Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=O)=[N+:2]=[N-:3].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].Cl.C([BH3-])#N.[Na+]>CO>[N:1]([CH2:4][CH:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[N+:2]=[N-:3]
Reactant: CCNCC
Reactant: [N-]=[N+]=NCC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(CN=[N+]=[N-])c1cccc2ccccc12

Procedure:
To a solution of 2.11 g (0.01 mol) of 2-azido-1-(naphthalen-1-yl)ethanone, and 3.66 g (0.05 mol) of diethylamine in 50 mL of dry methanol add 10 g of 3A molecular sieves. Adjust the pH of the mixture to pH=6 with 5N HCl in methanol and add 1 g (0.016 mol) of sodium cyanoborohydride. Follow the progress of the reaction by thin-layer chromatography on silica gel. Maintain the pH of the reaction mixture at pH=ca.6 by the addition of 5N HCl in methanol as necessary. At the completion of the reaction add concentrated hydrochloric acid until pH <2. Evaporate the solvent in vacuo. To the residue add 50 mL of water and extract with three 25 mL portions of diethyl ether. Adjust the pH of the aqueous phase to pH=11 with 4N sodium hydroxide solution and extract with three 100 mL portions of methylene chloride. Wash the combined extracts with 50 mL of water and 50 mL of saturated sodium chloride solution then dry over anhydrous sodium sulfate. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11]O)[CH2:2][CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:32]I.N1C=CN=C1>ClCCl>[I:32][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: II
Reactant: CCCc1ccccc1CCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccccc1CCI
Temperature: 30 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Into a 50-mL round-bottom flask was placed 2-(2-propylphenyl)ethan-1-ol (240 mg, 1.46 mmol, 1.00 equiv), PPh3 (498 mg, 1.90 mmol, 1.30 equiv), I2 (446 mg), imidazole (129 mg) and dichloromethane (20 mL). The resulting solution was stirred for 16 h at 30° C. The reaction was then quenched by the addition of 100 mL of NaHSO3 (aq.). The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). Purification afforded 200 mg (50%) of 1-(2-iodoethyl)-2-propylbenzene as a colorless oil.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1>C(OCC)(=O)C>[C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC1CCCNC1
Agent: O=C(O)C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]1CCCNC1
Reaction time: 24 h

Procedure:
(+) mandelic acid (45.64 g, 0.3 mol) is dissolved in 300 ml of warm ethyl acetate. 3-methylpiperidine (29.8 g, 0.3 mol) is added under agitation and the solution allowed to return to ambient temperature. After 24 hours, the salt obtained is filtered and rinsed with an EA/AcOEt (1/1) mixture then recrystallized 3 times from AcOEt. In this way, the (S)-(+)-3-methylpiperidine mandelate salt (22.7 g) is obtained. M.p.=120-122° C; αD=+58.0° (methanol, c=1.0).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[NH2:4].[Cl:17][C:18]1[C:19]([C:30](=[O:35])[NH:31][CH:32]2[CH2:34][CH2:33]2)=[CH:20][C:21]2[N:25]=[C:24]([C:26](O)=[O:27])[NH:23][C:22]=2[CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[C:19]([C:30]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:35])=[CH:20][C:21]2[N:25]=[C:24]([C:26]([NH:4][CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=3)[C:2]([F:15])([F:16])[F:1])=[O:27])[NH:23][C:22]=2[CH:29]=1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: O=C(O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC(c1cccc(C(F)(F)F)c1)C(F)(F)F)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
2,2,2-Trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine (0.23 g, 0.82 mmol) was dissolved in N,N-dimethylformamide (4 ml), and 6-chloro-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylic acid (0.23 g, 0.82 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (0.31 g, 0.82 mmol) and 4-methylmorpholine (0.25 g, 2.47 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then ethyl acetate was added. The organic phase was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution and dried over sodium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (1/1) and gave 0.24 g (57% of theory) of 6-chloro-N5-cyclopropyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazole-2,5-dicarboxamide.
Reaction SMILES: [OH:1]CC(CO)O.[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Zn+2:27].[C:28]([O-:47])(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>C(O)(=O)C>[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Zn+2:27].[C:28]([O-:47])(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[O-2:1].[Zn+2:27]
Reactant: OCC(O)CO
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: [O-2]

Procedure:
The procedure of Example 1 was essentially repeated using glycerol (66.67 cm3) and acetic acid (0.064 g; to pH 4.8) but with zinc stearate (16.67 g) instead of zinc oxide. Zinc stearate does not form zinc oxide under the reaction conditions employed. The slurry was heated at 100° C. for 2 hours, centrifuged with 4 washes, and dried at 80° C. to produce a white powder. From analysis using IR spectroscopy it was found that no glycerato complex was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([I:17])=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([I:17])=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(I)cc12
Temperature: 100 °C

