Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:47]=[O:48])=[C:7]([Cl:49])[N:6]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CCO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:47][OH:48])=[C:7]([Cl:49])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an EtOH (500 mL) solution of intermediate (1a) (41.0 g, 61.8 mmol) was added solid NaBH4 (2.8 g, 74.1 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to 0° C., the reaction was quenched by dropwise addition of a 50/50 solution of acetic acid/water until no effervescence was observed. EtOAc (500 mL) was added and the organic was washed three times with saturated aqueous NaCl (100 mL). Solvent was removed and purification was achieved by silica gel chromatography (50:50 EtOAc:hexanes) using an isocratic gradient to provide intermediate (1b) as a white solid (37 g). MS m/z: [M+H+] calcd for C41H37ClN6O, 665.28. found 665.3. 1H-NMR (d4-MeOH): 0.79 (m, 3H), 1.20 (m, 2H), 1.46 (m, 2H), 2.45 (m, 2H), 4.30 (s, 2H), 5.19 (s, 2H), 6.83-6.90 (m, 8H), 7.05 (d, 2H), 7.23-7.33 (m, 10H), 7.53 (m, 2H), 7.81 (d, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6]N(C2C([N+]([O-])=O)=CC=CN=2)[CH2:4][CH2:3]1.[Li].C[Si]([N-][Si](C)(C)C)(C)C.[Li].[O:28]1[C:32]2(CCC(=O)CC2)[O:31][CH2:30][CH2:29]1.[N+](C1C(N2CCC(=O)CC2)=NC=CC=1)([O-])=O>>[CH2:1]=[C:2]1[CH2:3][CH2:4][C:32]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:6][CH2:7]1
Reactant: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: [Li]
Product: C=C1CCC2(CC1)OCCO2

Procedure:
The title compound was prepared following the method reported here for Compound 2a, but using lithium-bis-trimethylsilylamide instead of buthyl lithium and carrying out the reaction at −20° C. As starting material 1,4-dioxaspiro[4.5]decan-8-one replaced 1-(3-nitro-2-pyridyl)-4-oxopiperidine. After the usual work-up procedure the residue was purified by means of automated flash chromatography (Horizon®TM-Biotage; Petroleum Ether EtOAc 95:5) to give the title compound as fluid colourless oil. Yield: 99.3%.
Reaction SMILES: Cl.[OH:2][C@@H:3]([CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH:27][CH3:28])[CH2:23][CH2:22]4)[C:10]=3[C:9]1=2)[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:38]>CN(C)C=O.O>[OH:2][C@@H:3]([CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:22][CH2:23][CH:24]([N:27]([CH3:28])[CH2:36][C:37](=[O:38])[N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[CH2:25][CH2:26]4)[C:10]=3[C:9]1=2)[C:4]([NH2:6])=[O:5]
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Reactant: O=C(CCl)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1

Procedure:
Into a 50-mL round-bottom flask, a solution of (2S)-2-hydroxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide hydrochloride (110 mg, 0.26 mmol, 1.00 equiv), potassium carbonate (179 mg, 1.30 mmol, 5.03 equiv) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (152 mg, 1.03 mmol, 4.00 equiv) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 4×20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product was purified by flash preparative HPLC under the following conditions (IntelFlash-1): column: silica gel; mobile phase; Detector, UV 254 nm. This resulted in (2S)-2-hydroxy-3-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (63.8 mg, 49%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 5.28 (m, 1H), 4.17-4.14 (m, 1H), 3.59-3.32 (m, 7H), 3.15-2.98 (m, 2H), 2.76-2.70 (m, 2H), 2.52-2.33 (m, 7H), 2.04-1.89 (m, 6H), 1.74-1.53 (m, 5H). MS: m/z 502 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](CC[C@]2(C2C(=O)OC(C)(C)OC2=O)C)=[CH:5][CH:4]=1.[OH2:23].CN1CCC[C:26]1=[O:30]>>[C:3]1([O:2][CH3:1])[C:4]([C:26]([OH:30])=[O:23])=[CH:5][CH:6]=[CH:10][CH:11]=1
Reactant: CN1CCCC1=O
Reactant: COc1ccc2c(c1)[C@](C)(C1C(=O)OC(C)(C)OC1=O)CC2
Reactant: O
Product: COc1ccccc1C(=O)O
Temperature: 125 °C
Reaction time: 1 h

