Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].Br[C:32]1[C:33]([C:45]([F:48])([F:47])[F:46])=[N:34][N:35]([CH2:37][C@@H:38]2[CH2:42][O:41]C(C)(C)[O:39]2)[CH:36]=1.C([O-])([O-])=O.[K+].[K+].O.Cl>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.O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:32]3[C:33]([C:45]([F:47])([F:48])[F:46])=[N:34][N:35]([CH2:37][C@@H:38]([OH:39])[CH2:42][OH:41])[CH:36]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CC1(C)OC[C@@H](Cn2cc(Br)c(C(F)(F)F)n2)O1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C[C@@H](O)CO)nc3C(F)(F)F)cc12
Temperature: 45 °C

Procedure:
A mixture of 3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (10.0 mg, 0.0232 mmol), 4-bromo-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3-(trifluoromethyl)-1H-pyrazole (15.3 mg, 0.0464 mmol), Pd(PPh3)4 (1.34 mg, 0.00116 mmol), K2CO3 (9.63 mg, 0.0696 mmol) and 4:1 dioxane:H2O (0.5 mL, 5 mmol) was heated in a microwave reactor at 95° C. for 20 min. 12 M of HCl in H2O (0.1 mL, 1 mmol) was added, and the solution was heated to 45° C. for 1 h. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.79 (d, J=7.1 Hz, 3H), 3.56 (d, J=5.3 Hz, 2H), 3.63 (br. s., 3H), 4.04 (dd, J=8.1, 3.8 Hz, 1H), 4.19 (dd, J=13.9, 8.1 Hz, 1H), 4.38 (dd, J=13.9, 3.8 Hz, 1H), 5.10 (q, J=7.0 Hz, 1H), 6.87 (dd, J=9.0, 4.2 Hz, 1H), 7.06 (t, J=8.8 Hz, 1H), 7.35 (d, J=1.3 Hz, 1H), 7.54 (s, 1H), 7.82 (s, 1H), 8.13 (br. s., 1H). MS (ES+): m/z=513.06/515.06 (100/50) [MH+]. HPLC: tR=3.26 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH2:42])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:42][C:34]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[O:41])=[O:13])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1cccnc1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)c2cccnc2)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and nicotinamide, the title compound was obtained as crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]2[C:15]=1[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]2[CH2:19][CH:20]([CH3:22])[CH3:21].[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]2[C:15]=1[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]2[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCCO)n(Cc3cccc4ccccc34)cc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(CCCCCO)n(Cc3cccc4ccccc34)cc21

Procedure:
The compound of Example 13, 5-(5-hydroxypent-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (75 mg) was suspended in ethanol (50 ml). A suspension of 10% palladium on carbon (7 mg) in ethanol (3 ml) was added and the mixture was hydrogenated. When hydrogen uptake ceased, the reaction mixture was filtered and the solvent was removed by rotary evaporation. The crude product was purified by chromatography on silica eluting with ethyl acetate:isohexane (3:1) to give the title compound (29 mg) as an oil.