Procedure:
To a solution of Example 87B (4 g, 7.87 mmol) in 75 mL dioxane was added 6M aqueous sodium hydroxide (13.12 mL, 79 mmol). The mixture was heated at 100° C. for 1 hour, cooled, and reduced to half volume in vacuo. The residue was diluted with 50 mL ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound. LCMS: 369.53 (M+H)+.
Reaction SMILES: C(N)CC.[CH2:5]([NH:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]([CH3:24])[CH:12]=1)[CH2:6][CH2:7]C>>[CH3:24][C:13]1[CH:12]=[C:11]([CH2:10][NH:9][CH2:5][CH2:6][CH3:7])[CH:23]=[CH:22][C:14]=1[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCCN
Product: CCCNCc1ccc(OCC(=O)OCC)c(C)c1

Procedure:
Prepared using n-propyl amine (1.67 mL, 20.3 mmol) and the synthetic procedure described for Intermediate 7. Purification of the crude product by SCX SPE (5×10 g) loading and washing with EtOH and then eluting product with 5% NH3 in EtOH, and removal of the solvent in vacuo yielded the title compound as a brown oil (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6](=[O:9])[C:7]=1[Cl:8].[Br:10]Br>O>[Br:10][C:3]1[C:2]([Cl:1])=[C:7]([Cl:8])[C:6](=[O:9])[NH:5][N:4]=1
Reactant: BrBr
Reactant: O=c1[nH]ncc(Cl)c1Cl
Solvent: O
Product: O=c1[nH]nc(Br)c(Cl)c1Cl
Temperature: 180 °C

Procedure:
4,5-dichloro-1H-pyridazin-6-one (1.95 g, 11.8 mmol) and bromine (0.73 ml, 14.2 mmol) are suspended in water (10 ml) and the mixture heated under microwave irradiation to 180° C. for 30 min. The resulting reaction mixture is filtered and the crude solid obtained washed thoroughly with water, then DCM, to yield 3-bromo-4,5-dichloro-1H-pyridazin-6-one, 2.06 g, as a white solid (71.5% yield).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)CC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(CC1CC1)C1CCNCC1
Temperature: 25 °C

Procedure:
To an ice-cold solution of tert-butyl 4-(cyclopropylmethylsulfonyl)piperidine-1-carboxylate (53, 0.9 g, 2.96 mmol) in CH2Cl2 (15 mL) was added TFA (3.0 mL). The mixture stirred at room temperature and stirred for 3 h and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (25 mL) and the organic layer was washed with saturated NaHCO3 solution (10 mL), H2O (15 mL) brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g Redisep column, 30% to 50% EtOAc in hexanes) to give 4-(cyclopropylmethylsulfonyl)piperidine as a white foam (54, 0.38 g, 63%); 1H NMR (300 MHz, MeOH-d4): δ 3.27-3.24 (m, 1H), 3.23-3.12 (m, 2H), 2.99 (d, J=7.2 Hz, 2H), 2.63 (dt, J=2.4, 12.0 Hz, 2H), 2.10-2.01 (m, 2H), 1.77-1.60 (m, 2H), 1.27-1.14 (m, 1H), 0.83-0.64 (m, 2H), 0.45-0.39 (m, 2H);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)CCC.CN(C=O)C.Cl>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[N:14]=1)[N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A mixture of 8-bromo-5-hydroxy-2-oxo-1,3-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.13 mmol), 3-tributylstannanyl-pyridine (0.064 mL, 0.20 mmol) and PdCl2(PPh3)2 (19 mg, 0.027 mmol) in 3 mL, of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (15-100% EtOAc/hexanes+1% AcOH) to give 34 mg of the title compound as a pale yellow solid. MS: (+) m/z 450.30 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH:8]=2)[NH:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[CH:22]=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](/[CH:29]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])=[CH:6][CH:5]=4)[CH:27]=2)[CH:22]=[N:21]1
Reactant: O=C1Cc2cc(C(=O)Nc3ccccc3)ccc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccc(C(=O)Nc3ccccc3)cc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 60 °C
Yield: 24.2 %

