Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=4[N:9]([CH3:18])[C:8]=32)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>CCOCC>[F:1][C:2]1[CH:20]=[C:19]2[C:5]([CH:6]([Si:27]([CH3:29])([CH3:28])[CH3:26])[C:7]3[C:15]4[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=4[N:9]([CH3:18])[C:8]=32)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc2c3c(n(C)c2c1)-c1cc(F)ccc1C3
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc2c3c(n(C)c2c1)-c1cc(F)ccc1C3[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
A round bottom flask containing 56 (201 mg, 0.75 mmol) in dry ether (6 mL) was immersed in a 25° C. water bath. n-BuLi (1.5 M in THF, 602 μL, 0.90 mmol) was added via syringe pump over one hour, generating an orange solution. Following addition of base, the reaction mixture was stirred at 25° C. for an additional 1.5 hours and then cooled to −78° C. TMSCl (200 μL, 1.58 mmol) was added rapidly via syringe, and the reaction mixture was stirred an additional 5 minutes at −78° C., then warmed to room temperature over 3.5 hours. The reaction was subsequently diluted with ether, filtered, and concentrated in vacuo. Crude product was purified by flash column chromatography (20:1 hexanes-ethyl acetate) to yield 57 as a solid in 62% yield (159 mg, 0.47 mmol). 1H NMR (600 MHz, CDCl3): δ 7.54 (d, 1H, J=8.4 Hz), 7.39-7.41 (dd, 1H, J=8.4, 4.8 Hz), 7.33-7.35 (dd, 1H, J=9, 2.4 Hz), 6.83-6.89 (m, 3H), 3.98 (s, 3H), 3.93 (s, 3H), −0.02 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 61.4 (d, J=238.5 Hz), 156.2, 144.5 (d, J=2.0), 143.0, 141.5 (d, J=3 Hz), 134.8 (d, J=9.5 Hz), 125.4, 124.79 (d, J=9.15 Hz), 120.9, 118.0, 109.4 (d, J=22.8 Hz), 108.6, 103.9 (d, J=24.3 Hz), 93.5, 5.6, 36.3, 31.0, −2.5; 19F NMR (CD3CD, 376 MHz): δ −117.6 (m); FTIR: cm−1 2952, 1608, 1523, 1372, 1223, 1163, 1107, 1042, 939, 841.
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Cl)=[CH:9][CH:8]=1.C(O[K])(C)(C)C>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]=[CH2:15])=[CH:9][CH:8]=1
Reactant: ClCCOc1ccc(Br)cc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: O
Product: C=COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 78.7 %

Procedure:
To a THF (250 mL) solution of 1-bromo-4-(2-chloroethoxy)benzene (58.6 g, 249 mmol) prepared in Example 5 (5a) was added tert-butoxy potassium (33.7 g, 300 mmol) at −10° C. over 10 minutes. The resulting mixture was stirred at room temperature for 21 hours. Water (500 mL) was added thereto, and the mixture was extracted with methyl tert-butyl ether (200 mL, 150 mL) twice. The organic layers were combined, washed with saturated brine (100 mL) twice, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was dissolved in n-hexane (100 mL), and the precipitated insoluble substance was removed by filtration, and this insoluble substance was further washed with n-hexane (5 mL) five times. These filtrates were combined and concentrated, and then purified by silica gel column chromatography (n-hexane) to give 39.0 g of the title compound (colorless oil, yield: 79%).
