Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]C1.ClCl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C1CC=CC=1>O.C(OC)(C)(C)C>[CH:4]12[CH2:3][CH:1]([CH:6]=[CH:5]1)[N:7]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[O:8]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: ON=C1CCCCC1
Agent: C1=CCC=C1
Agent: ClCl
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(OCc1ccccc1)N1OC2C=CC1C2
Temperature: -10 °C

Procedure:
Cyclohexanone oxime (20.04 g, 171.8 mmol) and methyl t-butyl ether (110 mL) were added to a reactor at 25° C. and stirred under N2 (g). The solution was cooled to −10° C. and Cl2 (g) was added during 15 min until a deep blue, clear solution was obtained. Vacuum was applied to remove remaining Cl2 and possible HCl from the reaction mixture. The temperature was set to −2° C., and a solution of Na2CO3 (11.03 g, 103 mmol) in water (90 mL) was slowly added during 30 min. The phases were separated and the organic phase transferred to a solution of Na2CO3 (19.3 g, 180.3 mmol) in water (126 mL) at 15° C. Benzyl chloroformate (32.3 g, 179.87 mmol) was added and the reaction mixture stirred for 10 min after which cyclopentadiene (25.2 g, 362.16 mmol) was added and the reaction mixture stirred for 3 h. Vacuum was applied and the remaining cyclopentadiene was removed. The phases were separated and the organic phase containing the title product was taken further directly to Example 2 as below.
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[CH:14]=[C:13]([O:15]CC2C=CC(B(O)O)=CC=2)[C:12]2CC[CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4].[OH-].[Na+]>O>[CH2:8]([C:7]1[NH:6][C:5]([CH2:3][CH3:4])=[CH:14][C:13](=[O:15])[C:12]=1[I:1])[CH3:9]
Reactant: II
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(=O)c(I)c(CC)[nH]1
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Iodine (720 mg) was added to a solution of compound C (430 mg) and sodium hydroxide (120 mg) in water (15 ml) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v), to give 2,6-diethyl-3-iodo-4-(1H)-pyridone (D) (290 mg), m.p. 225°-227° C.; NMR (d6 -DMSO): 1.15(t,6H), 2.5(q,2H), 2.8(q,2H), 5.9(s,1H), 11.4(br s, 1H).
Reaction SMILES: [CH:1]1[CH:15]=[C:14]2[C:4]([CH:5]([OH:16])[C:6]3[C:11]([CH:12]=[CH:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][CH:2]=1.[H-].[Na+].[C:19]([O:23]C(=O)CBr)(C)(C)[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH:15]1[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([O:16][CH2:20][CH2:19][OH:23])[C:4]=2[CH:3]=[CH:2][CH:1]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC1c2ccccc2C=Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCOC1c2ccccc2C=Cc2ccccc21
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Dibenzosuberenol (2.08 g, 10 mmol) was dissolved in dry THF (20 mL) at 0° C. Sodium hydride (1.0 g of 50% mineral oil dispersion, 20 mmol) was added. After 10 min. tert-butylbromoacetate (4.0 g, 20.0 mmol) was added over a period of 20 min and then stirred for 1 h. The reaction mixture was quenched with water at 0° C. and the product extracted with ethyl acetate. The combined extracts were dried (MgSO4), and concentrated in vacuo. The product was redissolved in ether (20 mL) and added dropwise to an ether (15 mL) suspension of lithium aluminium hydride (190 mg, 5.0 mmol). The reaction was stirred 16 h at room temperature, quenched with water. The ether solution was washed with water, dried, and concentrated in vacuo to give 1.3 g (50%) of 2-(5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH2:5][NH2:6]
Reactant: CCCOc1ccc(C#N)cc1O
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: CCCOc1ccc(CN)cc1O
Yield: 48 %

Procedure:
This compound was prepared by reduction of 3-hydroxy-4-propyloxybenzonitrile according to procedure described in preparation of 3,5-dibenzyloxybenzylamine. Yield was 48%: MP 110–113° C. (dec.); 1H NMR (CDCl3, 400 MHz) δ6.86 (s, 1H), 6.77 (d, 1H, J=8.4 Hz), 6.74 (d, 1H, J=8.1 Hz), 3.95 (t, 1H, J=6.6 Hz), 3.74 (s, 2H), 2.01 (br, 2H), 1.82 (m, 2H), 1.02 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[NH:6][C:7]([CH:9]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:10][CH2:11][C:12](O)=[O:13])=[N:8][C:4]=2[CH:3]=1.CN(C(O[N:42]1N=N[C:44]2C=CC=C[C:43]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(N)C.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[NH:6][C:7]([CH:9]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:10][CH2:11][C:12]([NH:42][CH2:43][CH3:44])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: CCN
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CCNC(=O)CCC(NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 67 %