Procedure:
A scintillation vial was charged with 2-oxo-N-phenylindoline-5-carboxamide (22 mg, 0.087 mmol), 1H-indazole-6-carbaldehyde (14 mg, 0.096 mmol), piperidine (1 uL, 0.008 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more MeOH (2 mL). The yellow solid was then filtered and washed with MeOH (10 mL) to give 8.0 mg, 24% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 13.42 (s, 1H), 11.02 (s, 1H), 10.16 (s, 1H), 9.01 (s, 1H), 8.39 (s, 1H), 8.14 (s, 2H), 8.03 (d, J=7.3 Hz, 1H), 7.89-7.82 (m, 2H), 7.79 (d, J=6.5 Hz, 2H), 7.36 (t, J=6.6 Hz, 2H), 7.11-7.09 (m, 1H), 6.96 (d, J=6.9 Hz, 1H); MS ESI 381.1 [M+H]+, calcd for [C23H16N4O2+H]+ 381.14.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 1H-Indole-5-carboxylic acid methyl ester (1 g, 5.71 mmol) in 10 mL of acetic acid at 0° C., was added sodium cyanoborohydride (1.08 g, 17.18 mmol) over 5 minutes. The mixture was stirred at room temperature for 1 h. Water (3 mL) was added and all the solvents were removed under vacuum. The residue was dissolved in ethyl acetate (150 mL) and saturated NaHCO3 (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined extracts were washed with brine (150 mL), dried, filtered and evaporated. The residue was purified by flash chromatography (0-50% ethyl acetate in hexane+0.1% triethylamine) to afford 0.99 g (99%) of 19a.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:9](=[O:11])[CH3:10])=[N:3][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(Br)cn1
Product: CC(=O)Nc1cnc(Br)cn1

Procedure:
2-Amino-5-bromopyrazine (500 mg, 2.87 mmol) is stirred in acetic anhydride (5 mL) for 12 h at RT. The resulting solid is filtered off, digested with toluene and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:31][C@@H:32]([O:34][CH3:35])[CH3:33])(=O)=O)=CC=1>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:31][C@@H:32]([O:34][CH3:35])[CH3:33])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: CO[C@@H](C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc2cc(F)c(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CO[C@@H](C)COc1cc2nc(C)ccc2cc1F
Temperature: 80 °C

Procedure:
To a stirred mixture of 6-fluoro-2-methylquinolin-7-ol (0.200 g, 1.13 mmol), Cs2CO3 (0.552 g, 1.69 mmol) and NMP (2.3 mL) was added (S)-2-methoxypropyl 4-methylbenzenesulfonate (0.303 g, 1.24 mmol). The reaction mixture was heated at 80° C. for 1 hour. After cooling, the reaction was partitioned between toluene and water. The aqueous layer was extracted with toluene. The combined organic layers were washed with water and brine, dried and concentrated to give the crude product, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][Li])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](COCC1C=CC=CC=1)(CCCC)(CCCC)CCCC.[Li]CCCC.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]2[C:47]([CH:56]=[O:57])=[CH:48][C:49]3[NH:53][CH:52]=[N:51][C:50]=3[C:54]=2[F:55])=[C:41]([Cl:58])[CH:40]=1>C1COCC1>[CH2:1]([O:8][CH2:9][CH:56]([C:47]1[C:46]([NH:45][C:42]2[CH:43]=[CH:44][C:39]([Br:38])=[CH:40][C:41]=2[Cl:58])=[C:54]([F:55])[C:50]2[N:51]=[CH:52][NH:53][C:49]=2[CH:48]=1)[OH:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]COCc1ccccc1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: CCCC[Sn](CCCC)(CCCC)COCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of benzyloxymethyllithium in THF (2 mL, prepared from n-Bu3SnCH2OBn (505 mg, 1.23 mmol) and n-BuLi (0.49 mL, 1.22 mmol, 2.5 M solution in hexane) by the procedure reported in J. Am. Chem. Soc. 1978, 100, 1481) is added a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (51 mg, 0.14 mmol) in THF (3 mL) at −78° C. The resulting solution is stirred for 1 hour at −78° C. The reaction is quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (100% CH2Cl2 to 3% MeOH in CH2Cl2) to afford the desired product (46 mg, 68%): MS APCI (+) m/z 490, 492 (M+, Br pattern) detected.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH3:10])[C:6]1=O)([O:3][CH3:4])=[O:2].Cl.[NH2:13][OH:14]>N1C=CC=CC=1>[C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH3:10])[C:6]1=[N:13][OH:14])([O:3][CH3:4])=[O:2]
Reactant: NO
Reactant: COC(=O)C1CSC(C)C1=O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C1CSC(C)C1=NO
Reaction time: 24 h
Yield: 99 %

