Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]I.C(OC([C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:39])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH:22]=[CH:21]3)[CH:14]=[CH:13][N:12]=1)=O)(C)(C)C.C(Cl)Cl>C1COCC1.CO>[F:36][C:35]([F:38])([F:37])[C:31]1[CH:30]=[C:29]([NH:28][C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:15]4[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])([CH3:16])[CH3:14])[CH:16]=4)=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)=[O:39])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Agent: C[Mg]I
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reaction time: 8 h

Procedure:
Methyl magnesium iodide (0.30 mL, 3.0 M) is added to a solution of 4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylic acid tert-butyl ester (0.150 g, 0.302 mmol) in THF (5 mL) at rt. After stirring overnight the reaction is diluted with MeOH (5 mL) and workup done with DCM and pH 7 buffer. Following concentration the residue is separated by FCC (80-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z 456.1 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([O:11][CH2:12][P@@:13]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:19])[O:14]CCCC)=[CH:9][CH:8]=1.Cl>>[OH:1][C@H:2]([CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH2:42][OH:43])[CH:36]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([O:11][CH2:12][P:13]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:14])[OH:19])=[CH:9][CH:8]=1
Reactant: CCCCO[P@@](=O)(CCCOCc1ccccc1)COc1ccc(CCNCC(O)COc2ccc(O)c(CO)c2)cc1
Agent: Cl
Product: O=P(O)(CCCOCc1ccccc1)COc1ccc(CCNC[C@H](O)COc2ccc(O)c(CO)c2)cc1

Procedure:
The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]ethyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester according to a modification of the procedure described in Example 5. Acidification to pH 3.5 with 1M hydrochloric acid followed by C18 reverse phase chromatography, eluting with water-methanol (30%) and freeze drying of the resultant foam gave the title compound as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH2:12][CH:11]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1.Cl.[CH3:24][C:25]1[N:26]=[C:27]([N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[C:28]2[CH:33]=[CH:32][S:31][C:29]=2[N:30]=1>CC(O)C.CS(C)=O>[OH:22][CH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][CH:11]([OH:10])[CH2:12][NH:40][CH:37]1[CH2:36][CH2:35][N:34]([C:27]2[C:28]3[CH:33]=[CH:32][S:31][C:29]=3[N:30]=[C:25]([CH3:24])[N:26]=2)[CH2:39][CH2:38]1
Reactant: Cc1nc(N2CCC(N)CC2)c2ccsc2n1
Reactant: OCc1cccc(OCC2CO2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc(N2CCC(NCC(O)COc3cccc(CO)c3)CC2)c2ccsc2n1
Yield: 20 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 1.2 eq. DIEA, 120° C., 90 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine HCl-salt to give the title compound with 20% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CCOC(=O)c1cnc2cc(OCCOC)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1ccn2c(C(=O)O)cnc2c1
Temperature: 40 °C
Yield: 90.6 %

Procedure:
Ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (6.06 g; 22.9 mmol) was mixed with tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL). Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. The mixture was stirred under an atmosphere of nitrogen and heated at 40° C. for 22 hours. The mixture was allowed to cool and then concentrated under reduced pressure to give a yellow gum. Water (50 mL) was added and the mixture stirred to until homogeneous. Hydrochloric acid (2N) was added with stirring to adjust to pH 3. The mixture was cooled with an ice/water bath. The resulting precipitate was collected by filtration and washed with a small amount of water (10 mL). The material was dried under vacuum to give 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid as a white solid (4.90 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40]O)[CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: OCCN1CCSc2ccccc21
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(OCCN2CCSc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.4 %

Procedure:
To a mixture of 4-hydroxy benzaldehyde (1.8 g, 14.8 mmol) and triphenyl phosphine (4.85 g, 18.5 mmol) in tetrahydrofuran (15 ml) was added 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethanol (2.39 g, 12.3 mmol) and diisopropyl azodicarboxylate (3.74 g, 18.5 mmol) in THF (20 ml) at 25° C. The reaction mixture was stirred for 12 h at 25° C. Water (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed over silica gel using a mixture of methanol and chloroform (5:95) as an eluent to afford the title compound (1.6 g, 44%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (28.2 g, 231 mmol), potassium carbonate (47.9 g, 347 mmol), potassium iodide (3.84 g, 23.1 mmol) and N,N-dimethylformamide (280 mL) was added benzyl bromide (27.5 mL, 231 mmol) with stirring at room temperature, and the mixture was stirred at the same temperature for 24 hrs. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid and saturated brine, dried, and concentrated under reduced pressure to give the title compound (48 g, yield 98%) as beige crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:44]#[C:43][CH2:42][NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCNC(=O)OC(C)(C)C
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CCNC(=O)OC(C)(C)C)cc2C(F)(F)F
Yield: 83 %