Reaction SMILES: C1(O[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:14][CH2:13]2)=[N:9][C:10]#[N:11])C=CC=CC=1.[CH2:28]([NH2:30])[CH3:29]>O1CCCC1>[C:10]([NH:9][C:8]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:16][CH2:17]1)=[N:30][CH2:28][CH3:29])#[N:11]
Reactant: N#CN=C(Oc1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CCN
Solvent: C1CCOC1
Product: CCN=C(NC#N)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
N-cyano-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboximidic acid phenyl ester (0.050 g; 0.14 mmol) was treated with a 2M Solution of ethylamine in tetrahydrofuran (2 mL) and subjected to microwave irradiation (temperature approximately 110° C.) for 0.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography to give N-cyano-N′-ethyl-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxamidine (0.01 g) as a white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=O)=[C:8]([N:19]2[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:21]=[C:20]2[CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)[CH:7]=[CH:6][CH:5]=1)=[O:2].O.NN>C(O)C>[CH2:24]([C:23]1[N:19]2[C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:3][CH:1]=[O:2])[C:9]=3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:32][CH2:31][C:20]2=[N:21][N:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=CNc1cccc(-n2c(Cc3ccccc3)nnc2CN2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: O=CNc1cccc2c1C(c1ccccc1Cl)=NCc1nnc(Cc3ccccc3)n1-2

Procedure:
In the manner given in Example 5, 6-formamido-2'-chloro-2-[3-(phthalimidomethyl)-5-benzyl-4H-1,2,4-triazol-4-yl]benzophenone was heated in ethanol with hydrazine hydrate to give 1-benzyl-7-formamido-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][CH:4]([C:7]([O:9][C@H](C2C=CC=CC=2)C)=[O:8])[CH2:3]1>C(O)C.[Pd]>[F:1][C:2]1([F:18])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: C[C@H](OC(=O)C1CCC(F)(F)C1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1-phenylethyl 3,3-difluorocyclopentanecarboxylate (diastereomer-1 or diastereomer-2, 0.15 g) in ethanol (5 mL) was added 10% Pd—C. The reaction mixture was stirred at rt under H2 for 16 h. The reaction mixture was filtered and the filtrate was concentrated to afford corresponding enantiomers of 3,3-difluorocyclopentanecarboxylic acid. 1H NMR (400 MHz, METHANOL-d4) ppm 2.97-3.08 (1H, m), 2.28-2.41 (2H, m), 1.93-2.23 (4H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=O.[N:9]#[C:10][NH2:11].[OH-].[Na+]>O.Cl>[CH3:6][C:5]([C:3]1[NH:9][C:10]([NH2:11])=[N:1][CH:2]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)CN
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cnc(N)[nH]1
Temperature: 90 °C
Yield: 6.1 %

Procedure:
To a stirred solution of 6.8 g of aminomethyl-(1,1-dimethylethyl)ketone, as the hydrochloride salt, in 30 ml of water were added portionwise 5.0 g of cyanamide. The pH of the reaction mixture was adjusted to 6.0 with 1N sodium hydroxide, and then the mixture was heated to 90° C. and stirred for fifty-five minutes. The reaction mixture was next cooled to room temperature, diluted with 100 ml. of water, and extracted several times with diethyl ether. The aqueous layer was made alkaline with ammonium hydroxide, and again extracted several times with diethylether. The extracts from the alkaline mixture were combined and concentrated to dryness to provide a solid residue. The residue thus obtained was dissolved in 20 ml of 6N hydrochloric acid and heated at reflux for sixteen hours. The reaction mixture was cooled, concentrated to an oil by evaporation of the solvent, and the oil was dissolved in water and made alkaline to pH 8.5. The alkaline mixture was extracted several times with diethyl ether. The etheral extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 0.5 g of 5-(1,1-dimethylethyl)-2-aminoimidazole.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[AlH4-].[Li+]>CCOCC>[OH:9][CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (2.0 g, 0.012 mol) was dissolved in ether (20.0 mL) and was then cooled at 0° C. Into the mixture was added 1 M lithium tetrahydroaluminate in ether (20 mL) and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was quenched with water (2 mL) and 1 N NaOH (2 mL) and ether was added (100 mL). The precipitated solids were filtered off and the residue was used in the next reaction. 1H NMR (CDCl3): δ 4.02 and 3.75 (m, 1H), 3.45-3.61 (m, 2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.52-1.80 (m, 2H), 1.44 (m, 1H), 1.32 (m, 2H), 1.03 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]([F:22])=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:23][NH2:24]>CO>[F:22][C:15]1[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]2[O:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:24][CH3:23])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: CN
