O)c1cc(Br)ccc1F
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)ccc1F

Procedure:
Prepared by general procedure C(iii) but using 2-(2-benzyloxy-5-trifluoromethylphenyl)cyclopentene-1-boronic acid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and 3-bromo-6-fluorobenzoic acid ethyl ester instead of 2-chloropyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]1[N:10]2[C@H:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@H:12]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3][CH2:2]1.[OH-].[K+]>C(O)CCC>[CH2:1]1[N:10]2[C@H:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3][CH2:2]1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCN2
Temperature: 119 °C
Yield: 87.7 %

Procedure:
To ethyl (6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (4.10 g, 14.3 mmol) was added n-butanol (18.0 mL) and KOH powder (3.0 g). The reaction was heated at 119° C. in a sealed tube for 18 hr. The solvent was removed under reduced pressure. To the residue was added water (30 mL) extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford the title compound as a pale yellow oil (2.70 g, 78%). MS-ESI: 216 [MH]+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[N:3]=1.NC1N=C(Cl)N=C(Cl)N=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23]>>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[N:5]=[C:6]([NH:23][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[N:7]=1
Reactant: COC(CN)OC
Reactant: Nc1nc(O)nc(Cl)n1
Agent: Nc1nc(Cl)nc(Cl)n1
Product: COC(CNc1nc(N)[nH]c(=O)n1)OC

Procedure:
2-Amino-4-chloro-6-hydroxy-s-triazine (hereinafter referred to as COMPOUND II) is described in Chem. Abst., 77, 165133y (1972). This compound in turn can be prepared from 2-amino-4,6-dichloro-s-triazine (hereinafter referred to as COMPOUND I) by controlled hydrolysis of one of the halogens of COMPOUND I. Condensation of COMPOUND II with aminoacetaldehyde dimethyl acetal in aqueous basic media at reflux temperatures gave crystalline 2-amino-4-(2,2-dimethoxyethylamino)-s-triazin-6-one (hereinafter referred to as COMPOUND III) in a good yield. Hydrolysis of the acetal groups of COMPOUND III was achieved by heating COMPOUND III in 6 N hydrochloric acid on a steambath under a nitrogen atmosphere to give the hydrochloride salt of 2-amino-4(2-hydroxyvinyleneamino)-s-triazin-4-one. The free-base of this compound, hereinafter referred to as COMPOUND IV, was obtained by careful neutralization of an aqueous solution of the hydrochloride salt. Ring annulation of either COMPOUND IV or its hydrochloride salt in concentrated sulfuric acid at 95° C. for 1.5 hours gave crystalline 2-aminoimidazo[1,2-a]-s-triazin-4-one (hereinafter referred to as COMPOUND V) in a good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([N:24]1[CH2:25][CH2:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:20][CH:19]=2)[CH2:22][CH2:23]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCNCC4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one (0.16 mmol) in CH2Cl2 (10 mL) was added Et3N (0.32 mmol) and acetyl chloride (0.17 mmol). The resulting solution was stirred at 0° C. overnight. The solution was concentrated in vacuo, basified with NaHCO3, extracted with CH2Cl2, and washed with water and brine. The material was dried (Na2SO4), filtered, and concentrated to afford the title compound 13 (0.020 g, 30%). 1H NMR (300 MHz, DMSO-d6): δ 11.93 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 4.42-4.64 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.06-3.21 (m, 1H), 2.77-2.94 (m, 1H), 2.54-2.68 (m, 1H), 2.03 (s, 3H), 1.73-1.91 (m, 2H), 1.56-1.73 (m, 1H), 1.36-1.56 (m, 1H), 1.06-1.36 (m, 1H). ESI MS m/z 408 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:27]([O:29]C)=[O:28])[C:12]3[CH2:13][CH2:14][N:15]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:16](=[O:19])[C:17]=3[CH:18]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:27]([OH:29])=[O:28])[C:12]3[CH2:13][CH2:14][N:15]([CH:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])[C:16](=[O:19])[C:17]=3[CH:18]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3cccc(C#N)c3)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(-c3cccc(C#N)c3)cc2C1=O
Yield: 89.5 %

Procedure:
103 mg of methyl 7-(3-Cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are dissolved in 2 cm3 of dioxane at a temperature close to 20° C. 0.6 cm3 of a 1N aqueous solution of sodium hydroxide are added, then the reaction mixture is heated at a temperature close to 60° C. for 30 min. The mixture is then concentrated to dryness under reduced pressure (5 kPa), taken up by 20 cm3 of water and 20 cm3 of ethyl ether. The aqueous phase is decanted, acidified with 0.4 cm3 of a 2N aqueous solution of hydrochloric acid and taken up with 20 cm3 of dichloromethane. The organic phase is extracted, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 89 mg of 7-(3-Cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of a white powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([N:15]([CH3:25])[C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:25][N:15]([CH:10]1[CH:11]([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[C:16]1[C:17]2[CH:24]=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CC1CCN(Cc2ccccc2)CC1N(C)c1ncnc2[nH]ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To the product from Method G (0.7 grams, 2.19 mmol) dissolved in 15 mL of ethanol was added 0.5 grams of 20% palladium hydroxide on carbon (50% water) (Aldrich) and the resulting mixture agitated (Parr-Shaker) under an atmosphere of hydrogen (50 psi) at room temperature for 2 days. The Celite filtered reaction mixture was concentrated to dryness in vacuo and the residue purified by flash chromatography (silica; 5% methanol in dichoromethane) affording 0.48 grams (90%) of the title compound. LRMS: 246.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([F:17])[CH:10]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Br:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[C:11]([F:17])[CH:10]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (S)-(−)-2-methyl-2-propanesulfinamide (20.20 g, 0.167 mol) in 350 mL CH2Cl2 were added 4-bromo-2-fluorobenzaldehyde (35.53 g, 0.1750 mol), pyridinium-p-toluenesulfonate (2.09 g, 8.33 mmol), and magnesium sulfate (200.6 g, 1.667 mol). The reaction mixture was stirred at room temperature for 48 hours. Additional magnesium sulfate (100.3 g, 0.833 mol) was added, and the reaction was stirred 24 hours. The mixture was filtered through celite, washing with CH2Cl2 and concentrated in vacuo. The resulting residue was subjected to column chromatography on silica gel eluted with 0-10% ethyl acetate in hexanes to afford N-[(1E)-(4-bromo-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide as a white solid that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 308.09 for M+H+ (81Br).
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: O=c1c(I)coc2ccccc12
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc[nH]2)coc2ccccc12
Temperature: 0 °C
Yield: 56.7 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 mg) prepared in Example 1, pyrrol (134 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added and the mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by the silica gel column chromatography, and the purified product was recrystallized from benzene/hexane to give the titled compound (59.9 mg; yield=56.4%) as light ocher crystals. Melting point: 134°-135 ° C. 1H-NMR(CDCl3, δ ppm): 6.31 (s ,H3), 8.22 (dd, H5), 7.41-7.54 (m, H6), 7.70 (t, H7), 7.41-7.54 (m, H8), 7.32 (br. t, H2'), 6.44(br. t, H3'), 6.44(br. t, H4'), 7.32(br. t, H5').