Procedure:
The title compound (170 mg, 83%) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (195 mg, 0.343 mmol) and 3-t-butoxycarbonylamino-1-propyne by the procedure similar to that described in Reference Example 21.
Reaction SMILES: O.NN.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:22])[C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([N+:19]([O-])=O)=[CH:13][CH:12]=2)=[O:8])[CH3:5]>CO.C1(C)C=CC=CC=1.[Ni]>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:22])[C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=2)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(Cl)c2cc([N+](=O)[O-])ccc2n1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Cl)c2cc(N)ccc2n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.3 %

Procedure:
To a refluxing mixture of hydrazine hydrate (10.8 ml, 222 mmol) and Raney Ni (6 g) in MeOH (200 mL) was slowly added the product of step (b) (12.6 g), and the refluxing was continued for 6 hours. After cooling to room temperature, the Raney Ni was removed by filtration through Celite, and the solvent was removed in vacuo to give the crude product. The residue was dissolved in toluene (100 mL), and concentrated in vacuo. The residue was again dissolved in toluene (100 mL), and concentrated in vacuo, the residue was suspended in diethyl ether, and the product was collected by filtration to afford 11.3 g of the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:39][Si](CC)(CC)CC)[CH2:16][NH:17][C@H:18]([CH3:38])[CH2:19][C:20]2[C:28]3[C:23](=[C:24]([O:29][CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH2:36]([N:33]([CH2:34][CH3:35])[C:31](=[O:32])[CH2:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH2:19][C@H:18]([NH:17][CH2:16][C@H:15]([OH:39])[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[CH3:38])[CH3:37]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O[Si](CC)(CC)CC)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3ccc(O)cc3)c[nH]c12
Yield: 56.9 %

Procedure:
A solution of 2-[3-((2R)-2-{2-[4-(tert-butyldimethylsilyloxy)-phenyl]-(2R)-2-(triethylsilyloxy)ethylamino}-propyl)-1H-indol-7-yloxy]-N,N-diethylacetamide (40 mg, 0.060 mmol) and TBAF (261 mg, 1 mmol) in tetrahydrofuran (1 mL) is stirred at room temperature for 8 hours. After concentrated, the resultant is purified by preparative TLC (thickness: 0.5 mm, methanol/(a saturated ammonia solution in chloroform)=1/10), extracted with saturated aqueous sodium hydrogen carbonate solution/chloroform. The organic layer is dried over sodium sulfate, and concentrated to give the desired N,N-diethyl-2-(3-{(2R)-2-[(2 R)-2-hydroxy-2-(4-hydroxyphenyl) ethylamino]propyl}-1H-indol-7-yl-oxy)acetamide (15 mg, yield: 55%).
Reaction SMILES: [C:1]([N:4]([C:20](=[O:22])[CH3:21])[C:5]1[C:10]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:6]=1[S:16](O)(=[O:18])=[O:17])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>ClCCl>[C:1]([N:4]([C:20](=[O:22])[CH3:21])[C:5]1[C:10]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:6]=1[S:16]([Cl:24])(=[O:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1c(C2CCCC2)cccc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N(C(C)=O)c1c(C2CCCC2)cccc1S(=O)(=O)Cl