Procedure:
Prepared analogously to Example 1g from rac.-N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, and ethylamine in tetrahydrofuran. Yield: 67%; Rf value: 0.24 (silica gel; ethyl acetate/ethanol=95:5); C26H30ClN5O3 (496.01); mass spectrum: (M+H)+=496/498 (chlorine isotope).
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH2:13]([OH:16])[C:14]#[CH:15]>C(OCC)C>[OH:16][CH2:13][C:14]1[CH:15]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: CCOCC
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
2.0 g (0.0126 mole) of 3-diazooxindole is dissolved in 22 ml of propargyl alcohol (0.378 mole) and refluxed under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and diluted with 10 volumes of ethyl ether. The solid is filtered, washed with ethyl ether and dried to give 2.0 g of product (75% direct yield). Recrystallization from methanol gives 1.5 g of title compound, m.p. 286°-288° (sl. dec.).
Reaction SMILES: O1CCCC1.CC(C)([O-])C.[K+].[CH2:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH3:22])[C:15]=1[CH2:23][C:24]([N:26]([CH3:35])[N:27]=[C:28]([CH3:34])[C:29]([O:31]CC)=O)=[O:25])[CH3:13].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:21]([C:16]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH2:12][CH3:13])[C:15]=1[C:23]1[C:24](=[O:25])[N:26]([CH3:35])[N:27]=[C:28]([CH3:34])[C:29]=1[OH:31])[CH3:22]
Reactant: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(C)cc1CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Under a nitrogen atmosphere, 13 mL of a tetrahydrofuran solution of potassium tert-butoxide (1 mol/L) was stirred at room temperature, to which a solution of 1.9 g of ethyl 2-[2-(2,6-diethyl-4-methylphenylacetyl)-2-methylhydrazono]propanoate (Compound VI-2) in 55 mL of toluene was added dropwise over about 1 hour. The mixture was further stirred at room temperature for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure. To the residue obtained was added 30 mL of ice-water, which was extracted with tert-butyl methyl ether (20 mL×2). To the aqueous layer was then added 1.6 g of 35% hydrochloric acid, which was extracted with ethyl acetate (20 mL×3). The ethyl acetate extracts were combined, washed with saturated sodium chloride aqueous solution (20 mL×2), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to a silica gel column chromatography (ethyl acetate:hexane=1:3 as eluent) to yield 0.76 g of a solid. The solid was washed with cold hexane and air-dried to yield 0.59 g of the title compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[OH-].[Li+]>O1CCCC1.CO.C(OCC)C>[CH3:1][O:2][C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(C)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(C)(C)c1ccc(C(=O)O)cc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of methyl 4-(1-methoxy-1-methylethyl)benzoate (120 mg, 0.57 mmol) in tetrahydrofuran (6 mL) and methanol (2 mL) was added 1 M aqueous lithium hydroxide (2 mL). After stirring for 2 h, the reaction mixture was diluted with diethyl ether and washed with 1 N hydrochloric acid (4 mL) and water (4 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to give 93 mg (84%) of the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[N:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:31][C:27]1[C:26]([CH3:39])=[CH:25][C:24]([C:14]2([C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)[C:15]2=[O:23])=[CH:29][C:28]=1[CH3:30]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3ccncc3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.700 g, 1.16 mmol), pyridine-4-boronic acid (0.286 g, 2.33 mmol), copper (II) acetate (0.211 g, 1.16 mmol), triethylamine (0.33 mL, 2.33 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 10% ethyl acetate in hexanes. Dissolve the resulting compound (0.103 g, 0.152 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.40 mL). Stir for 1 h. Add saturated aqueous ammonium chloride(10 mL), water (40 mL)m and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with a gradient from 50% to 75% ethyl acetate in hexanes to give 0.109 g (21%) of the title compound: mass spectrum (ion spray): m/z=451(M+1); 1H NMR(DMSO-d6): δ8.46 (dd, 2H), 8.27 (s, 2H), 7.59 (dd, 2H), 7.34 (d, 1H), 7.29 (t, 1H), 7.16 (t, 1H), 7.06(d, 1H), 6.73 (s, 4H), 2.06(s, 12H).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:15]([OH:16])[CH:14]=1>CN(C=O)C.CCOCC>[CH:1]([O:16][C:15]1[CH:14]=[C:13]([CH:21]=[CH:20][C:17]=1[O:18][CH3:19])[CH:12]=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC(C)C
Temperature: 80 °C