Procedure:
(S)-5-(6-Methoxy-1-methyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (290 mg, 960 μmol) was dissolved in N-methylpyrrolidinone (2 mL). Water (17.2 μL, 960 μmol) was added, and the reaction was heated and stirred at 125° C. for one hour to give the intermediate anisole carboxylic acid. The reaction was cooled and NaOH (170 mg, 4.3 mmol) and 1-dodecanethiol (0.80 mmol, 3.3 mmol) were added. The reaction was reheated to 125° C. and stirred for 2.5 days. Another 2.25 equivalents of NaOH was added along with 1.75 equivalents of the thiol. The resulting mixture was stirred at 125° C. for an additional 16 hours. The reaction was then cooled to room temperature and diluted with water (about 25 mL). The resulting mixture was extracted with diethyl ether (2×50 mL) and then the aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with EtOAc (2×75 mL). The combined EtOAc layers were washed with water (2×75 mL) and brine (1×25 mL) and dried over magnesium sulfate. The organic layer was filtered and the solvent was removed. The residue was used directly in the next step (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (370 mg, 190% yield) (contains residual NMP). The (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (197 mg, 955 mmol) was dissolved in MeOH (10 mL) and a catalytic amount of sulfuric acid was added. The mixture was heated at reflux and stirred for three hours. The reaction was cooled, basified with saturated sodium bicarbonate, and the solvent was removed. The residue was then partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc (1×50 mL), and the combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. After filtration and solvent removal, the residue was purified by medium pressure chromatography (silica, 0 to 15% EtOAc:DCM) to give (S)-methyl 2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetate (141 mg, 67% yield). LCMS ESI (neg.) m/e: 219.1 (M−1)−. Chiral Analytical HPLC (ChiralPak AD-H column, 8% isopropanol:hexanes): retention time=18.1 minutes (second peak).
Reaction SMILES: NC1C=CC=CC=1[C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:20]=1)=C[CH:14]=[C:15]1[C:19]=2[NH:18][CH:17]=[CH:16]1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=O.[CH2:28](O)[CH3:29]>>[CH:29]1[CH:28]=[CH:10][CH:11]=[C:19]2[C:15]=1[C:16]1[C:17](=[N:18][C:19]3[C:15]=1[CH2:14][C:22]([C:21]([O:25][CH2:26][CH3:27])=[O:24])=[C:12]1[CH:20]=[CH:8][CH:9]=[CH:10][C:11]=31)[CH:17]=[N:18]2
Reactant: CCOC(=O)C=O
Reactant: CCO
Reactant: Nc1ccccc1-c1ccc2c(ccc3cc[nH]c32)c1
Product: CCOC(=O)C1=c2ccccc2=C2N=c3cnc4ccccc4c3=C2C1
Yield: 53 %

Procedure:
Subsequently, 20 ml of ethanol was added to 540 mg (2.1 mmol) of 7-(2-aminophenyl)benz[g]indole and 260 mg (2.5 mmol) of ethyl glyoxylate (polymeric) and the obtained mixture was heated under reflux for 8 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography to thereby give 380 mg (yield: 53%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[N:3]=[N:2]1.S(Cl)([Cl:15])=O>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[N:3]=[N:2]1
Reactant: O=C(O)CCCCc1c[nH]nn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCCCc1c[nH]nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(1H-1,2,3-triazol-4-yl)pentanoic acid (Example 20, step 3) (100 mg, 0.591 mmol) in DCM (5 mL) at RT under nitrogen was added thionyl chloride (0.518 mL, 7.09 mmol). The reaction mixture was stirred at rt for 2 hours and concentrated under reduced pressure to afford the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23](OCC)=[O:24])[CH:20]=[C:19]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[C:17]=2[CH:18]=1>ClCCCl>[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:24])[CH:20]=[C:19]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=3)[C:17]=2[CH:18]=1
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
2-Amino-5-methylpyridine (289 mg, 2.67 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH3)2Cl (2.67 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 min at room temperature. Ethyl 2-methyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (100 mg, 0.267 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The crude product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 98/2) to give the title compound (100 mg, 86%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.32 (s, 3 H) 2.48 (s, 3 H) 3.07 (s, 3 H) 6.24 (s, 1 H) 7.08-7.16 (m, 2 H) 7.48 (d, J=1.32 Hz, 1 H) 7.57 (dd, J=8.29, 2.35 Hz, 1 H) 7.81-7.97 (m, 3 H) 8.12 (d, J=2.35 Hz, 1 H) 8.25 (d, J=8.29 Hz, 1 H) 8.44 (s, 1 H). LCMS for C23H20N2O5S m/z 437.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([O:12][C:13](=[O:20])[CH2:14][O:15][C:16](=[O:19])[CH2:17][OH:18])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.COC1C=CC(O)=CC=1.[C:37](Cl)(=[O:41])[C:38]([CH3:40])=[CH2:39]>C(OCC)C.C1COCC1>[C:37]([O:18][CH2:17][C:16]([O:15][CH2:14][C:13]([O:12][C:2]1([CH3:1])[CH:9]2[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]1[CH2:11]3)[CH2:10]2)=[O:20])=[O:19])(=[O:41])[C:38]([CH3:40])=[CH2:39]
Reactant: CC1(OC(=O)COC(=O)CO)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)OCC(=O)OCC(=O)OC1(C)C2CC3CC(C2)CC1C3
Yield: 97 %