Procedure:
A solution of 1.55 g (3.6 mmol) of 2-(diacetylamino)-3-cyclopentylbenzenesulphonic acid and 1.12 g (5.4 mmol) of phosphorus pentachloride in 10 ml of dichloromethane is heated at the reflux temperature for 2.5 hours, and the reaction medium is then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of florisil™, eluting with dichloromethane.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH3:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:22]=1>N1C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:19]1[CH:18]=[C:17]([CH3:16])[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(O)cc(-c2ccccc2)c1
Solvent: c1ccncc1
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
Triflic anhydride (26 ml; 0.15 mol) was added to a solution of 3-methyl-5-phenylphenol (22.4 g; 0.15 mol) in pyridine (140 ml), at 0° C. The mixture was stirred at ambient temperature for 4 hours. After evaporation of the pyridine, the residue was acidified to pH 3 with 6N HCl and extracted with ether. The organic phase was evaporated and the residue purified by flash chromatography eluting with petroleum ether/ethyl acetate (94/6) to give 3-trifluoromethanesulfonyloxy-5-phenyltoluene as an oil. Yield=83%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2=[N:11][C:12]([NH:15][C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[N:13][CH:14]=[C:9]2[CH:8]=[N:7]1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCOCC1.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.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:21][N:19]1[CH:20]=[C:16]([NH:15][C:12]2[N:11]=[C:10]3[N:6]([CH2:5][C:4]4[CH:22]=[CH:23][CH:24]=[C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:3]=4)[N:7]=[CH:8][C:9]3=[CH:14][N:13]=2)[CH:17]=[N:18]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(I)c4)c3n2)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCOCC5)c4)c3n2)cn1
Temperature: 140 °C
Yield: 52.6 %

Procedure:
1-(3-iodobenzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (80 mg, 0.185 mmol), was dissolved in dioxane (1.2 mL) and added to a microwave tube. A mixture of Cs2CO3 (150 mg, 0.462 mmol) and X-Phos ligand (dicyclohexyl(2′,4′,6′-triisopropyl-[1,1-biphenyl]-2-yl)phosphine, 4.4 mg, 9.2 μmol) and morpholine (40 μL, 0.462 mmol) was then added to the stirred solution, followed by the catalyst Pd2(dba)3 (1.65 mg, 1.8 μmol). The solution was degassed for 5 minutes with nitrogen and the tube was sealed under Nitrogen. The tube was heated in the microwave oven for 1 h at 140° C. then the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine and dried over Na2SO4. The solution was then filtered and the solvent removed in vacuo to obtain a crude solid which was purified by flash chromatography (ethyl acetate 100% to ethyl acetate/MeOH=85:15) to give the title compound as a white solid (38 mg, 52% yield). 1H NMR (d6-DMSO) δ 9.83 (br s, 1H), 8.91 (s, 1H), 8.08-7.98 (m, 2H), 7.59 (s, 1H), 7.15 (t, 1H), 7.03 (s, 1H), 6.84 (dd, J=8.2, 2.1 Hz, 1H), 6.69 (d, J=6.1 Hz, 1H), 5.49 (s, 2H), 3.84 (s, 3H), 3.72-3.63 (m, 4H), 3.07-2.95 (m, 4H); LC-MS method B, (ES+) 391.0, RT=7.44 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[N:25]1[O:29][N:28]=[C:27]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:26]=12>>[N:25]1[O:29][N:28]=[C:27]2[CH:30]=[C:31]([C:34]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=5)=[CH:5][C:4]=4[N:1]=3)[CH:32]=[CH:33][C:26]=12
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc2nonc2c1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5nonc5c4)nc3c2)cc1

Procedure:
Compound 186 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzofurazan-5-carboxaldehyde. [M+H]+ calcd for C22H18N6O2: 399.15; found: 399.47.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[NH2:6].[N+](C1C=CC=CC=1C=O)([O-])=O>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[CH:3]=[CH:4][C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: COc1cc(N)ccc1-c1ccccn1
Agent: O=Cc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2ccccn2)cc1