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Solvent: CO
Product: CNCc1ccc(-c2nc3cc(F)cc(C(=O)OC)c3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To the solution of methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate (350 mg, 0.96 mmol) in methanol (20 mL), methylamine (6 mL) was added, the mixture was stirred at room temperature for 1 hr, then heated to 30° C. for 30 min; the solvents were evaporated and the residue was purified by pre-HPLC to obtain methyl 5-fluoro-2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate as a white solid (25 mg, yield 8%). LC-MS (ESI) m/z 315 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(Cl)Cl.CO>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH2:17][Br:19])=[CH:14][CH:15]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: [Br-]
Reactant: CCOP(=O)(Cc1ccc(C(C)=O)cc1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C(=O)CBr)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a stirred solution of (4-acetylbenzyl)-phosphonic acid diethyl ester (2.56 g, 9.48 mmol) in DCM (100 ml) and MeOH (40 ml) at room temperature was added tetra-n-butylammonium tribromide (5.03 g, 10.43 mmol) followed by a drop of concentrated hydrochloric acid. The reaction mixture was stirred at room temperature for 18 h. The solvents were then removed under reduced pressure and the residue was partitioned between Et2O (100 ml) and sat. NaHCO3 (60 ml). The aqueous phase was separated and the organic phase was washed with brine (60 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a pale yellow oil which was purified by flash chromatography (3:1 EtOAc/DCM) to give the title compound (2.01 g, 61%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1NC(=O)C.C(Cl)(=O)C.N([O-])=O.[Na+].[I-:25].[Na+].S(=O)(=O)(O)[O-].[Na+]>CO.O.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1[I:25]
Reactant: [I-]
Reactant: CC(=O)Nc1cc(F)c(C(F)(F)F)cc1F
Agent: O=N[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: O
Product: Fc1cc(C(F)(F)F)c(F)cc1I
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
N-(2,5-difluoro-4-(trifluoromethyl)phenyl)acetamide (950 mg, 4.0 mmol) (Prepared according to Y. Tanabe et al, J. Org. Chem. 1988, 53, 4585-4587) was stirred in methanol (25 mL), treated with acetyl chloride (3 mL) and heated at reflux for 2 h. The volatiles were removed by evaporation and the solid residue was dissolved in 6 N HCl (50 mL), cooled to 5° C. and treated in portions with a solution of sodium nitrite (410 mg, 6.0 mmol) in water (5 mL). After 30 min, this mixture was poured into a solution of sodium iodide (2.4 g, 16 mmol) in water (50 mL) and rapidly stirred with dichloromethane (50 mL). After 30 min, solid sodium bisulfate was added to destroy the iodine color, and the separated organic phase was washed with sat. NaCl, dried (Na2SO4), and evaporated. The material was purified by flash chromatography (SiO2, eluting with hexanes) to provide the title compound as a volatile clear liquid (250 mg, 20%): 1H NMR (400 MHz, CDCl3) δ 7.64 (ddd, J=8.8, 4.8, 0.4 Hz, 1H), 7.28 (dd, J=11.1, 4.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −61.92, −97.64, −97.68, −118.59, −118.63, −118.64, −118.67; EIMS m/z 308.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Brc1ccc2c(N3CCNCC3)nncc2c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 6-bromo-1-(piperazin-1-yl)phthalazine (0.12g, 0.41 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.12g, 0.41 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.0205 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.14g) as a yellow solid. Found MS (ES+): 388(M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:21]1.C([O-])(=O)C.[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([OH:21])=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1OC(F)(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(O)cc1OC(F)(F)F
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
To a stirring degassed solution of N,N-diethyl-4-bromo-2-(trifluoromethoxy)benzamide (2768 mg, 8.2 mmol), bis(pinacolato)diboron (2281 mg, 9.0 mmol), and potassium acetate (2402 mg, 24.5 mmol) in dry DMF (60 mL) was added palladium(II) acetate (55 mg, 0.25 mmol). The reaction was heated to 80° C. for 2 h and then cooled to room temp. The reaction was quenched with water and extracted with EtOAc (3×75 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was dissolved in THF (40 mL) and acetic acid (2.0 mL) and treated with hydrogen peroxide (8 mL). The reaction was stirred for 15 min and then quenched with st. aq. NaHSO3. The reaction was extracted with EtOAc (3×40 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 20-70% EtOAc in hexanes) to give 1876 mg of the desired product as a white solid. MS (ESI) 278 (M+H).