Procedure:
A 2 liter 3-neck flask fitted with a thermometer, a cooling tube and a stirrer was charged with 165 g (584 mmol) of 2-(2-(2-methyl-2-adamantyloxy)-2-oxoethoxy)-2-oxoethanol, 2,000 ml of THF, 105 ml (754 mmol) of triethylamine and 0.165 g (1,000 ppm) of p-methoxyphenol, and the mixture was stirred to form a solution. Following dissolution, the solution was cooled in an ice bath and 62.7 ml (648 mmol) of methacryloyl chloride was added gradually to the solution. The reaction mixture was then returned to room temperature, and stirred for 3 hours. Following completion of the reaction, 1,000 ml of diethyl ether was added, and the filtrate was washed 5 times with 200 ml samples of distilled water. The washed extract was then concentrated, yielding 198 g (yield: 97%, GC purity: 99%) of the targeted colorless liquid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B#B>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: OCCCCCCc1ccccc1

Procedure:
A solution of 6-phenylhexanoic acid (19.8 mmoles) in sieve dried tetrahydrofuran (5 ml) and reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmoles) at 0° C. for 4 hours to give 6-phenylhexanol. To an ice cold solution of the hexanol (ca. 19.8 mmoles) and carbon tetrabromide (21.98 mmoles) in methylene chloride (50 ml) was added triphenylphospine (22.30 mmoles) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 6-phenylhexyl bromide as an oil. A mixture of the bromide (8.00 mmoles), salicylaldehyde (8.19 mmoles) and potassium carbonate (9.33 mmoles) in dimethylformamide (10 ml) was heated to 100° C. and maintained at that temperature for one hour. The cooled reaction mixture was taken up in hexane (50 ml) and washed with 5% sodium hydroxide (50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation yielded a colorless oil which was purified by flash chromatography over silica gel with 5% ethyl acetate in hexane as eluant to afford the desired product as an oil.
Reaction SMILES: [Na+].C([N-:4]C=O)=O.[Cl:7][CH2:8][C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1>CN(C=O)C.C(OCC)(=O)C>[ClH:7].[NH2:4][CH2:8][C:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[O:21]
Reactant: O=C[N-]C=O
Reactant: O=C(CCl)Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cl
Product: NCC(=O)Cc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Under argon and with ice cooling, 1.13 g (11.8 mmol) of diformylamide sodium salt were added a little at a time to a solution of 2.67 g (11.2 mmol) of 1-chloro-3-[3-(trifluoromethyl)phenyl]propan-2-one in 11 ml of DMF. The mixture was stirred in an ice bath for 1 h and then at RT overnight. The mixture was then diluted with 25 ml of ethyl acetate and washed successively with in each case 15 ml of 0.5 N hydrochloric acid, water, saturated sodium bicarbonate solution and once more with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The dark oily residue was pre-purified on a short silica gel column (mobile phase: dichloromethane/ethanol 95:5). This gave 2.0 g of a dark-brown solid. This was taken up in 25 ml of a 7 N solution of hydrogen chloride in isopropanol, and the mixture was stirred overnight. The solvent was removed under reduced pressure on a rotary evaporator, and the residue was dissolved in about 15 ml of methanol. 100 ml of diethyl ether were stirred into this solution, and the precipitated solid was isolated by filtration. The filter cake was washed with about 10 ml of diisopropyl ether and dried under high vacuum. This gave 0.79 g (28% of theory) of the target compound as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:17])[NH:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([O:19][CH3:18])=[O:28])=[CH:26][CH:25]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Into a solution of 6 (8.11 g, 33.0 mmol) in CHCl3 (200 mL) was added 4-amino-benzoic acid methyl ester (5.00 g, 33.0 mmol), EEDQ (9.81 g, 39.6 mmol), and triethylamine (6.9 mL, 49.6 mmol). The solution was stirred at reflux for 19 h before cooling to RT and adding EtOAc. The solution was washed sequentially with 1N HCl, 0.1N NaOH, water, and brine, before drying over MgSO4 and concentrating under reduced pressure to give 7 (12.50 g, 100%). MS: APCI (AP+): 379.3 (M)+, (AP−): 377.3 (M)−.
Reaction SMILES: [CH:1]1([C:4]2(O)[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[O:16])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH:1]1([CH:4]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:7](=[O:16])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=C1CCC(O)(C2CC2)N1Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(C2CC2)N1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To 5-cyclopropyl-5-hydroxy-1-(phenylmethyl)-2-pyrrolidinone (400 mg, 1.73 mmol) in CH2Cl2 (10 mL) at −78° C. was added a mixture of triethylsilane (2.76 mL, 17.3 mmol) and BF3.OEt2 (0.88 mL, 6.92 mmol) dropwise. The resulting reaction mixture was stirred for 2 hours at −78° C., then allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding a saturated aqueous NaHCO3 solution, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 100% EtOAc) afforded the title compound (240 mg, 65%) as a colorless oil. LC-MS (ES) m/z=216 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:20]([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:22])[NH:4][CH2:3]1>O1CCOCC1.O>[CH3:1][C@H:2]1[C@H:20]([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:22])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)[C@H](C)CNC3=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)cc3n2[C@H]1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.5 %

