Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[NH2:47][CH:48]1[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49]1>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:47][CH:48]4[CH2:52][CH2:51][NH:50][CH2:49]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC5CCNC5)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl) imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, step A) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (14 mg, 0.086 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. tert-Butyl 3-aminopyrrolidine-1-carboxylate (32 mg, 0.17 mmol) was added to the reaction mixture. The mixture was sealed and heated at 70° C. for 2 hours and cooled to ambient temperature. DMF was removed under reduced pressure. The residue was triturated with Et2O. The resulting tan solid was dissolved in DCM (1 mL). TFA (1 mL) was added to the DCM solution. The reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to provide the final product (10 mg). MS (ES+APCI) m/z=523 (M+H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH:12]([CH3:14])[CH3:13]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:21]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: CC(C)COc1cccc(B(O)O)c1
Product: CC(C)COc1cccc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 68.8 %

Procedure:
The title compound (0.180 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and 3-isobutoxyphenylboronic acid (0.224 g, 1.16 mmol) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.44-7.41 (m, 2H), 7.27 (t, J 7.9, 1H), 7.17-7.10 (m, 2H), 6.84-6.81 (m, 1H), 5.50 (s, 2H), 3.83 (d, J 6.5, 2H), 2.07-1.97 (m, 1H), 1.00 (d, J 6.7, 6H).
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.O[C:14]([C:17](O)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[C:17]([CH3:19])([CH3:18])[O:12][B:2]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C

Procedure:
A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) and pinacol (12 mmol) in toluene (70 mL) was refluxed in a Dean-Stark apparatus for 16 hours and concentrated. The concentrate was triturated with diethyl ether and filtered to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:16][CH2:15][CH2:13][OH:14])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NCCO
Reactant: Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Product: Nc1cc(Cl)cc(NCCO)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.05 mole (11.2 g) of 2-amino-4,6-dichloronitrobenzene (Recueil. Trav. Chim. 68, p. 88 [1949]) in 45 ml of ethanolamine was heated for 2 hours over a boiling water bath. The reaction medium was diluted with 150 ml of ice water. After acidification with 80 ml of hydrochloric acid, the desired product precipitated out. It melted at 183° C. after recrystallization from 400 ml isopropanol.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>CN(C=O)C.O>[CH:1]([C:4]1[N:5]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1c[nH]c(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)C)n1
Temperature: 80 °C

Procedure:
Into a flask containing a solution of methyl 2-isopropyl-1H-imidazole-4-carboxylate (2.7 g, 16.1 mmol) in DMF (20 ml), K2CO3 (5.5 g, 40.2 mmol) and SEM-Cl (3.5 g, 21.0 mmol) were added. The resulting mixture was heated at 80° C. for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The product was purified with flash chromatography. Yield 830 mg. 1H-NMR (400 MHz; CDCl3): δ 0.04 (s, 9H), 0.85-0.89 (m, 2H), 1.28 (d, 6H), 3.15-3.20 (m, 1H), 3.57 (t, 2H), 3.83 (s, 3H), 5.74 (s, 2H), 7.69 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: Clc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4ccc(Cl)cc4C3)c(F)cc2c1=O
Yield: 10.2 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 89 mg of 5-chloroisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 25 mg of the target compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:17][C:18]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)=O)C.[BH4-].[Na+]>>[Cl:29][C:27]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:20]([CH3:21])([CH3:22])[CH2:19][C:18]([C:32]([F:33])([F:34])[F:35])([OH:36])[CH2:17][NH:16][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[CH:15][C:6]([CH2:4][OH:3])=[N:7]3)[CH:28]=1
Reactant: CCOC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)ccc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(Cl)cc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F

Procedure:
Analogously to Example 40, 120 mg (0.23 mmol) of 5-[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylidenamino]-quinoline-2-carboxylic acid ethyl ester is reacted with 35 mg (0.92 mmol) of sodium borohydride. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol (0-20%), 61 mg (55% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:47])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)=[CH:31][C:30]=1[CH3:48].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH3:48][C:30]1[CH:31]=[C:32]([NH:35][C:36](=[O:47])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=2)[CH:33]=[CH:34][C:29]=1[O:28][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Reactant: CN1CCN(c2ccc(Nc3nccc(-c4cccnc4Cl)n3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1Oc1ncccc1-c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2)n1
Temperature: 130 °C

Procedure:
To 4-(2-chloropyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (35 mg, 0.092 mmol), N-(4-hydroxy-3-methylphenyl)-3-(trifluoromethyl)benzamide (27 mg, 0.092 mmol) and Cs2CO3 (60 mg, 0.18 mmol) was added DMSO (0.6 mL). The mixture was heated overnight at 130° C. The crude material was purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound as a light yellow solid after aqueous workup. MS m/z=640 [M+1]+Calc'd for C35H32F3N7O2: 639.69.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=1[CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=2[C:15]([OH:26])=[C:14]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Cl:9][C:10]1[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=1[CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=2[C:15]([O:26][CH3:1])=[C:14]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[CH2:28]1
Reactant: Cn1c(=O)c2c(c(O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.1 %

