Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(NC[C@@H]1OC(=O)N(C2C=CC(N3CCN(C(CO)=O)CC3)=C(F)C=2)C1)=[O:3].[CH2:29]([O:36][CH2:37][C:38](Cl)=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C(Cl)Cl>[CH2:29]([O:36][CH2:37][C:38]([OH:39])=[O:3])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
To a mixture of 200 mg (0.508 mmol) of U-100592 (Ex. 1), 149 mg (1.47 mmol, 0.205 mL), and 5 mL methylene chloride at 0° C. benzyloxyacetylchloride was added dropwise. The reaction was allowed to warm slowly up to room temperature. After stirring for 5 hours, 5 mL of 1N HCl was added, and the resulting layers were separated. The aqueous layer was extracted with methylene chloride (3×5 mL). The combined organic layers were washed with brine and dried (MgSO4) then filtered and concentrated to a white solid. The crude was dissolved in a small amount of methylene chloride and methanol and was placed on a 22 cm×2.5 cm 40-60 μ silica column. The column was eluted with ethyl acetate, 2% methanol/ethylacetate, 4% methanol/ethyl acetate, 6% methanol/ethyl acetate, 8% methanol/ethyl acetate, and 10% methanol/ethyl acetate (250 mL each). The appropriate fractions were pooled to provide 120 mg (44%) of benzyloxyacetic acid, 2-[-[4-[5-(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethyl ester, (S)-; as a white solid (mp=146°-148° C.).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH:9]([OH:12])CO)[CH2:3][CH2:2]1.[H-].[Na+]>C1COCC1>[CH:1]1([CH2:4][CH:5]=[CH:6][CH2:7][CH:8]2[CH2:9][O:12]2)[CH2:3][CH2:2]1
Reactant: OCC(O)CCC=CCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C(=CCC1CO1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-Cyclopropyl-hept-5-ene-1,2-diol (1.45 g, 9.28 mmol) in THF (30 mL) was added 60% sodium hydride (1.1 g, 27.84 mmol) at 0° C. The mixture was slowly warmed to room temperature and stirred for 1 h. TrisIm (3.41 g, 10.2 mmol) was added in one portion at 0° C. followed stirring at room temperature for 1.5 h. The mixture was quenched with water and extracted with Et2O. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (7% EtOAc in hexanes gradient to 14% EtOAc in hexanes) gave 2-(4-Cyclopropyl-but-2-enyl)-oxirane as a clear oil; 1H NMR (400 MHz, CDCl3): δ 5.54–5.48 (m, 1H), 5.44–5.37 (m, 1H), 2.94–2.91 (m, 1H), 2.75 (dd, 1H, J1=4.9 Hz, J2=4.1 Hz), 2.48 (dd, 1H, J1=5.0 Hz, J2=2.7 Hz), 2.19 (q, 2H, J=7.3 Hz), 1.98 (t, 2H, J=7.0 Hz), 1.62–1.56 (m, 2H), 0.75–0.66 (m, 1H), 0.44–0.39 (m, 2H), 0.09–0.05(m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([C:26]#[N:27])[C@H:15]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([C:26]#[N:27])[C@H:15]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 88 %