Procedure:
A solution of 37.26 g. (0.214 mole) of 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene in 100 ml. anhydrous pyridine was treated with 18.0 g. (0.261 mole) hydroxylamine hydrochloride. The mixture was stirred 24 hours at 25°. The reaction was concentrated and partitioned between 1 N hydrochloric acid/methylene chloride. The aqueous phase was extracted two times with methylene chloride. The combined organic extracts were dried and evaporated to yield 40.1 g (99%) of pure 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene oxime as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:16]1[CH:24]=[C:23]2[C:19]([C:20]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]=3[N:22]2[CH3:25])=[CH:18][CH:17]=1>>[CH3:25][N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:24]=2)[C:20]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:21]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)cn1
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CN(C(=O)OC(C)(C)C)CC5)c(=O)c2)cn1
Yield: 54.9 %

Procedure:
4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (208 mg, 55%) as a yellow/green solid: 1H NMR (300 MHz, CDCl3) δ 8.79 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.0, 2.3 Hz, 1H), 7.58-7.51 (m, 2H), 7.36 (s, 1H), 7.30 (1H, partially under solvent), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 6.90 (d, J=1.7 Hz, 1H), 6.50 (dd, J=7.1, 2.0 Hz, 1H), 4.65 (br s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 2.64 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Cl[C:13]1[CH:14]=[C:15]([C:19](=O)[CH2:20][CH3:21])[CH:16]=[CH:17][CH:18]=1>>[C:15]1([C:19]2[C:5]3[C:6](=[C:7]4[C:8](=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=3)=[CH:20][CH:21]=[N:10]4)[N:11]=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=1
Reactant: CCC(=O)c1cccc(Cl)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Product: O=[N+]([O-])c1cc2c(-c3ccccc3)ccnc2c2nccc(-c3ccccc3)c12
Yield: 15 %

Procedure:
In another approach illustrated in FIG. 21 the inventors performed a double Skraup reaction between 4-nitro-o-phenylenediamine 60 and two molecules of 3'-chloropropiophenone 61 to afford in ca. 15% yield 4,7-diphenyl-5-nitro-1,10-phenanthroline 62. Specifically, 4-Nitro-o-phenylenediamine 60 was reacted with β-chloropropiophenone 61 under the Skraup reaction conditions to afford in 15% compound 62, which was analyzed and found to have the following physical characteristics:
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[Cl:23][C:24]1[C:25]([O:34][CH2:35][C:36]23[CH2:46][C:40]4([F:47])[CH2:41][C:42]([F:45])([CH2:44][C:38]([F:48])([CH2:39]4)[CH2:37]2)[CH2:43]3)=[CH:26][C:27]([F:33])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]>>[Cl:23][C:24]1[C:25]([O:34][CH2:35][C:36]23[CH2:46][C:40]4([F:47])[CH2:41][C:42]([F:45])([CH2:44][C:38]([F:48])([CH2:39]4)[CH2:37]2)[CH2:43]3)=[CH:26][C:27]([F:33])=[C:28]([CH:32]=1)[C:29]([O:31][CH3:1])=[O:30]
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Product: COC(=O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 150 step 2 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-chloronicotinic acid with 5-chloro-2-fluoro-4-((−3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid, the title compound was obtained as a colorless solid (0.90 g, quant.): 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=7.5 Hz, 1H), 6.62 (d, J=12.0 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 2H), 2.24-2.05 (m, 6H), 1.87-1.78 (m, 6H); MS (ES+) m/z 407.3, 409.1 (M+1).
Reaction SMILES: BrBr.C(C1C=C[C:11]([C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][CH3:28])[CH:22]=3)[CH:17]=2)=C)=CC=1)CCCC.C(O)(C)(C)C.O.[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO>[CH3:41][C:35]1[CH:40]=[CH:39][C:38]([C:11]#[C:14][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][CH3:28])[CH:22]=3)[CH:17]=2)=[CH:37][CH:36]=1
Reactant: Cc1ccccc1
Reactant: C=C(c1ccc(CCCCC)cc1)c1ccc2cc(OCC)ccc2c1
Agent: BrBr
Solvent: CO
Solvent: O
Solvent: CC(C)(C)O
Product: CCOc1ccc2cc(C#Cc3ccc(C)cc3)ccc2c1

Procedure:
0.112 mol of Br2 is added to 0.112 mol of 1-(4-pentylphenyl)-1-(6-ethoxy-2-naphthyl)ethene in 150 ml of toluene and 100 ml of methanol at about 10°. The reaction mixture is evaporated and the residue is heated at reflux for 4 hours together with 0.4 mol of potassium tert.-butylate and 200 ml of tert.-butanol. After cooling, pouring into water and filtering the product with suction gives, after purification by recrystallization, 1-(4-pentylphenyl)-2-(6-ethoxy-2-naphthyl)-acetylene having M. 110° and C. 157.3°.