Procedure:
Potassium carbonate (41 mg) and methyl iodide (13 μl) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (50 mg) in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at room temperature for 5 hours. A 10% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1>O.CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1
Solvent: CO
Solvent: O
Product: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 15 h

Procedure:
A mixture of 5-(4-chlorobenzyloxy)-2-nitropyridine (0.5 g), Na2S (0.25 g) and methanol (12 ml) is heated to reflux for about 3 hours. Then, a few drops of water is added and refluxing continued about 15 hours. After cooling, the reaction is diluted with methanol, filtered through celite and stripped. The concentrate is taken up in CHCl3, washed with water, dried and stripped giving 2-amino-5-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[O-]CC.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39](OCC)=[O:40])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1>C(O)C>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([CH2:19][CH:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39](=[O:40])[NH:1][C:2]([NH2:4])=[O:3])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C(Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CC(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1

Procedure:
3-(3,5-Dimethoxyphenyl)-2-{4-[4-(2-ethoxycarbonylvinyl)-phenoxy]-phenyl}-acrylic acid (4, 2.37 g, 5.0 mmol) was dissolved in a mixture of ethanol-dioxane (2:1, 150 mL), and palladium charcoal (10%, 500 mg) was added. The mixture was stirred under hydrogen for 15 hr. Catalyst was then removed by filtration, and solvent was evaporated under reduced pressure to yield 3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2-ethoxycarbonylethyl)-phenoxy]-phenyl}-propionic acid (18) quantitatively. Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide (2.7 M, 2.2 mL, 5.92 mmol) at 80° C. under argon, and to this a solution of 18 (1.13 g, 2.37 mmol) in anhydrous ethanol (15 mL) was added and heated at this temperature for 13 hr. Ethanol was evaporated under reduced pressure, water (20 mL) was added, acidified to pH 1 by 5% aqueous HCl and extracted with ethyl acetate (50 mL). The organic layer was washed with water (2×25 mL), brine (2×20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (3:7) containing acetic acid (1%), followed by recrystallization from ethanol. Yield: 256 mg, 22.8%.
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].CI>C(OCC)(=O)C>[CH3:2][O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:11][CH2:12]1
Reactant: C1CCOC1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 94 %

Procedure:
To a 20 ml tetrahydrofuran solution of 1.87 g (7.95 mmol) of benzyl 4-hydroxy-1-piperidinecarboxylate, 413 mg (60% in oil, 10.33 mmol) of sodium hydride and 792 μl (12.72 mmol) of methyl iodide were added at 0° C., and the mixture was stirred at room temperature for 16.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and washed with water. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 2.08 g (94%) of the captioned compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:2][C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:12]1
Reactant: N#Cc1ccccn1
Reactant: CNNC(=O)c1ccncc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccncc2)nc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
To 2-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). The solution is allowed to stand 0.5 hours at ambient temperature and is then added to a solution of 1-methyl-2-isonicotinoylhydrazine (3 g.) in methanol (50 ml.). The solution is heated at reflux 4 hours and concentrated to a gum. After chromatography on silica gel and recrystallization from acetronitrile-water 450 mg. of 1-methyl-3-(4-pyridyl)-5-(2-pyridyl)-1,2,4-triazole are obtained, melting at 145°-146°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][S:10][C:11]=3[CH:16]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: C1CNC1
Product: Clc1ccc(-c2nsc3cc(C#CCCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Azetidine were converted to yield 6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-chloro-phenyl)-benzo[d]isothiazole, MS: 367 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH3:23])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]CCCC.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.CCCCC>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH3:23])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:12]([CH2:14][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Reactant: BrCCCCCCCCCOCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1nc(-n2c(C)ccc2C)nc(CCCCCCCCCCOCc2ccccc2)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 500 mg (1.62 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-benzyloxy-4,6-dimethylpyrimidine (6) in 10 mL of anhydrous THF were added 1.11 mL (1.76 mmol) of a 1.6 M solution of n-BuLi in pentane followed by 509 mg (1.62 mmol) of 9-bromo-1-(benzyloxy)nonane (1). The reaction mixture was stirred under argon atmosphere at −78° C. for 30 min. then the reaction mixture was warmed to room temperature slowly, and the reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 and the poured into 70 mL of water. The mixture was then extracted with two portions of 70 mL of ethyl acetate. The combined organic solution was then washed with a portion of 100 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 5:1 gave the expected product as light yellow oil: yield 175 mg (20%). 1H-NMR (CDCl3) δ 7.48-7.37 (m, 10H), 5.93 (s, 2H), 4.94 (s, 2H), 4.55 (s, 2H), 3.51 (t, 2H, J=6.8), 2.84 (t, 2H, J=7.6) 2.52 (s, 3H), 2.39 (s, 6H), 1.82 (m, 2H), 1.65 (m, 2H), 1.33 (m, 12H); 13C-NMR (CDCl3) δ 165.16, 161.60, 152.48, 147.71, 138.79, 136.28, 129.16, 128.59, 128.26, 107.99, 75.29, 72.96, 70.70, 31.70, 29.85, 29.62, 29.52, 27.79, 26.27, 22.73, 19.32, 14.37
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[S:8][C:5]2=[N:6][CH:7]=1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([N:27]3[CH2:33][C:32]4[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=4[O:30][CH2:29][CH2:28]3)=[N:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>>[CH3:21][N:27]([CH2:33][C:23]1[N:22]=[C:21]([N:27]2[CH2:33][C:32]3[CH:34]=[C:35]([C:2]4[CH:3]=[C:4]5[N:10]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[S:8][C:5]5=[N:6][CH:7]=4)[CH:36]=[CH:37][C:31]=3[O:30][CH2:29][CH2:28]2)[C:20]2[C:25](=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:24]=1)[CH3:28]
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Reactant: CC(=O)Nc1nc2cc(Br)cnc2s1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc6sc(NC(C)=O)nc6c5)cc4C3)nc(CN(C)C)nc2c1