Procedure:
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 342 (95 mg, 0.16 mmol) in tetrahydrofuran (6 mL) was added an aqueous solution (1 N) of NaOH (6 mL, 6 mmol) and methanol (2 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (80 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][NH:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24](Cl)=[O:25]>CN(C=O)C>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24]([N:5]1[CH2:6][C:2]([CH3:10])([CH3:1])[CH2:3][CH:4]1[C:7]([OH:9])=[O:8])=[O:25]
Reactant: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Reactant: CC1(C)CNC(C(=O)O)C1
Solvent: CN(C)C=O
Product: CC1(C)CC(C(=O)O)N(C(=O)CCN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,4-dimethylpyrrolidine-2-carboxylic acid 137f (13.0 g, 72.5 mmol) in DMF (250 mL) was added 137h (17.0 g, 72.5 mmol) and TEA (14.5 g, 145 mmol). See FIG. 2. The mixture was stirred at RT (room temperature) for 16 h (sixteen hours). Upon reaction completion, the mixture was washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1-(3-(1,3-dioxoisoindolin-2-yl)propanoyl)-4,4-dimethylpyrrolidine-2-carboxylic acid 137i, which was used directly without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH3:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCC2)c1C
Temperature: 80 °C
Yield: 82.7 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclobutylamino)-2-methylbenzoate (0.7 g, 2.8 mmol) in acetonitrile-(10 mL), cesium carbonate (2.2 g, 6.8 mmol) and methyl iodide (3.9 g, 28 mmol) were added. The resulting reaction mass was heated at 80° C. for 8 h. On completion, the reaction mass was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give the title compound (0.62 g, 84%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:25][C:23](=[O:24])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:25][C@@H:23]([OH:24])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Smilagenone (657 g) was dissolved in tetrahydrofuran (4000 ml) and the solution purged with nitrogen and cooled to provide an internal temperature of ca. −10° C. L-Selectride® (2400 ml 1M in THF) was added over ca. 50 minutes and stirred for 90 minutes. A solution of citric acid (600 g) in water (2000 ml) was added slowly, maintaining the temperature below 0° C. The mixture was allowed to warm to ambient temperature and stirred for 30 minutes. The aqueous layer was separated and extracted with dichloromethane (2000 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (1500 ml). The combined organic extracts were washed with water (4000 ml) and dried over MgSO4. The organic extracts were evaporated to dryness to yield smilagenin.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[N:8][OH:9])[CH:6]=[CH:5][C:4](=[O:10])[CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:9][N:8]=[C:7]1[CH:6]=[CH:5][C:4](=[O:10])[CH:3]=[C:2]1[CH3:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CC(=O)C=CC1=NO
Solvent: c1ccncc1
Product: CC(=O)ON=C1C=CC(=O)C=C1C
Temperature: 70 °C

Procedure:
One drop of pyridine was added to a mixture of 0.5 g (3.6 mmol) of 3-methyl-1,4-benzoquinone-4-oxime and 1 mL of acetic anhydride and the resulting mixture was heated to 70° C. At the end of the reaction, the reaction mixture was poured on 10 mL of water/ice. The precipitated product was filtered off, washed with water and then dried.
Reaction SMILES: C(OC([N:8]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[C:19]([CH3:25])=[C:20]([C:22]([OH:24])=O)[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.Cl.[N+:34]([C:37]1[CH:38]=[C:39]([NH:43][NH2:44])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]>>[N+:34]([C:37]1[CH:38]=[C:39]([NH:43][NH:44][C:22]([C:20]2[O:21][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:18]=3[C:19]=2[CH3:25])=[O:24])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: Cc1c(C(=O)O)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: Cc1c(C(=O)NNc2cccc([N+](=O)[O-])c2)oc2cccc(OCCCNCc3cccnc3)c12

Procedure:
This compound was prepared from 4-[3-(tert-butoxycarbonyl-pyridin-3-ylmethyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid (Example 139-a) and 3-nitrophenylhydrazine hydrochloride in a similar manner to Example 139-b and 139-c. ESI-MS: m/z 476 (MH+), 1H-NMR δ: 2.07 (2H, tt, J=5.9, 6.8 Hz), 2.69 (3H, s), 2.88 (2H, t, J=6.8 Hz), 3.84 (2H, s), 4.18 (2H, t, J=5.9 Hz), 6.51 (1H, m), 6.66 (1H, d, J=7.9 Hz), 7.07 (1H, d, J=7.9 Hz), 7.20-7.42 (4H, m), 7.67 (1H, m), 7.74-7.77 (2H, m), 8.41 (1H, m), 8.49 (1H, m), 8.56 (1H, m).
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[BrH:11]>O>[Br:11][C:2]([F:10])([F:1])[CH2:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1
Reactant: Br
Reactant: O=C1CC(C=C(F)F)CN1
Solvent: O
Product: O=C1CC(CC(F)(F)Br)CN1
Temperature: 25 °C
Yield: 49 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, 0.1 g of 4-(2,2-difluoro-vinyl)-pyrrolidin-2-one a5 (0.6 mmol) is heated in HBr (62% w/w in H2O, 10 ml) for 0.75 h at reflux. The reaction mixture is cooled down to room temperature, diluted with water and extracted with CH2Cl2 (3 times), dried over MgSO4, filtered and concentrated in vacuo to afford 0.076 g of 4-(2-bromo-2,2-difluoro-ethyl)-pyrrolidin-2-one a6 (49%).
Reaction SMILES: [C:1]([C:5]1[C:6]([CH:42]=[CH2:43])=[C:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=[CH:30]3)[CH:8]=[C:9]([C:11]2[C:12]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:13][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([C:5]1[C:6]([CH2:42][CH3:43])=[C:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=[CH:30]3)[CH:8]=[C:9]([C:11]2[C:12]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:13][C:14]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:15][CH:16]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Reaction time: 24 h

