Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.II.CON(C)[C:17](=[O:28])[C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19].C([Mg]Cl)(C)C>O1CCCC1>[O:9]1[C:5]2[CH:4]=[C:3]([C:17](=[O:28])[C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH3:19])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Brc1ccc2c(c1)OCC2
Agent: CC(C)[Mg]Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCC2
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36.3 %

Procedure:
Magnesium (711 mg, 29.3 mmol) was placed in a screw-cap reaction tube, and a solution of 6-bromo-2,3-dihydrobenzofuran (4.16 g, 20.9 mmol) in tetrahydrofuran (30 mL) was added, followed by a small crystal of iodine. The tube was sealed and flushed with argon. The mixture was heated at 60° C. for 1 h, and then the reaction mixture was allowed to cool to r.t. A slurry of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (4.85 g, 20.9 mmol) in THF (20 ml) was cooled on a acetone/ice bath to −10° C., and a solution isopropylmagnesium chloride (2 M in THF, 10.5 mL, 21 mmol) was slowly added. The mixture was stirred for 15 min, the cooling bath was removed. Stirring was continued for 10 min. Then the preformed Grignard reagent was added in small portions with stirring. After the addition the mixture was allowed to reach r.t. and stirred for 2 h. The solvent was evaporated, and the mixture was poured into an ice-cold ethyl acetate (150 ml) and aq. HCl (1M, 35 ml) mixture. The organic layer was separated, washed with water and brine, filtered, and evaporated. The product was purified by flash chromatography on silica with ethyl acetate/n-heptane (3:7) to give 2.21 g (36%) of the subtitle compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:14][CH:15]=[C:16]([F:18])[F:17])[CH2:12][CH2:11][CH2:10][CH2:9]1>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:14][CH2:15][CH:16]([F:17])[F:18])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: FC(F)=CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: FC(F)CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
4-[1-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine trifluoroacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol) was dissolved in methanol (3 mL), and a catalytic amount of 5% Pd on C was added. The mixture was stirred at room temperature for 2 hours, under an atmosphere of hydrogen provided by an affixed balloon. The mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford product (4 mg, 21%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1.Cl>CCCCCC.CCOCC.CCOCC.CCCCCC>[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[C:10](=[N+:30]=[N-:31])[C:9]=2[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: Fc1ccc2c(c1)Cc1cc(F)ccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [N-]=[N+]=C1c2cc(F)ccc2-c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
Under nitrogen, n-butyllithium (20 mL of a 2.5M solution in hexane, 1 eq) was added dropwise to a stirred, -20 ° C. solution of commercially available (Alfred Bader Library of Rare Chemicals) 2,7-difluorofluorene (24) (10 g, 49.5 mmoL) [which may also be prepared according to U.S. Pat. No. 4,436,745] in 250 mL of anhydrous ether. After 10 min., this mixture was transferred via a cannula using nitrogen pressure into a 0° C. solution of p-toluenesulfonylazide [prepared by the method described in Doering, et al. J. Am. Chem. Soc. (1953) 75, 5955] in 200 mL of anhydrous ether over 20 min. The reaction was allowed to warm to room temperature over 1.5 h and was then acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine (3×100 mL), dried (MgSO4), and concentrated to provide 10 g of crude material which was leached with ether/hexane to provide 4 g (37%) of product (25): mp 148°-150 ° C.; IR (KBr) 2070, 1600, 1575, 845 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.77 (ddd, 2H, J=0.5, 5.0, 8.7Hz), 7.14 (ddd, 2H, J=0.5, 2.5, 8.5Hz), 7.0 (ddd, 2H, J=2.3, 8.5, 9.3Hz); MS m/z 228 (M+), 200 (base peak). Anal. Calcd. for C13H6N2F2 : C, 68.42;H, 2.65; N, 12.28. Found: C, 68.25;H, 2.78; N, 12.50.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:15])[CH2:9][CH2:8]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][CH2:6][C@@:7]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:15])[CH2:9][CH2:8]1
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCN=[N+]=[N-])(c2ccc(F)cc2)OC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCN)(c2ccc(F)cc2)OC1=O
Yield: 25.5 %