Reaction SMILES: Cl.Cl.C([O:6][CH:7]([CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[C:26]4[CH:27]=[CH:28][O:29][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31])(=O)C.N.Cl.C(OCC)C>C(Cl)Cl.C(O)(C)C>[O:29]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:20][C:14]3[C:13]4[C:18](=[CH:19][C:10]([O:9][CH2:8][CH:7]([OH:6])[CH2:32][N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)=[C:11]([O:30][CH3:31])[CH:12]=4)[N:17]=[CH:16][N:15]=3)[C:26]=2[CH:27]=[CH:28]1
Reactant: COc1cc2c(Nc3cccc4occc34)ncnc2cc1OCC(CN1CCOCC1)OC(C)=O
Agent: Cl
Agent: N
Solvent: CCOCC
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc2c(Nc3cccc4occc34)ncnc2cc1OCC(O)CN1CCOCC1
Yield: 115.7 %

Procedure:
A mixture of 7-(2-acetoxy-3-morpholinopropoxy)-4-(4-benzofuranylamino)-6-methoxyquinazoline dihydrochloride (0.14 g) and a saturated methanolic ammonia solution (3 ml) was stirred at ambient temperature overnight. The solvent was removed by evaporation and the mixture was dissolved in methylene chloride (3 ml) and adsorbed on the top of a pre-packed chromatography column containing 5 g of NH2-silica (Isolute sorbent from International Sorbent Technology Ltd, ref 9470-0100) and eluted with a 19:1 mixture of methylene chloride and methanol. The material so obtained was dissolved in methylene chloride (3 ml) and a 6M solution of hydrogen chloride in isopropanol (0.3 ml) was added with stirring. Diethyl ether (10 ml) was added and the resultant precipitate was collected, rinsed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.129 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 3.15-3.48 (m, 4H), 4.56 (d, 2H), 3.76-3.94 (m, 2H), 3.94-4.06 (m, 2H), 4.06 (s, 3H), 4.26 (d, 2H), 4.53-4.61 (m, 1H), 6.91 (d, 1H), 7.4 (d, 1H), 7.46 (m, 1H), 7.51 (s, 1H), 7.55 (s, 1H), 8.03 (d, 1H), 8.38 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 451.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C[N+]1C2C(=CC=CC=2)N=C2C=1C=CC=C2.COS([O-])(=O)=O>O>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([CH:2]=[O:1])=[O:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: COS(=O)(=O)[O-]
Agent: C[n+]1c2ccccc2nc2ccccc21
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: O=CC(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The reaction mixture containing 100 ml of cell free extract of UV-10, FERM BP-1267 (total enzyme activity, 123 units), as prepared by the manner as described in steps (1) to (2) of Example 1, 50 ml of 0.5M potassium phosphate buffer (PH 6.0), 50 ml of 1M L-sorbose solution, 10 ml of 0.2M phenazine methosulfate solution and 290 ml of water was incubated at 30° C. with gentle shaking. As a result, L-sorbosone was formed with the rate of 142 mg/hr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH:24]=[O:25])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][OH:25])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(C=O)n1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CO)n1-c1ccc(F)cc1
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde (740 mg, 1.96 mmol) in anhyd ethanol (15 mL) was added NaBH4 (91 mg, 2.4 mmol). After stirring 3 h, the mixture was poured into water, and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give (5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methanol as a white solid (670 mg, 88% yield).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH2:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C@H:35]([NH:39]C(OC(C)(C)C)=O)[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH:25]=[C:24](Cl)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>[NH2:39][C@@H:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH:25]=[C:24]([O:4][C@H:3]([C:5]3[CH:6]=[CH:7][C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)=[CH:9][CH:10]=3)[C:2]([F:19])([F:20])[F:1])[N:23]=[C:22]([NH2:21])[N:27]=2)=[CH:29][CH:30]=1)[C:36]([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Reactant: COc1cccc(-c2ccc([C@@H](O)C(F)(F)F)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2ccc([C@@H](Oc3cc(-c4ccc(C[C@H](N)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