Procedure:
To a 100 mL round-bottomed flask was added the product from Example 35 Part A (132 mg, 0.219 mmol), 10% palladium on carbon (20 mg, 0.019 mmol) and methanol (10 mL). The mixture was hydrogenated for 24 hours, filtered and concentrated in vacuo to give crude product which was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (10% to 20%) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5].[Cl:20]C1C=CC=C(F)C=1C(O)=O>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1Cl

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 2-chloro-6-fluorobenzoic acid as the starting acid to give 4-(2-chloro-6-fluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (4.42 g) as a pale blue solid. (LC/MS: Rt 2.35, [M+H]+ 283.94).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]([Mg]Br)[CH:19]=[CH2:20]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([CH:14]([CH3:16])[CH3:15])([OH:17])[CH2:20][CH:19]=[CH2:18])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: CC(C)C(=O)CCN[C@@H](C)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: C=CCC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of (S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (740 mg, 2.5 mmol) in THF (25 mL) was added dropwise allylmagnesium bromide (25 mL, 25 mmol) under N2 at −78° C. The reaction mixture was stirred at −78° C. for 2 h, quenched by addition of satd aq NH4Cl, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and filtered. The solvent was removed under vacuo to give 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg, 95% yield), which was used directly in the next step.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11](Br)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:8][C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cc(Br)cc(C=C(c2ccccc2)c2ccccc2)c1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: Brc1cc(C=C(c2ccccc2)c2ccccc2)cc(-c2ccccc2)c1
Yield: 55.8 %

Procedure:
Under an atmosphere of argon, 1-(2,2-diphenylvinyl)-3,5-dibromobenzene (7.0 g, 17 mmole), phenylboronic acid (2.1 g, 17 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.35 mmole, 2% Pd) were dissolved into toluene (40 ml). To the obtained solution, a 2 M aqueous solution of sodium carbonate (25 ml, 51 mmole, 3 eq) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (30 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (3.9 g, 56%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:6]([C:19](OC)=[O:20])=[CH:5]2.[NH:23]1[C:27]2=[N:28][CH:29]=[C:30]([NH2:32])[CH:31]=[C:26]2[CH:25]=[CH:24]1.C[Al](C)C>>[NH:23]1[C:27]2=[N:28][CH:29]=[C:30]([NH:32][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=4)[C:8]4[C:9]([CH:5]=3)=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)=[O:20])[CH:31]=[C:26]2[CH:25]=[CH:24]1
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: COC(=O)c1cc2cc(F)ccc2n1Cc1cccc(C)c1
Agent: C[Al](C)C
Product: Cc1cccc(Cn2c(C(=O)Nc3cnc4[nH]ccc4c3)cc3cc(F)ccc32)c1
Yield: 39.9 %

Procedure:
Compound 5 was prepared according to a process similar to that described in step 5.2 by reacting 200 mg (0.673 mmol) of methyl 5-fluoro-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate prepared according to the protocol described in step 6.1 with 107 mg (0.807 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.5 mL (1.01 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give 107 mg of the expected product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13](=[O:20])[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:16][C:15]2[CH:17]=[CH:18][S:19][C:14]=2[C:13]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)c1ccc(-c2nc3ccsc3c(=O)o2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2sccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 40.8 %

