Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][CH:25]=4)=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[O:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:9]1)C1C=CC=CC=1.[CH:39]([OH:41])=[O:40]>[Pd].CO.C(O)C>[CH:39]([O-:41])=[O:40].[CH2:30]([C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:16]3[C:15]([O:14][C@@H:10]4[CH2:11][CH2:12][CH2:13][NH2+:8][CH2:9]4)=[N:20][CH:19]=[N:18][C:17]=3[O:21][C:22]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[CH:25][CH:26]=1)[CH3:31]
Reactant: O=CO
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCC[NH2+]C4)c23)cc1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add 30 mg of 10% palladium on activated carbon to an argon-blanketed solution of 275 mg (0.54 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-5-(4-ethylphenyl)-6-(2-fluorophenyl)furo-[2,3-d]pyrimidine in 5 ml of methanol/ethanol (1:2), and stir at room temperature under a hydrogen atmosphere (standard pressure) for three hours. After adding a further 70 mg of 10% palladium on activated carbon, stir the reaction mixture for another 19 hours under a hydrogen atmosphere (standard pressure) at room temperature. Add a further 175 mg of 10% palladium on activated carbon and 0.2 ml of formic acid, and stir the reaction mixture once again at room temperature under a hydrogen atmosphere (standard pressure) for 15 hours. After filtering off the catalyst, wash the catalyst residue with methanol/water. Concentrate the filtrate under reduced pressure, take up the residue in acetonitrile/DMSO and purify by means of preparative RP-HPLC (gradient: water/acetonitrile/formic acid). 137 mg (54% of theory) of the desired product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.[NH:16]1[CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
Commercially available 4-fluoro-3-(trifluoromethyl)benzoic acid (230 mg, 1.10 mmol) was dissolved in dichloromethane (50 mL), and azetidine hydrochloride (120 mg, 1.28 mmol), HATU (550 mg, 1.45 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. 0.5N hydrochloric acid (100 mL) was added, and extraction was carried out with dichloromethane (100 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (211 mg, yield 78%) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=Cc2cc(OCc3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 4-chlorobenzyl chloride (210 mg), potassium carbonate (214 mg) and DMF (10 ml) was stirred at room temperature for 13 hours and at 50° C. for 3 hours. The reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (272 mg) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O-2].[Ca+2:7]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Ca+2:7]
Reactant: NCC(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
To about 2600 grams of water was stirred 455 grams of glycine and 173 grams of calcium oxide. Once the glycine and calcium oxide had dissolved, a calcium bisglycinate chelate or complex solution was formed.
Reaction SMILES: [C:1]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.C[Sn:22](Cl)(C)C.[Li]>O1CCCC1>[SnH3:22][SH:12]1[C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:15][CH:14]=[CH:13]1
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCC#Cc1cccs1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC#CC1=CC=C[SH]1[SnH3]
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a 1 L schlenk flask with egg-shaped stirbar in a glove box, the 2-decynylthiophene 22a (57.44 mmol, 12.658 g) was added by pipette. On a schlenk line, tetrahydrofuran (300 mL) was cannula transferred to the reaction vessel through a septum. The reaction mixture was cooled to −78° C. and n-butyl lithium (35.9 mL, 1.6 M solution in hexanes,) was added dropwise via syringe and the reaction mixture stirred for 45 min. The reaction vessel was fitted with an addition funnel and trimethyltin chloride (57.4 mL, 1.0 M solution in tetrahydrofuran) was cannula transferred to the funnel under positive argon pressure through a septum. The trimethyltin chloride solution was added dropwise to the stirring lithium salt solution over a period of 15 min. at −78° C. The reaction mixture was allowed to warm to ambient temperature with stirring overnight. The solvent was removed in vacuo on the schlenk line and trapped in a 1 L schlenk flask. The resulting residue was dissolved in diethyl ether (500 mL) washed with brine (3×200 mL), dried over magnesium sulfate, filtered and the solvent removed by roto-evaporation to afford 1-stannyl-5-decynyl-thiophene 22b as a light brown oil (20.6 g, 94% yield). 1H NMR (CDCl3) δ 7.20 (d, 1H), 7.00 (d, 2H), 2.43 (t, 2H), 1.60 (m, 2H), 1.44 (m, 2H), 1.30 (m, 8H), 0.899 (t, 3H), 0.37 (s, 9H); GC/MS (M+) 384 m/z, (M+-CH3) 369 m/z.
