Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1>>[OH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CC[C@H](O)CC1
Temperature: 100 °C

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and trans-4-aminocyclohexanol (32.7 mg, 0.283 mmol; Alfa Aesar, Ward Hill, Mass.), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 10% MeOH/DCM) provided 2-(3-((trans-4-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (54% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.57 (m, 4H) 1.93 (d, J=11.54 Hz, 2H) 2.09 (d, J=12.32 Hz, 2H) 2.54 (s, 3H) 2.92 (t, J=6.85 Hz, 2H) 3.42-3.54 (m, 3H) 3.91-4.04 (m, 1H) 4.60 (br. s., 1H) 6.75 (d, J=7.43 Hz, 1H) 6.94 (s, 1H) 7.08 (d, J=2.15 Hz, 1H) 7.32 (t, J=7.82 Hz, 1H) 7.57 (dd, J=8.02, 1.37 Hz, 1H) 7.89 (dd, J=7.53, 1.27 Hz, 1H) 11.96 (br. s., 1H). MS (ESI, pos. ion) m/z: 392.3 (M+1).
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[C:26]([O:27][CH3:28])=[CH:25][C:15]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][OH:24])=[O:17])=[C:14]([N+:29]([O-])=O)[C:13]=1[O:32][CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO.[Ni]>[NH2:29][C:14]1[C:13]([O:32][CH3:33])=[C:12]([O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:26]([O:27][CH3:28])=[CH:25][C:15]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][OH:24])=[O:17]
Reactant: [H][H]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1OCc1ccccc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Hydrazine hydrate (2.31 g, 72.2 mmol) was added dropwise to a solution of 125 (6.01 g, 14.4 mmol) in methanol (60 mL) gently refluxing over Raney nickel (1.1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the produc as a brown oil (3.97 g, 10.3 mmol, 73%): 1H NMR (270 MHz, CDCl3) δ 1.6-2.2 (m, 4H), 3.5-3.8 (m, 4H), 3.8 (s, 3H), 3.9 (s, 3H), 4.4 (br s, 1H), 5.1 (s, 2H), 6.6 (s, 1H), 7.3-7.6 (m, 5H); 13C NMR (67.8 MHz, CDCl3) δ 171.5, 144.9, 143.5, 141.9, 137.5, 134.6, 128.6, 128.5, 128.3, 128.2, 128.0, 115.1, 107.3, 75.1, 66.9, 61.0, 60.6, 60.4, 56.9, 50.9, 28.5, 24.9, 21.1, 14.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[N:16]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][C@@H:14]2[O:28]C(C)(C)[O:30][C@@H:13]2[C@H:12]1[O:33]C1CCCCO1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C:9]([C@H:11]1[C@H:12]([OH:33])[C@H:13]([OH:30])[C@@H:14]([OH:28])[CH2:15][N:16]1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=[O:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@@H]3[C@@H](OC3CCCCO3)[C@@H]2C(=O)OCc2ccccc2)cc1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
The above compound (3) (10.6 g) was dissolved in methanol (110 mL) and a cation exchange resin (Muromac, 50 g) was added, and then the mixture was stirred overnight at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol 50:1→30:1→10:1) to obtain the titled compound (7.4 g) as a syrup.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:50][CH2:49][C:48]2[C:51]3[CH2:57][CH2:56][CH2:55][CH2:54][C:52]=3[S:53][C:47]=2[C:46]1=[O:58])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[C:46](=[O:58])[C:47]3[S:53][C:52]4[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=4[C:48]=3[CH2:49][CH2:50]2)=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 65 %