Procedure:
To a solution of (R)-6-(3-azidopropyl)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (210 mg, 0.54 mmol) in THF (5 mL) and H2O (0.25 mL) was added Ph3P (420 mg, 1.60 mmol). After refluxing for 3 h, the mixture was concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-aminopropyl)-3-((S)-1-cyclohexyle-thyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2OCC[O:9]2)=[CH:4][C:3]=1[S:13][CH3:14].C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:13][CH3:14]
Reactant: CSc1cc(C2OCCO2)ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1cc(C=O)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of the product from Example 226B (1.4 g, 6.7 mmol) in acetonitrile (50 mL) was added 2.OM HCI (50 mL) and the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction mixture was poured onto a mixture of ice and saturated aqueous sodium bicarbonate, diluted with ethyl acetate, and the layers were separated. The organic layer was dried (Na2SO4), concentrated, and purified by flash chromatography (hexanes/ethyl acetate 5:1) to provide 1,1 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:31])OCC(Cl)(Cl)Cl)[C:5]=1[CH3:32])(=[O:3])[CH3:2].[OH:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24]([NH:37][CH2:36][CH2:35][CH2:34][OH:33])=[O:31])[C:5]=1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reactant: NCCCO
Product: CC(=O)c1c(C)c(NC(=O)NCCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl (7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 206 and 3-hydroxypropylamine, the title compound was obtained in the same as manner as in Example 143. Yield: 59%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C1COCC1>[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CN(S(=O)(=O)c2ccc(I)cc2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 14.3 %

Procedure:
To a mixture of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (549 mg), sodium bicarbonate solution (5 ml), ethyl acetate (10 ml) and THF (5 ml) was added dropwise, under ice-cooling, a solution of 4-iodobenzenesulfonyl chloride (1.21 g) in THF (10 ml), and the mixture was stirred at 0° C. for 1 hour. The separated organic layer was washed with saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9: 1→1:1) and washed with water to give colorless crystals of 4-(4-iodobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (155 mg). A part of the crystals were treated with hydrochloric acid to give colorless crystals of the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:12])[OH:11])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:15][C:3]1[C:2]([Cl:1])=[C:13]([Cl:14])[C:6]2[S:7][C:8]([CH:10]([OH:11])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(C(C)O)sc2c(Cl)c1Cl
Yield: 86.4 %

Procedure:
To a solution of 17 g of 6,7-dichloro-5-hydroxy-α-methylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 11.8 g of ethyl bromoacetate in 50 ml 2-butanone and the mixture is heated at 95°. To the mixture is added 12 g of potassium carbonate and 5.3 ml of dimethylformamide and the reaction mixture is refluxed at 100° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The aqueous phase is extracted two times with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from acetone and hexane gives 19.5 g of ethyl[(6,7-dichloro-2-(1-hydroxyethyl)benzo[b]thien-5-yl)oxy]acetate, mp 101°-103°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1>C1COCC1.CCC(C)C.C1COCC1>[CH3:30][N:31]1[CH2:36][CH2:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]4)[N:9]=3)=[CH:6][CH:7]=2)([OH:37])[CH2:33][CH2:32]1
Reactant: CN1CCC(=O)CC1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCC(C)C
Product: CN1CCC(O)(c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)CC1
Reaction time: 0.25 h