Procedure:
Synthesized according to the method of example 5 using N-(6-bromothiazolo[5,4-b]pyridin-2-yl)acetamide (J. Heterocyclic Chemistry 2003, 40, 261) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO) δ 12.60 (s, 1H), 8.86 (d, 1H), 8.45 (d, 1H), 8.23-8.07 (m, 2H), 7.70 (dd, 1H), 7.27-7.17 (m, 2H), 7.02 (d, 1H), 5.43 (s, 2H), 4.65-4.57 (m, 2H), 4.46 (s, 2H), 4.43-4.37 (m, 2H), 3.94 (s, 3H), 2.73 (s, 6H), 2.25 (s, 3H); MS (EI) for C29H29N7O3S: 556 (MH+).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([OH:10])=[N:2]1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[O:1][N:2]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Oc1noc2ncccc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)Oc2noc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
125 mg (0.918 mmol) of isoxazolo[5,4-b]pyridin-3-ol, 178 mg (1.1 mmol) of 4-methylpiperidine-1-carbonyl chloride and 255 μl (1.84 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred at room temperature for 4 h. A further 89 mg (0.55 mmol) of 4-methylpiperidine-1-carbonyl chloride and 128 μl (0.92 mmol) of triethylamine were added, and stirring was continued at room temperature for 6 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 101 mg (42%), M+H+: 262.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([N:12]1[C:11](=[O:16])[CH:10]([C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:14][C:13]1=[O:15])(=[O:19])[CH3:18]
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(Cl)c1C1OC(=O)N(C(C)=O)C1=O
Temperature: 25 °C
Reaction time: 44 h

Procedure:
5-(2-Chloro-6-methoxyphenyl)oxazolidin-2,4-dione (1.21 g., 5 mmoles) was dissolved in 10 ml. of tetrahydrofuran. Acetic anhydride (613 mg., 0.57 ml. 6 mmoles) was added and the solution stirred at room temperature for 44 hours. The reaction mixture was concentrated to an oil, partitioned between chloroform and saturated sodium bicarbonate. The chloroform layer was washed with fresh bicarbonate and then brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to solid. Repulp of the residue in about 50 ml. of ether gave 3-acetyl-5-(2-chloro-6-methoxyphenyl)oxazolidin-2,4-dione (790 mg., 56%; m.p. 132°-135° C. m/e 285/283).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[CH2:24]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]([OH:37])([C:9]2[C:18]3[O:17][CH2:16][CH2:15][O:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1cccc2c1OCCO2
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2cccc3c2OCCO3)CCN(Cc2ccccc2)CC1

Procedure:
A toluene solution (10 ml) of 5-bromo-2,3-dihydrobenzo[1,4]dioxin (10 mmol) was stirred under argon at 0° C. and was treated with the dropwise addition of n-butyllithium (10 mmol) over ten minutes. After stirring for a further twenty minutes a solution of 1-benzyl-4-piperidone in toluene (10 mmol in 10 ml) was added dropwise over five minutes. Stirring was continued for two hours, at which point water (100 ml) was added and the product extracted into ethyl acetate (4×50 ml). The combined organics were washed with water (2×50 ml), brine (75 ml) and dried (MgSO4). Filtration and concentration in vacuo gave an oil.