Procedure:
Following Example 136e, 170b and (2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 111a were reacted to give 170c in 65% yield. LCMS: (M+H)+ 668
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a suspension of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (26.7 g; 100 mmol; example 5 e]) in dichloromethane (100 ml), was added at 0° C. 10.9 ml (150 mmol) of thionyl chloride within 0.5 hours. Stirring was continued at ambient temperature for 1 hour. Afterwards, ice water was added and the mixture was stirred vigorously. Then, the layers were separated, the aqueous phase was extracted with 100 ml of dichloromethane. The combined organic phases were washed with water, aqueous sodium hydrogen carbonate, brine, and dried with anhydrous sodium sulfate. After evaporation, 27.9 g (97.6%) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine were obtained as a light brown solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:26]([C:28]1[C:29](=[C:36]([C:39]#[N:40])[C:37]#[N:38])[O:30][C:31]([CH3:35])([CH3:34])[C:32]=1[CH3:33])#[N:27].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:33][C:32]3[C:31]([CH3:34])([CH3:35])[O:30][C:29](=[C:36]([C:37]#[N:38])[C:39]#[N:40])[C:28]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)cc1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2)cc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
In an ethanol/tetrahydrofuran mixed solvent were dissolved 180 mg (0.54 mmol) of 4-[2-(4-dibutylaminophenyl)vinyl]benzaldehyde and 118 mg (0.59 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene]propanedinitrile. To this mixture, 46 mg (0.60 mmol) of ammonium acetate was added, and the mixture was stirred at room temperature. The solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with ethanol to give 245 mg of a black crystal having a mp of 224-226° C. (yield: 88.4%).
Reaction SMILES: [CH:1]([C@H:9]1[C:13](=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:12](=[O:24])[CH:11]=[CH:10]1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:25]O.[Cl-].[NH4+]>CO.[OH-].[Na+]>[O:25]1[C:10]2[C@@H:9]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13](=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:12](=[O:24])[C:11]1=2
Reactant: CCCCCCC=C[C@@H]1C=CC(=O)C1=CCCCCCC(=O)OC
Reactant: OO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC=C[C@H]1C(=CCCCCCC(=O)OC)C(=O)C2=C1O2
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
To a solution of 600 mg (1.8 mmol) of (4R)-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone in 6 ml of methanol was added 0.92 ml (9.0 mmol) of 30% aqueous hydrogen peroxide with ice cooling and stirring, and then 60 microliters (60 micromol) of 1N aqueous sodium hydroxide was added. The mixture was stirred at 0 C. for 45 minutes. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with hexane. The organic layer was washed with a saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated and subjected to silica gel column chromatography (silica gel, 40 g; eluent, hexane:ethyl acetate=10:1→5:1) to give 491 mg (yield 78%) of (4S)-2,3-epoxy-4-(1-octenyl)-5-(6-methoxycarbonyl-hexylidene)cyclopentenone.
Reaction SMILES: ClCC([NH:5][C:6]([CH3:19])([CH3:18])[CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)=O.NC(N)=S.[C:24](O)(=O)[CH3:25]>C(O)C>[CH2:24]([O:17][C:15](=[O:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][C:6]([NH2:5])([CH3:18])[CH3:19])[CH:9]=1)[CH3:25]
Reactant: CC(C)(Cc1cccc(CC(=O)O)c1)NC(=O)CCl
Reactant: CC(=O)O
Agent: NC(N)=S
Solvent: CCO
Product: CCOC(=O)Cc1cccc(CC(C)(C)N)c1
Yield: 63 %