Procedure:
[4-(4-Bromophenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (116 mg; 0.3 mmol) in THF/isopentane (3 ml/0.6 ml) was cooled to −100° C. nBuLi (1.6M in hexane, 0.56 ml; 0.9 mmol) was added within 5 minutes and the reaction mixture stirred for 15 minutes at this temperature. N-methyl-4-piperidone (71 μl, 0.6 mmol) was added in THF (71 μl), the reaction mixture stirred for 10 minutes at −100° C., poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via chromatography on silicagel (EtOAc/MeOH/ammonia:90/9/1 to 80/18/2) to give the title compound as a white solid. Yield: 25 mg (17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:29]4[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N)nc4)c(C)nc3s2)cc1OC
Yield: 31.9 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.041 g, 0.102 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.056 g, 0.255 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.007 g, 0.0102 mmol, 0.1 eq) and potassium carbonate (0.07 g, 0.51 mmol, 5 eq) in water (0.3 mL) and dioxane (2.2 mL) was subjected to MW irradiation (120° C., 35 min, 200 W). The solvents were evaporated, and the residue obtained was purified by silica gel chromatography (0-3% MeOH in DCM) and preparative HPLC (RP-C18, ACN/water) to give the desired product (0.012 g). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=4.08 min, [M+H]+ m/z 369.1
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=C(C3C=C(C)N=C(NCC)N=3)O[N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH2:35]([NH:39][C:40]1[N:45]=[C:44]([C:46]([OH:48])=O)[CH:43]=[C:42]([CH3:49])[N:41]=1)[CH:36]([CH3:38])[CH3:37].OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH2:35]([NH:39][C:40]1[N:45]=[C:44]([C:46]2[O:48][N:23]=[C:19]([C:17]3[CH:18]=[C:3]([CH3:1])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:15]([CH3:34])[CH:16]=3)[N:20]=2)[CH:43]=[C:42]([CH3:49])[N:41]=1)[CH:36]([CH3:37])[CH3:38]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: Cc1cc(C(=O)O)nc(NCC(C)C)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)nc(NCC(C)C)n1

Procedure:
rac-N-(3-{4-[5-(2-Isobutylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-isobutylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.96 min; [M+H]+=485.31.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
A mixture of 2-Fluoro-5-Chloro Nitro benzene (0.5 g, 2.85 mmol), 4-Acetamidophenol (0.45 g, 3.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in DMSO (5 mL) was heated 6 hr at 90° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer washed with water, 20% aqueous potassium hydroxide solution and aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent concentrated under vacuum leaving the title compound as a tan solid (0.71 g, 81%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][N:4]=1.[CH3:21]N>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[CH2:9][C:3]([NH:2][CH3:21])=[N:4][CH:5]=[C:6]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:13]=1
Reactant: CN
Reactant: NC1=NC=C(c2ccccc2)c2cc(Cl)ccc2C1
Agent: Cl
Solvent: CCO
Product: CNC1=NC=C(c2ccccc2)c2cc(Cl)ccc2C1

Procedure:
2-Amino-7-chloro-5-phenyl-1H-3-benzazepine hydrochloride (8 g; 0.027 mole) [see Example (e)] in 33% w/w methylamine in ethanol (100 ml) was maintained at 40° for 3 days. The solution was then evaporated to dryness and the residual amine was azeotropically removed with toluene. The residue was treated with dry acetone, acidified with a few drops of ethanolic hydrogen chloride, filtered, and washed with acetone to give the title compound as the hydrochloride. Crystallisation of this hydrochloride from absolute ethanol gave a fine white granular powder; m.p. 318°-320°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2.[OH:25]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2)=[O:25]
Reactant: O=C1CCc2cc(OCCCCCSc3ccccn3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCCS(=O)c3ccccn3)ccc2N1

Procedure:
Prepared analagous to Example 2 from 6-[5-(2-pyridyl-mercapto)-pentoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1/[CH:13]=[CH:14]/[C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]3[CH2:41][CH2:40][CH2:39][N:38]3C(OC(C)(C)C)=O)=[O:36])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]1([N:20]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35]([C@@H:37]3[CH2:41][CH2:40][CH2:39][NH:38]3)=[O:36])=[CH:32][CH:33]=2)[CH2:19][C:18]2[CH:17]=[CH:16][C:15](/[CH:14]=[CH:13]/[C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:50][CH:49]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(CN(Cc2ccc(/C=C/[C@@H]3CCCN3)cc2)c2ccccc2)cc1)[C@@H]1CCCN1