Procedure:
A mixture of ethyl trans-4,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (363 mg, 1.2 mmol) and LiOH monohydrate (76 mg, 1.8 mmol) in dioxane:water (1:1, 10 mL) is stirred at room temperature for 6 h. The solvents are removed and water is added. The solution is acidified to pH 5 with 1M HCl and the resulting white solid is filtered and dried to afford the title compound (201 mg, 61%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:8])[N:4]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1nc(=O)[nH]cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(F)c(N)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-Fluorocytosine (500 mg) and potassium carbonate (803 mg) were suspended in N,N-dimethylformamide (5 mL) and ethyl bromoacetate (430 μL) was added to the suspension. The mixture was stirred at 100° C. overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride: methanol=99:1 to 92:9) to give 329 mg (39% yield) of the desired product as a white amorphous.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N+:15]#[C-:16].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1>Cl(O)(=O)(=O)=O>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:23]=1[C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1nccs1
Reactant: [C-]#[N+]c1c(C)cccc1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1cccc(C)c1Nc1c(-c2cccnc2)nc2sccn12

Procedure:
Compound 20 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) 2,6-dimethylphenylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 3-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-methoxyphenyl) benzoic acid (100 mg, 0.2369 mmol) was dissolved in methylene chloride (20 ml), then p-anisidine (58 mg, 0.4715 mmol), triethylamine (48 mg, 0.4752 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (80 mg, 0.4733 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (78 mg, 0.1480 mmol, 62%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:13].[K+].Br[CH2:16][C:17](C1C=CC=CC=1)=O.Cl>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:16]=[C:17]([OH:13])[C:7]([CH3:6])=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: [OH-]
Reactant: O=C1Nc2cc(F)ccc2C1=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1nc2cc(F)ccc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7.96 g of the crude product of 6-fluoroisatin were added to 55 mL of water followed by the addition of 16.2 g (6 equivalents) of KOH while cooling with ice and stirring for 30 minutes. 9.9 g (1.5 equivalents) of bromoacetophenone were dropped into the resultant suspension while holding the internal temperature of the reaction mixture at 20° C. to 25° C. followed by additionally stirring overnight at room temperature. After neutralizing with concentrated hydrochloric acid, the precipitated crystals were filtered out and washed with a small amount of water. After adequately drying the resulting crystals, 70 mL of nitrobenzene heated to 120° C. to 130° C. were added a little at a time followed by further stirring for 1 hour at 140° C. to 150° C. After cooling the reaction mixture to room temperature, the precipitated crystals were washed with chloroform to obtain 5.4 g of 7-fluoro-3-hydroxy-2-methylquinoline.