Procedure:
A solution of {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid (Preparation 48) (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered. The filtrate was reduced in vacuo, the residue dissolved in ethanol (150 ml), saturated with hydrogen chloride gas and the resulting solution heated to reflux for 16 hours. The solvent was reduced in vacuo and the residue partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml). The organic extract was washed with saturated sodium chloride (100 ml), dried (sodium sulfate) and reduced in vacuo. The residue was purified by strong cation exchange resin, eluting with methanol and then 2N ammonia in methanol to elute the product. The eluent was concentrated in vacuo giving the title compound as a yellow oil (2.68 g, 63%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[I-].[K+]>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: OCCCCCCCCCCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Temperature: 80 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
25.9 g (170 mmol) of 4-hydroxy-3-methoxybenzaldehyde and 38.9 g (155 mmol) of 11-bromoundecan-1-ol are dissolved in 200 mL of N,N-dimethylformamide. 23.57 g (170 mmol) of potassium carbonate and 2.47 g (15 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 12 h, the reaction mixture is cooled to room temperature and poured to icy water. The precipitate is filtered off, digested in 500 mL of water and the mixture was neutralized with hydrochloric acid 37%. The precipitate is filtered off, washed with water and dried overnight at 40° C. 48.5 g of 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde are obtained as a slightly pink solid (97% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:56])([F:55])[C:9]1[CH:10]=[C:11]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44]C)=[O:43])=[CH:38][C:37]=3[CH3:46])[CH:32]=[CH:33][C:34]=2[Cl:35])[O:15][C:14]1=[O:47].O.[OH-].[Li+].Cl>O>[F:56][C:8]([F:7])([F:55])[C:9]1[CH:10]=[C:11]([CH:48]=[C:49]([C:51]([F:53])([F:54])[F:52])[CH:50]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([OH:44])=[O:43])=[CH:38][C:37]=3[CH3:46])[CH:32]=[CH:33][C:34]=2[Cl:35])[O:15][C:14]1=[O:47]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2[C@H]2OC(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
To a 1,4-dioxane solution (3 mL) of methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (65 mg, 0.089 mmol) was added a solution of lithium hydroxide monohydrate (26 mg, 0.623 mmol) in water (1.2 mL). Aliquot at reaction time 2 hours indicated completion of reaction (atropisomers present). Crude mixture was acidified by HCl (aq, 1N, 1 mL). The cloudy precipitation was dissolved by MeCN (2 mL). The resulting solution was purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/ a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixtureaffording 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=715.12; found=716.20 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:29])([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:28][CH:17]1[N:16]2[C:21]([CH2:22][O:23][C:24]3[C:15]2=[CH:14][C:13]([O:12][C:10]2([CH3:29])[CH2:9][NH:8][CH2:11]2)=[CH:26][CH:25]=3)=[N:20][NH:19][C:18]1=[O:27]
Reactant: CC1C(=O)NN=C2COc3ccc(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3ccc(OC4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.064 g, 0.159 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 4-methyl-6-(3-methyl-azetidin-3-yloxy)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as white solid (0.045 g, 68%). LC/MS (Table 1, Method 5) Rt=1.691 min; MS m/z: 303 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11](O)[C:7]=3[NH:8][C:9]=2[CH:10]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11]([Cl:24])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Oc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(C2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Yield: 72 %

Procedure:
650 mg (1.90 mmol) 7-bromo-2-(4-piperidyl)-5H-pyrimido[5,4-b]indol-4-ol were kept at reflux in POCl3 for 9 h. Then, POCl3 was removed in vacuo, the residue was mixed with water and neutralized with NaHCO3. The precipitate formed was sucked off and washed with water. 500 mg (72%) 7-bromo-4-chloro-2-(4-piperidyl)-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 365, 367 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:31]#[C:30][CH2:29][OH:32])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1I
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1C#CCO
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A mixture of 2-chloro-6-iodotoluene (5.00 g), copper(I) iodide (75.4 mg), triphenylphosphine (260 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (410 mg), propargyl alcohol (1.29 ml), diisopropylethylamine (13.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (2.58 g) as a brown oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].C1C(=O)N([Br:27])C(=O)C1.O>CN(C)C=O>[Br:27][C:12]1[S:13][CH:14]=[CH:15][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][CH:7]=1
Reactant: CCCCC(CC)Cc1ccc(-c2ccsc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)Cc1ccc(-c2ccsc2Br)cc1
Reaction time: 2 h