Procedure:
To a solution of the product of Example 149G (50 mg, 0.073 mmol) dissolved in dichloromethane (0.3 mL) was added trifluoroacetic acid (2.7 mL) and the resultant solution stirred at room temperature for 20 minutes. The solution was then concentrated under vacuum, the residue dissolved in a chloroform/isopropanol mixture and extracted with aqueous sodium bicarbonate, the organic solution was then dried, filtered, and concentrated to afford the title compound. m/z 481 (M+H)+.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]>CO.O>[O:1]=[CH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cccc(CC(O)CO)c1
Solvent: O
Solvent: CO
Product: N#Cc1cccc(CC=O)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-(2,3-dihydroxypropyl)benzonitrile (2.7 g, 15.3 mmol) in MeOH/H2O (v/v=3:1, 40 mL) was added NaIO4 at 0° C. and then stirred at 0° C. for 1.5 h. The result mixture was filtered and the filtrate was concentrated to afford 3-(2-oxoethyl)benzonitrile, which was used next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH:11](=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].C(OCC)(=O)C>CCCCCC>[OH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[CH:11]=[N:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: O=Cc1ccccc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Temperature: 55 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 13.72 grams (0.10 mole) of 4-amino-3,5-dimethylphenol, 12.21 grams (0.10 mole) of salicylaldehyde and 250 milliliters of ethyl acetate. The resulting reaction mixture was then heated to 55° C. and stirred for 19 hours at ambient pressure. After cooling the reaction mixture to room temperature, it was filtered and concentrated under reduced pressure to give a brown oil which solidified on standing. The resulting solidified material was slurried in hexane, collected by filtration and dried to yield 19.66 grams (0.082 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol in the form of a yellow solid having a melting point of 145°-147° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 24.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.12 g, 3.26 mmol) in 25 mL of dichloromethane and 4-aminobenzotrifluoride (1.05 g, 6.53 mmol) in 8 mL of pyridine. The crude product was recrystallized from water-DMF to yield 0.47 g of the title compound, mp 272-275° C.
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH2:6])[NH:4][CH:5]=1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:28](=O)[CH2:29][CH2:30][CH3:31])[C:23](OCC)=[O:24])=[CH:17][CH:16]=1)#[N:8]>ClC1C=CC(Cl)=CC=1Cl>[O:24]=[C:23]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([C:7]#[N:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][CH:17]=2)=[C:28]([CH2:29][CH2:30][CH3:31])[N:2]2[N:1]=[CH:5][N:4]=[C:3]2[NH:6]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Nc1nnc[nH]1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Yield: 37.9 %

Procedure:
A solution of 4H-1,2,4-triazol-3-amine (2.4 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (10 g) in 1,2,4-trichlorobenzene (50 mL) was stirred at 180° C. for 6 hr. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4 g, 38%).
Reaction SMILES: CO[C:3](=[O:22])[NH:4][C:5]1[C:10]2=[CH:11][N:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:13]=[C:9]2[CH:8]=[CH:7][N:6]=1.ClC1C=CC=C(Cl)[C:25]=1[N:31]1C=C2C(N)=NC=CC2=N1.CN=C=O>>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:12]1[CH:11]=[C:10]2[C:5]([NH:4][C:3]([NH:31][CH3:25])=[O:22])=[N:6][CH:7]=[CH:8][C:9]2=[N:13]1
Reactant: Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Reactant: COC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Agent: CN=C=O
Product: CNC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Yield: 78 %

Procedure:
Following the procedure described for [2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]carbamic acid methyl ester, 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-ylamine and methyl isocyanate were reacted to afford the title compound as a white solid (78% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.06 (br s, 1H), 9.75-9.70 (m, 1H), 9.04 (d, J=0.9 Hz, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.83-7.76 (m, 2H), 7.70 (dd, J=9.0, 7.3 Hz, 1H), 7.17 (dd, J=6.5, 0.9 Hz, 1H), 2.84 (d, J=4.6 Hz, 3H). LCMS (Method B): RT=2.69 min, m/z: 336 [M+H+].