Procedure:
A solution of 2-[4-(tert-butyl)phenyl]-4-oxo-4H-thieno[3,2-d] [1.3]oxazine (60 mg, 0.21 mmol) and p-anisidine (26 mg, 0.21 mmol) in toluene (1 mL) was treated with p-toluenesulfonic acid (4 mg) and the resulting mixture heated at relux for 30 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate) to yield 35 mg (41%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.C([Li])CCC.CCCCCC.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:31]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:19])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (130 mg, 0.50 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol) with stirring. The reaction mixture was stirred at 0° C. for 2 hours, followed by addition of a second portion of 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol), and the mixture stirred for another 2 hours. To this mixture was added slowly a solution of benzyl bromide (855 mg, 5.00 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C., stirred overnight, and allowed to warm to room temperature. The reaction was followed by LCMS and stirring was continued until all of the starting material was consumed. The reaction mixture was quenched by slow addition of saturated aqueous ammonium chloride (10 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture, which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (62 mg, 0.18 mmol, 35%). LCMS mz 350.0 (M+H), 372.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; CDCl3) δ7.10-7.40 (m, 8H); 6.80-7.00 (m, 3H); 5.22 (s, 2H); 3.05 (m, 2H); 2.85 (m, 2H).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH:11]([O:12]C(=O)C)[CH:10]([O:16]C(=O)C)[CH:9]([O:20]C(=O)C)[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[C:30](=[O:39])[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:7]1)(=O)C.C[O-].[Na+].Cl>CO>[CH2:32]([NH:31][C:30]([C:26]1[S:27][CH:28]=[CH:29][C:25]=1[O:24][CH:8]1[CH:9]([OH:20])[CH:10]([OH:16])[CH:11]([OH:12])[CH:6]([CH2:5][OH:4])[O:7]1)=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)OCC1OC(Oc2ccsc2C(=O)NCc2ccccc2)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NCc1ccccc1)c1sccc1OC1OC(CO)C(O)C(O)C1O
Temperature: 22 °C
Reaction time: 2 h

Procedure:
600 mg of 3,4,5-triacetoxy-6-(2-benzylcarbamoyl-thiophen-3-yloxy)-tetrahydro-pyran-2-ylmethyl acetate were dissolved in 40 ml of methanol, and 1.40 ml of a 30% strength methanolic sodium methanolate solution were added. The reaction mixture was stirred at 22° C. for 2 h, neutralized with 0.5 molar methanolic HCl solution and concentrated. The crude product was purified by column chromatography (SiO2, ethyl actate/methanol=10:1).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:25])[NH:7][C:6]1=[O:26])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].Cl>CN(C)C=O.O>[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:11]2[N:10]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:9]3[C:8](=[O:25])[NH:7][C:6](=[O:26])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=3[N:12]=2)=[CH:16][CH:17]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cc3ccc(NC(C)=O)cc3)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)[nH]c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Temperature: 50 °C
Yield: 41.4 %

Procedure:
A mixture of N-[4-(3-butyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-phenyl]-acetamide (196 mg, 0.55 mmol) in N,N-dimethylformamide (5.0 mL) at 25° C. was treated with sodium carbonate (117 mg, 0.55 mmol) and 2,2-dimethyl-propionic acid chloromethyl ester (0.10 mL, 0.55 mmol). The resulting mixture was warmed to 50° C. for 8 h. At this time, the reaction mixture was poured into a solution of water (2.5 mL) containing a 1N aqueous hydrochloric acid solution (1.65 mL). This solution was extracted with ethyl acetate. The organics were washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3:2 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (107 mg, 41.4%) as a yellow foam: FAB-HRMS m/e calcd for C24H31N5O5 (M+H)+ 470.2403, found 470.2408.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].B(Br)(Br)Br>>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: COc1ccc(-c2sc(NC(N)=O)c(C(N)=O)c2C)cc1
Agent: BrB(Br)Br
Product: Cc1c(-c2ccc(O)cc2)sc(NC(N)=O)c1C(N)=O

Procedure:
Prepared by demethylating 2-[(aminocarbonyl)amino]-4-methyl-5-(4-methoxyphenyl)-3-thiophenecarboxamide using boron tribromide as in Example 9(a).