Procedure:
A 250-mL round bottom flask was charged with 3-[4-(2-ethylhexyl)-phenyl]-thiophene (7 g, 0.026 mol), N,N-dimethyl formamide (DMF) (65 mL). The reaction mixture was stirred at ambient temperature for 5 minutes, whereupon a 0.4 M solution of NBS (0.026 mol) in DMF was added and the stirring continued for 2 hours. After addition of water, the mixture was extracted with diethyl ether (3×150 mL). The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified using column chromatography on silica gel with hexane as the eluent (Rf=0.35). The compound was dried under vacuum to yield 8.7 g (95%) of slightly yellow oil.
Reaction SMILES: C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:41][C:42]1[CH:50]=[CH:49][C:48]([C:51]([C:53]2[N:61]3[C:56]([CH:57]=[CH:58][CH:59]=[CH:60]3)=[C:55]([Br:62])[C:54]=2[CH3:63])=[O:52])=[CH:47][C:43]=1[C:44](O)=[O:45].Cl.[CH3:65][O:66][C:67](=[O:70])[CH2:68][NH2:69].C(=O)([O-])O.[Na+]>CN1C(=O)CCC1>[NH2:41][C:42]1[CH:50]=[CH:49][C:48]([C:51]([C:53]2[N:61]3[C:56]([CH:57]=[CH:58][CH:59]=[CH:60]3)=[C:55]([Br:62])[C:54]=2[CH3:63])=[O:52])=[CH:47][C:43]=1[C:44]([NH:69][CH2:68][C:67]([O:66][CH3:65])=[O:70])=[O:45]
Reactant: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)O)c1
Reactant: COC(=O)CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Triethylamine (7.34 mL; 52.3 mmol) and PyBOP (9.97 g; 19.2 mmol) are added to a solution of 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoic acid (6.5 g; 17.4 mmol) in 58 mL of NMP at 0° C. under nitrogen. After 30 min of stirring at 0° C., glycine methyl ester hydrochloride (2.4 g; 19.2 mmol) is added. After 1 h of stirring at ambient temperature, the reaction medium is run into a saturated aqueous solution of sodium hydrogen carbonate. The yellow precipitate formed is filtered off and dried under vacuum to give 6.45 g (83%) of a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5](C(OCC)=O)[NH:6]2.ClC1C=C(Cl)C=C2C=1CCN2>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)c(F)ccc2[nH]1
Agent: Clc1cc(Cl)c2c(c1)NCC2
Product: Fc1ccc2c(c1Cl)CCN2

Procedure:
The above ethyl 4-chloro-5-fluoroindole-2-carboxylate was treated in a manner similar to Reference Example 10-(3), (4) and 1 to give the titled compound, 4-chloro-5-fluoroindoline as a brown oil. APCI-Mass m/Z 172/174 (M+H). 1H-NMR (DMSO-d6) δ 2.97 (t, J=8.7 Hz, 2H), 3.48 (td, J=8.7, 1.9 Hz, 2H), 5.67 (s, 1H), 6.37 (dd, J=8.5, 3.7 Hz, 1H), 6.90 (t, J=9.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][NH:22][O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]([O:23][CH3:24])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(NC(C)=O)cc1
Product: CON(Cc1ccc(NC(C)=O)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 92 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-acetamidobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (92% yield): mp 212-215° C. (dec.) (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.73 (6H, s, CH3), 2.16 (3H, s, CH3), 3.67 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.39 (1H, s, CH), 7.32 (3H, m, aromatics and NH), 7.45 (2H, m, aromatics). Anal. calcd. for C17H20N2O6: C, 57.87; H, 5.86; N, 7.94. Found: C, 57.76; H, 5.68; N, 8.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([C:15]#[N:16])=[CH:6]2.[CH3:17][N:18]([CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>COCCO>[CH3:17][N:18]([CH3:26])[C:19]1[CH:20]=[C:21]([NH:25][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][C:7]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: COc1cc2cc(C#N)cnc2cc1OC
Solvent: COCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(N(C)C)c3)c2cc1OC
Yield: 19 %

Procedure:
A 1.25 gram (5 mmole) portion of 4-chloro, 6,7-dimethoxy-quinoline-3-carbonitrile and a 1.05 gram (5 mmole) portion of N, N-dimethyl-1,3-phenylenediamine in 10 ml of 2-methoxyethanol were refluxed for 2 hours in an oil bath at 154 deg. Cooling gave a solid which was recrystallized from water to give 0.4 grams (19%) of 4-(3-Dimethylamino-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile which melted at 246-249° C.: mass spectrum (electrospray m/e):.(M+H)=349.2., (M+2H)'2 =174.9.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: OB(O)c1cccs1
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Product: Nc1nc2ccccc2n1-c1cccc(-c2cccs2)c1

Procedure:
2-Amino-1-[3-(2-thienyl)phenyl]benzimidazole was prepared from 1-(2-amino-1-benzimidazolyl)-3-iodobenzene and 2-thienylboronic acid by method B. mp 142°-144° C.