To a 3-neck 250 ml round-bottom flask equipped with a mechanical stirrer, a thermocontroller, was charged compound 3 (8.62 g, 1.2 equiv), 8 (10.00 g, 25.46 mmol), tetrabutylammonium bisulfate (0.86 g, 10 mol %), and cesium carbonate (29.04 g, 3.5 equiv). Dioxane (50 ml) was added and the resulting mixture was heated at 100° C. for 18 hours. HPLC analysis showed 99% conversion of the starting material 8. The mixture was cooled down to 60° C. and water (60 ml) was added. The top organic layer was diluted with THF (80 ml), washed with brine (50 ml), transferred to a 500 ml round-bottom flask, and 80 ml of 6 N hydrochloric acid was added. The mixture was stirred at room temperature for 16 hours. LC-MS analysis of the reaction mixture showed complete consumption of the intermediate compound 9. The reaction mixture was transferred to a 500 ml separatory funnel. The round-bottom flask was washed with water (2×40 ml) and the washes were also transferred to the funnel. The mixture was washed with ethyl acetate (2×100 ml) and the aqueous layer was collected and concentrated at 40° C. (bath temperature) under 80 mbar vacuum to remove any remaining organic solvents. The resulting aqueous solution was then transferred to a 500 ml three-necked round-bottom flask equipped with a mechanical stirrer, a pH meter, a thermocontroller and an addition funnel. At 60° C., a solution of 50% aqueous sodium hydroxide solution was added slowly until pH=4, then a solution of 1N aqueous sodium hydroxide was added until pH reached 6.5. The mixture was stirred at 60° C. for additional 30 minutes and the yellow solids were collected by filtration. HPLC analysis of this solid showed a purity of about 95%. The solids were dried under vacuum at 50° C. overnight to give the crude product compound 10 as a yellow solid (9.48 g, 69% overall yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:18]=[CH:17][C:5]=1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=[O:7])[CH3:2].[CH3:26][N:27]([CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:35][N:34]([CH3:36])[C:30]1[CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=[CH:32][C:31]=1[C:6]1([C:5]2[CH:17]=[CH:18][C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:20][C:4]=2[O:3][CH2:1][CH3:2])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])[O:7]1
Reactant: CCOc1cc(N(CC)CC)ccc1C(=O)c1ccccc1C(=O)O
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc(N(CC)CC)ccc1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of 2-(2-ethoxy-4-(diethylamino)benzoyl)-benzoic acid (6.82 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (2.80 g.) and acetic anhydride (20 g.) was heated (70°-75° C.) during one hour, let stand overnight and poured into dilute hydrochloric acid. The resulting mixture was basified. Recrystallization of the resulting red precipitate from hexane followed by slurrying in alkaline water afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(2-ethoxy-4 -(diethylamino)phenyl)phthalide (I: X= (CH3)2N, Y2 = CH3CH2O, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = H) (m.p. 146°-150° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:22][CH3:23])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([C:42](O)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:31])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:42](=[O:43])[CH:33]([NH:32][C:30]([O:29][C:26]([CH3:27])([CH3:25])[CH3:28])=[O:31])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH:18]([CH2:22][CH3:23])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 91 %

Procedure:
2-(3-Ethyl-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 34, (2.1 g, 6.4 mmol) and N-Boc-D-4-fluorophenylalanine (1.9 g, 6.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (4.9 g, 12.9 mmol) are dissolved in anhydrous DMF (20 mL). This reaction mixture is cooled to 0° C., then N-methylmorpholine (0.75 mL, 6.8 mmol) is added. The reaction mixture is placed in a refrigerator overnight. EtOAc (75 mL) and water (300 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×150 mL). The combined organic layers are washed with water (100 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue is purified over silica (EtOAc/Hexane, 1:2) to afford 3.5 g (91% yield) of the desired product. 1H NMR (CDCl3, δ): 7.82–7.75 (m, 3H), 7.62 (s, 1H), 7.52–7.40 (M, 2H), 7.34 (m, 1H), 7.22–7.25 (m, 2H), 7.02–6.92 (m2H), 5.75–5.62 (M, 1H), 5.18 (d, J=7.7 Hz, 0.5H), 4.90 (quartet, J=7.7 Hz, 1H), 4750–4.62 (m, 0.5H), 4.50–4.25 (m, 1H), 3.64 (d, J=9.7 Hz, 3H), 3.58–3.38 (m, 1.5H), 3.30–2.90 (m, 6H), 2.90–2.70 (m, 1H), 2.62–2.25 (d, J=11.6 Hz, 1H), 2.15–2.00 (m, 1H), 1.78–1.50 (m, 1.5H), 1.42 (s, 9H), 1.35–1.20 (m, 1H), 0.6 (t, J=9.7 Hz, 2H); 13C NMR, δ 174.2, 171.6, 171.0, 170.2, 164.0, 160.2, 156, 135.7, 133.7, 132.4, 131.4, 131.3, 128.1, 127.8, 127.6, 127.5, 126.2, 125.7, 115.7, 115.5, 115.4, 115.3, 79.9, 68.9, 68.7, 55.9, 54.1, 53.7, 51.4, 51.2, 51.0, 47.5, 46.6, 40.1, 39.1, 38.1, 35.4, 28.5, 22.9, 21.9, 10.6, 10.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[NH:15][NH2:16].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.[Cl-].[Na+].O.O>[C:19]([O:18][C:14]([NH:15][NH:16][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 8, 2.05 g, 10.4 mmol) in DMF (30 mL), tert-butyl carbazate (1.38 g, 10.4 mmol), DIPEA (3.5 mL, 20.4 mmol), HOBt (1.58 g, 10.3 mmol) and EDCI (2.54 g, 13.3 mmol) were added successively. The resulting solution was stirred for 12 h at rt before adding water and brine (1:1, 200 mL). The solution was extracted with ethyl acetate (4×50 mL) and the combined organic layers were washed with dilute hydrochloric acid (1N, 50 mL), dilute sodium hydroxide solution (1N, 50 mL) and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to give a solid residue, which was purified by flash chromatography on silica gel (hexane/ethyl acetate, 1:3) to give the title compound. δH (CDCl3): 1.42 (9H, s), 7.19 (1H, s), 7.78 (1H, s), 8.60 (1H, s), 9.28 (1H, br s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:23][C:5]2[N:6]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>ClCCl>[C:13]([C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)[C:5]3[CH2:23][CH:2]([NH:1][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])[CH2:3][C:4]=3[C:12]=2[CH:11]=1)#[N:14]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CC(N)C1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NC1Cc2c(n(Cc3cccc(F)n3)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-2-amino-4-(6-fluoro-pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (70 mg, 0.23 mmol) and diisopropylethylamine (0.35 mmol, 61 μL) in dichloromethane (1 mL) add N,N-dimethylcarbamoyl chloride (0.35 mmol, 32 μL) and stir at room temperature overnight. Load the solution on silica gel and purify by column chromatography (0-100% ethyl acetate/dichloromethane) to obtain the title compound. LCMS 378.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C([O:24][B:25](OCCC)[O:26]CCC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:25]([OH:26])[OH:24])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CCCOB(OCCC)OCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C

Procedure:
20 g (76 mmol) of 3-Benzyloxybromobenzene was dissolved in 200 mL of anhydrous THF and cooled to -78° C. under a nitrogen atmosphere. To the stirring solution, 90 mL of 1.6 M n-BuLi (83.6 mmol) was slowly added. After several minutes, 33.6 mL (83.6 mmol) tripropylborate was added and the reaction was allowed to slowly warm to ambient temperature over the next four hours. The reaction was quenched with the addition of 400 mL of 1N HCl. The reaction mixture was extracted three times with EtOAc. The EtOAc solution was washed twice with brine, dried with Na2SO4, and evaporated to dryness. The final product was crystallized from EtOAc-hexane. This yielded 10 g of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][P:7](=[O:10])([OH:9])[OH:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:12]>CO>[C:1]([NH:5][CH2:6][P:7](=[O:8])([O-:10])[O-:9])([CH3:4])([CH3:3])[CH3:2].[Na+:12].[Na+:12]
Reactant: CC(C)(C)NCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)NCP(=O)([O-])[O-]