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.C=C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([C:6]23[CH2:7][CH:8]([CH2:4][CH2:5]2)[CH:9]=[CH:10]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reactant: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C1=CC2(c3ccccc3)CCC1C2
Temperature: 180 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
DCPD (Aldrich, 55 mL, 0.41 mol), styrene (Aldrich, 146 mL, 1.27 mol), and 4-t-butylcartechol (1.9 g, 11.4 mmol) were put in a 2 L autoclave. After heating to 180° C., reaction was carried out for 4 hours while stirring the autoclave at 300 rpm. After the reaction was completed, the reaction mixture was cooled down. The reaction mixture was diluted with toluene and precipitated in ethanol. After the obtained polystyrene was filtered, the solvent was removed, and the filtrate was transferred to a distillation unit. The filtrate was distilled at 1 torr twice using a vacuum pump at 70° C. to obtain the product (yield: 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]2[C:17]([C:18]3[CH:34]=[CH:33][O:32][C:19]=3[C:20](=[O:31])[O:21]2)=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[C:22]2[C:17]([C:18]3[CH:34]=[CH:33][O:32][C:19]=3[C:20](=[O:31])[O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)c1c(N)ccc2c1oc(=O)c1occc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1oc(=O)c1occc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.229 g) was added to a solution of tert-butyl 7-amino-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 57, 0.210 g) and pyridine (1.13 mL) in DCM (20 mL) and the mixture was stirred at room temperature overnight. The mixture was reduced to half volume in vacuo and the resultant mixture was stirred and heated at 35° C. for 6 hours. Further 2-bromo-4-fluorobenzenesulfonyl chloride (0.572 g) was added and the reaction mixture was heated at 35° C. overnight. The mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with ethyl acetate and cyclohexane, with a gradient of 5-20% to give tert-butyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.329 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[O:16][CH3:17].N1CCCCC1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:36]2[S:32][C:33](=[O:38])[NH:34][C:35]2=[O:37])=[CH:20][CH:19]=1)[O:16][CH3:17]
Reactant: O=C1CSC(=O)N1
Reactant: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 86.6 %

Procedure:
The title compound of Example 16 (580 mg, 1.7 mmol), piperidine (30 mg, 0.34 mmol) and 2,4thiazolidinedione (405 mg, 3.4 mmol) were combined in ethanol (20 mL) and the resulting solution was refluxed overnight. The solvent was removed in vacuo and the residue was purified on silica gel, eluting with hexane/ethyl acetate (3/1) plus 5% acetic acid, to afford the title compound as a solid (640 mg, 87%). mp 205-206° C. 1HNMR (300 MHz, DMSO-d6): δ2.0 (m, 2H), 2.3 (s, 3H), 2.4 (t, 2H), 3.1 (s, 3H), 4.2 (dd, 1H), 7.4 (m, 5H), 7.6 (d, 2H), 7.7 (s, 1H), 7.9 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=O)C.CC(C[Al]CC(C)C)C>C(Cl)Cl>[CH2:15]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:4][OH:3])[CH:14]=2)[C:10]([C:25]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)=[O:36])=[C:11]1[CH:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(CO)cc2n1Cc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of ethyl1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 43, 200 mg, 0.408 mmol) in CH2Cl2 (10 ml) at −78° C. under argon was added Dibal-H (1.0 M in CH2Cl2, 1.6 ml, 1.63 mmol) slowly. The reaction was stirred for 3 h, quenched with methanol, celite, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[OH-:19].[Na+]>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:4]2[C:3](=[O:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:14]=1
Reactant: Clc1c(-c2cccnc2)cnc2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2cccnc2)c[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2N Hydrochloric acid (10 ml) was added to a DMF solution (5 ml) of 4-chloro-(3-pyridin-3-yl)quinoline (0.51 g), and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, 2N sodium hydroxide aqueous solution (10 ml) was added dropwise under ice cooling. The mixture was stirred. The precipitated insoluble matter was separated, washed with water and ether, and dried to give the title compound (0.35 g) as a pale whitish purple powder.