Procedure:
Isopropyl bromide (19.0 mL, 200 mmol) was added to a suspension of K2CO3 (42.0 g, 302 mmol) and isovanillin (23 g, 151.3 mmol) in DMF (100 gmL) and the stirring slurry heated to 80° C. for 13 h. The reaction mixture was then cooled to room temperature, diluted with ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (29.3 g, 100%) which required no further purification. The spectra of this material are identical with those previously reported (H. Ishii, I.-S. Chen and T. Ishikawa J. Chem. Soc., Perkin Trans. 1, 1987, 671.).
Reaction SMILES: [Si]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)CCN(C)C.[Li]CCCC.CCCCCC.[S:45]1[CH:49]=[CH:48][C:47]2[CH2:50][CH2:51][C:52](=O)[C:46]1=2>CCOCC.C1COCC1.Cl.O>[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[C:52]1[C:46]2[S:45][CH:49]=[CH:48][C:47]=2[CH2:50][CH:51]=1
Reactant: O=C1CCc2ccsc21
Reactant: CC(C)(C)[Si](NCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NCc1ccccc1C1=CCc2ccsc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the title compound of Example 1 (3.45 g, 10.0 mmol) and N,N,N',N'-tetramethylethylenediamine (0.75 mL, 5.0 mmol) in dry ether (70 ml) was cooled to 0° C. and treated with a solution of n-BuLi (2.5M) in hexane (8.0 mL, 20 mmol). The mixture was stirred at 0° C. for 0.25 hours and then at room temperature for an additional 3 hours. At this point the mixture was cooled to -78° C. A solution of 4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (1.5 g, 10.8 mmol) in dry THF (15 ml) was then added dropwise and the resulting mixture was stirred at 78° to -60° C. over 1 hour. The reaction was quenched by addition of saturated NH4C1 solution and was allowed to warm to room temperature. The mixture was diluted with ether and H2O. The ether layer was separated and concentrated to leave an oil which was taken up in a mixture of 1N HCl (70 mL) and THF (105 mL). The resulting solution was stirred at room temperature overnight. The mixture was then diluted with H2O and extracted twice with ether. The extracts were set aside for later recovery of unreacted ketone while the aqueous layer was made basic by addition of solid NaOH and extracted twice again with ether. These extracts were combined, dried (Na2SO4) and concentrated in vacuo to leave a dark oil. This was placed under high vacuum and warmed at 50° C. for 1 hour to remove benzenemethanamine leaving 540 mg (23%) of the title compound. An NMR spectrum of this material showed it to be of sufficient purity to use directly in the next step. In other runs of this reaction, however, this material could be purified by flash chromatography on SiO2 using successively 1) CHCl3 and 2) 10% MeOH/CHCl3 as eluants.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19][NH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])[CH2:20][CH2:19][N:18]1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CCc1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CCc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
209 μl (0.936 mmol) of phenylacetaldehyde are added dropwise over the course of 10 minutes to a solution of 100 mg (0.233 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine, 58 mg (0.702 mmol) of sodium acetate, 44 mg (0.702 mmol) of sodium cyanoborohydride and 67 μl (1.17 mmol) of acetic acid in 2 ml of ethanol at room temperature. The reaction mixture is left to stir at room temperature for 16 hours. The residue after evaporation in a rotary evaporator is taken up in ethyl acetate, and the organic phase is washed with water and with brine, dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (2000:50:1). The title compound is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.33, FD-MS: M+ =531.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[N:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1>C1COCC1>[N:21]1[CH:26]=[CH:25][C:24]([C:27]([C:16]2[S:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:6])([F:19])[F:20])=[CH:13][CH:12]=3)=[N:18][CH:17]=2)([OH:29])[CH3:28])=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccncc1
Reactant: FC(F)(F)c1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78556.6 %