Yield: 86.1 %

Procedure:
tert-Butylaminomethylphosphonic acid (18.4 g, 0.11 mol) was added to sodium hydroxide (8.8 g, 0.22 mol) solution in methanol (100 mL). The mixture was stirred under reflux for 2 hours. The mixture was concentrated in vacuum until solidifying (approximately to ⅓ of volume) and diethyl ether was added (200 mL). The precipitate was filtered and washed with diethyl ether to give disodium tert-butylaminomethylphosphonate (20 g, 86%), white micro-crystals, decomposition 350-400° C.; 1H NMR (D2O) δ 1.02 (s, 9H), 2.47 (d, J=15.0 Hz, 2H); 13C NMR δ 26.4, 40.1 (d, J=136.3 Hz), 50.6 (d, J=12.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
10 g (50.6 mmol) of 6-chloroisatoic acid anhydride are stirred at 110° C. for 2 hours with 5.82 g (50.6 mmol) of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallised from ethyl acetate. There is obtained (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 264°-266° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][C:5]2=[CH:6][C:7]3[CH2:8][C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:8]2[C:7]3[CH:6]=[C:5]4[O:16][C:2]([CH3:1])([CH3:17])[CH2:3][C:4]4=[CH:12][C:11]=3[N:10]([CH2:13][CH3:14])[C:9]2=[O:15])=[O:27])=[CH:21][CH:20]=1
Reactant: CCN1C(=O)Cc2cc3c(cc21)CC(C)(C)O3
Reactant: O=C=Nc1ccc(F)cc1
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2)c2cc3c(cc21)CC(C)(C)O3
Yield: 62 %

Procedure:
Employing the procedure of Example 1, and starting with 500 mg. (2.16 mmoles) of 2,2-dimethyl-5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole and 0.34 ml. (2.99 mmoles) of 4-fluorophenylisocyanate, 493 mg. (62% yield) of N-(4-fluorophenyl)-2,2-dimethyl-5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole-7-carboxamide (2, R1 =C2H5, R2 =4-fluorophenyl, R3 and R4 =CH3, and n=1) m.p. 160°-162° C., was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3CCN(C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=CC=C(C([OH:38])CC)N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]([OH:38])[CH2:12][CH3:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Reactant: CCC(O)c1ccc2c(N)ncnn12
Product: CCC(O)c1cc(Br)c2c(N)ncnn12

Procedure:
This compound was prepared in a manner similar to the bromination procedure described for the preparation of tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate, using 1-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol as the starting material. 1H NMR (300 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.59 (broad s, 6.80 (d, 1H), 6.52 (d, 1H), 5.11 (d, 1H), 4.98 to 4.93 (m, 1H), 1,83 to 1.66 (m, 2H), 0.84 (t, 3H); ES-MS m/z 271.3/273.1 [M+H]+, RT (min) 1.86.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.CC(OC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:25])([F:24])[F:13]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(O)c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 4-bromo-3-hydroxybenzoate (Combi-Blocks CA-4189, 4.00 g, 17.3 mmol), 2-(trifluoromethyl)phenylboronic acid (3.95 g, 20.8 mmol), cesium fluoride (7.90 g, 52 mmol), palladium(II) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (426 mg, 1.05 mmol) was prepared in dioxane (40 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was heated at 90° C. After 90 minutes, additional amounts of 2-(trifluoromethyl)phenylboronic acid (1.90 g, 10 mmol), palladium(II) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (426 mg, 1.05 mmol) were added. After 45 additional minutes, additional amounts of 2-(trifluoromethyl)phenylboronic acid (2.7 g, 14.2 mmol), palladium(II) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (426 mg, 1.05 mmol) were added. After 15 hours, the reaction mixture was cooled to RT, diluted with MTBE (200 mL), and then washed with water (30 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (100 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc/heptane), the title compound was obtained as a yellow oil (5.03 g containing 12% w/w of DCM). HPLC (Method A), Rt 3.6 min (purity: 98.8%). LC/MS (Method B): 297.0 (M+H)+. 295.0 (M−H)−.