Procedure:
A solution of 3-methoxy-4-pyridin-2-ylaniline (130 mg, 0.65 mmol) and 2-nitrobenzaldehyde (100 mg, 0.65 mmol) in toluene (1 mL) was heated to 60° C. for 12 h and the reaction mixture was concentrated to afford 3-methoxy-N-[2-nitrophenyl)methylidene]-4-pyridin-2-ylaniline. The 3-methoxy-N-[2-nitrophenyl)methylidene]-4-pyridin-2-ylaniline was dissolved in freshly distilled triethylphosphite (1.1 mL) and was heated to 110° C. for 5 h under an atmosphere of nitrogen. The reaction was cooled to 60° C. and the triethylphosphite was distilled off leaving a residue which was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 3:2) to afford the desired 2-(3-methoxy-4-pyridin-2-ylphenyl)-2H-indazole. 1H NMR (CDCl3, 500 MHz) δ 8.74 (m, 1H), 8.50 (s, 1H), 7.99 (d, 1H), 7.92 (dt, 1H), 7.83 (d, 1H), 7.75 (m, 3H), 7.52 (dd, 1H), 7.36 (ddd, 1H), 7.25, ddd, 1H), 7.14 (dd, 1H), 4.05 (s, 3H) ppm. 13C NMR (CDCl3, 125 MHz) δ 157.9, 154.9, 149.7, 149.5, 141.6, 135.7, 132.0, 128.4, 127.0, 125.1, 122.8, 122.5, 121.9, 120.6, 120.4, 117.8, 112.4, 104.7, 56.0 ppm. MS (ESI) 302 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])([CH3:29])[CH3:28]
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC(C)(C)CO)s1
Yield: 46 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (46 mg, 46%) which was obtained as an off white solid after recrystallization from heptane/ethyl acetate. MS: m/e=403.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCc1ccccn1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCc1ccccn1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(aminomethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.30 (1H, br), 11.21 (1H, br), 10.20 (1H, br), 8.52 (1H, d, J=4.2 Hz), 8.26 (1H, br s), 7.75 (1H, t, J=7.6 Hz), 7.36-7.24 (5H, m), 7.15 (2H, t, J=8.9 Hz), 4.62 (2H, br m), 4.04 (2H, s); ES+ MS: 405 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.O.Cl[O-].[Ca+2].Cl[O-]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F
Reaction time: 2.25 h

Procedure:
2.11 g (0.01 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 20 ml of methylene chloride at room temperature. After addition of 4 ml of water and 1.72 g (0.012 mol) of calcium hypochlorite the mixture is stirred for 2.25 hours with vigorous mixing, during which the reaction temperature rises to 28° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.4 mbar, 100°-110° C. bath temperature), 1.69 g (81% of theory) of 2-chloro-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>CN(C)C(=O)C>[CH3:45][S:46]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 1 °C

Procedure:
To a mixture of 5-(4'-hydroxymethyl-1,1'-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole (0.01 m=4.90 g) and potassium carbonate (0.05 m=6.90 g) stirred in 50 mL N,N-dimethylacetamide chilled at 1° C. was added a total of 3.34 g (0.024 m) of methanesulfonyl chloride in portions over 6 hours. The progress of the reaction was monitored by thin layer chromatography or HPLC. The title compound was formed in better than 90% in the mixture which was used in the next example.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6](CC1C=CC(OC)=CC=1)[C:5]2([CH3:22])[CH3:21]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:22])[CH3:21]
Reactant: COc1ccc(CN2C(=O)c3ccc(Cl)cc3C2(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)NC(=O)c2ccc(Cl)cc21
Yield: 85.2 %

Procedure:
A solution of 5-chloro-2-(4-methoxy-benzyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (0.38 g, 1.2 mmol) in trifluoro acetic acid (5 mL) was heated to reflux for 20 hours. After removal of trifluoro acetic acid under reduced pressure, the crude product was purified by flash column chromatography (silica gel 14 g, 5% to 50% ethyl acetate in DCM) to give the title compound (0.20 g, 85%) as a white solid. MS: 196.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:13][N:14](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:13]([C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1)#[N:14]
Reactant: CNS(=O)(=O)c1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CNS(=O)(=O)c1cncc(C#N)c1
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-N-methylpyridine-3-sulfonamide (0.1 g, 0.39 mmol) in N,N-dimethylformamide was added zinc cyanide (0.056 g, 0.47 mmol). The solution was degassed with nitrogen for 10 min, then tetrakis(triphenylphosphine)palladium(0) (30 mg) was added. The reaction mixture was heated to 100° C. for 2 h. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude compound was purified by rinsing with diethyl ether to afford 5-cyano-N-methylpyridine-3-sulfonamide (60 mg) which was used without further purification.