Procedure:
To a stirred solution of DIPA (0.09 mL, 0.000655 mmol) in THF (7 mL) at −78° C. was added n-BuLi (0.54 mL, 0.000873 mmol) and the mixture stirred at 0° C. for 30 min. After the reaction mixture was cooled to −78° C., a solution of 2-(4-(trifluoromethyl)phenyl)thiazole (0.1 g, 0.000436 mmol) in THF (2 mL) was added dropwise over 30 min 1-(Pyridin-4-yl)ethanone (0.05 mL, 0.000480 mmol) in THF (2 mL) was then added and the reaction mixture was stirred for an additional 1 hour at −78° C. The work up and purification was done as described in Example 23, Step 2, to provide 1-(pyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethanol (0.12 g, 80%) as off-white solid in 99% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (dd, 2H), 8.07 (d, 2H), 7.90 (s, 1H), 7.80 (d, 2H), 7.50 (dd, 2H), 6.71 (s, 1H), 1.94 (s, 3H); LC-MS m/z calculated for [M+H]+ 351.07. found 351.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:39]#[C:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1>C1(C)C=CC=CC=1>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]#[C:39][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH2:3][C:4]2=3)=[CH:42][CH:43]=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(Cl)cc2)CN(C)CC1
Temperature: 80 °C
Yield: 7.2 %

Procedure:
2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 1 mmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (24 mg) as brown semi solid. 1H NMR (CDCl3) FREE BASE 7.42 (m, 3H), 7.36 (m, 3H), 7.10 (d, 1H), 3.70 (s, 2H), 2.80 (m, 4H), 2.60 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC2)nc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
Add, dropwise, 4.7 g (80.76 mmol) of azetidine to a suspension, stirred at 20° C., of 27.9 g (0.201 mole) of potassium carbonate and 11 g (67.3 mmol) of 2-chloro-5-nitropyridine in 100 mL of dimethylformamide. Stir the mixture for 5 minutes at 20° C., then for 6 hours at 70° C. After this time, the suspension is poured into a mixture of 300 mL of water and 300 mL of ethyl acetate. The aqueous phase is separated, then extracted with 200 mL of ethyl acetate. The organic phases are combined, washed three times with 250 mL of water, then dried over sodium sulfate and concentrated at reduced pressure. We thus obtain 11.7 g of the expected product in the form of a solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:3]=[N:2]1.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>CC1C=CC=CC=1C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].ClCCl>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[CH:3]=[N:2]2)[CH:14]=1
Reactant: Brc1cccnc1
Reactant: c1ccc(-c2cn[nH]c2)nc1
Agent: [Cu+2]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: c1ccc(-c2cnn(-c3cccnc3)c2)nc1
Temperature: 25 °C

Procedure:
2-(1H-Pyrazol-4-yl)pyridine (292 mg, 2 mmol), 3-bromopyridine (0.23 mL, 2.4 mmol), Cu(OTf)2 (50 mg, 0.1 mmol), dibenzylideneacetone (24 mg, 0.1 mmol), Cs2CO3 (780 mg, 2.4 mmol) and 1,10-phenanthracene (360 mg, 2.4 mmol) in dry o-xylene (1.5 mL) under Ar (g) were heated at 115° C. for 18 h. After cooling to ambient temperature, NH4Cl (20 mL) and dichloromethane (20 mL) were added and the reaction mixture shaken, the dichloromethane layer was separated and the aqueous layer shaken with dichloromethane (2×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to a brown oil. This was purified by liquid chromatography on silica gel eluting with EtOAc to give a solid that was further purified by HPLC to afford 2-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine. 1H NMR (CD3Cl, 300 MHz) δ 9.08 (1H, d), 8.58-8.64 (2H, m), 8.56 (1H, s), 8.24 (1H, s), 8.12 (1H, ddd), 7.73 (1H, ddd), 7.56-7.59 (1H, m), 7.45 (1H, dd), 7.19 (1H, ddd). MS (ESI) 223 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O.C(B)#N.[Na]>CO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(OCC=O)cc1
Agent: BC#N
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccc(OCCNc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
p-Chloroaniline (0.99 g) and methyl 4-formylmethoxybenzoate (1.5 g) were dissolved in anhydrous methanol (10 ml), and stirred at room temperature for 30 minutes. To the mixture was added sodium cyanoboron hydride (in solid form) (0.24 g) over a period of 30 minutes and further stirred for 30 minutes. After the reaction solution was concentrated under reduced pressure, water and chloroform were added thereto, and the mixture was separated into layers. The organic layer was concentrated under reduced pressure, and subjected to column chromatograpy on silica gel and eluted with chloroform to give the desired product (0.42 g).