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[O-:18][CH2:19][CH3:20].[Na+].Cl>O>[F:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2)=[C:3]([N+:15]([O-:17])=[O:16])[C:2]=1[O:18][CH2:19][CH3:20]
Reactant: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOc1c(F)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Yield: 91 %

Procedure:
A solution of 24 mg (0.098 mmol) of 6,7-difluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione and 24 mg (0.33 mmol) of sodium ethoxide (96%) in 0.5 mL of DMSO-d6 was kept at room temperature for 5 h. The red solution was added to 3 mL of water and acidified with 2 N HCl to pH=4. The precipitate was filtered, washed with water, and dried to leave a yellow solid (24 mg, 91%); mp 293-295° C.; 1H NMR (DMSO-d6), 1.239 (t, 3, J=7.0), 4.141 (q, 2, J=7.2), 7.152 (1, d, J=11.7), 11.975 (s, 1), 12.135 (s, 1). 19F NMR, -134.06 (mb). MS, 269 (M+, 90), 241 (100), 195 (70). HRMS, Calcd for C10H8FN3O5 269.0443, found 269.0454.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[NH2-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1>O>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1)[C:8]#[N:9])([CH3:18])[CH3:17]
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(CCN1CC2CCC(CC2)C1)c1ccccc1)C(C)C

Procedure:
A solution of 16 parts of α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 5 parts of sodium amide in 200 parts by volume of toluene is heated to about 100° C. over a period of 15 minutes and then 20 parts of 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane in 100 parts by volume of toluene is added slowly over a period of 20 minutes. This mixture is heated at 105°-110° C. for an hour and then cooled to room temperature when 200 parts by volume of water is added. The organic layer is separated, dried over calcium sulfate, concentrated, and then distilled to afford 2-[2-(diisopropylamino)ethyl]-2-phenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile, as an oil. This compound is represented by the following structural formula ##STR16##
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:38])[N:4]([CH2:22][C@H:23]([NH:30]C(OC(C)(C)C)=O)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3](=[O:38])[N:4]([CH2:22][C@H:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(1H,3H)-dione 1e was dissolved in 20 mL/20 mL CH2Cl2/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave 2a as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:5]=[C:4]([O:20]CCCC(O)=O)[CH:3]=1.CN1CCCC1=O.Cl.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:15]([F:17])([F:18])[F:16])([OH:19])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1
Reactant: O=C(O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 200 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
To 4-[(9R)-4-chloro-9-hydroxy-9-(trifluoromethyl)-9H-fluoren-2-yloxy]butyric acid (50 g) were added N-methylpyrrolidone (200 ml) and pyridine hydrochloride (298 g), and the mixture was stirred at an oil bath temperature of 200° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 ml), and washed twice with water. The obtained aqueous layer was extracted again with ethyl acetate (300 ml). The combined organic layer was washed successively with water, 1N hydrochloric acid and saturated brine. To the obtained organic layer were added anhydrous magnesium sulfate and activated carbon (10 g), and the mixture was stirred at room temperature. The insoluble material was filtered off through celite. The solvent in the obtained organic layer was evaporated, hexane was added to the residue, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, and dried under reduced pressure at room temperature. The obtained crude product was dissolved in ethyl acetate (500 ml), washed 3 times with water, dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solvent in the filtrate was evaporated. To the residue was added hexane, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, dried under reduced pressure at room temperature to give the title compound (22.4 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>O1CCCC1>[CH2:13]([O:12][C:10]([N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C=CC=CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
A solution of pyridine (4.0 g., 0.050 mol) and NaBH4 (1.0 g, 0.026 mol) in 20 ml of tetrahydrofuran is treated with benzyl chloroformate (8.5 g, 0.05 mol) over about 1 hour followed by stirring for 1.5 hour at -78° C. The mixture is added to ice-water and extracted with ether, and the extract is washed with 3% HCl solution and 3% NaOH solution. After the extract is dried and evaporated, 8.0 g of N-benzyloxycarbonyl-1,2-dihydropyridine is obtained in 74% yield. A 5% solution of N-benzyloxycarbonyl-1,2-dihydropyridine is then irradiated using a Rayonet photochemical reactor (RP-300 lamps) until the NMR spectrum shows consumption of the starting materials. The solvent is evaporated to give the crude product, N-(benzyloxycarbonyl)-2-azabicyclo[2.2.0]hex-5-ene (VIII). Pure (VIII) is obtained by passing the crude product through basic alumina with ether. (VIII) is then reacted with ozone in methanol at -78° C. followed by reaction with peroxyacetic acid to form cis-N-(benzyloxycarbonyl)-azetidine-2,3-dicarboxylic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.O>CCCCCC.O1CCCC1>[C:4]1([CH2:3][O:10][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccnc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccnc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
Sodium hydride (60% paraffin dispersion, 5.0 g, 120 mmol) was washed with hexane (5 mL) twice, and suspended in tetrahydrofuran (200 mL). To this suspension was added dropwise a solution of benzyl alcohol (14 g, 120 mol) in tetrahydrofuran (50 mL) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 15 minutes. To this solution was added a solution of 2-bromo-4-methylpyridine (20 mL, 110 mol) in tetrahydrofuran (50 mL), and the mixture was heated to reflux for 14 hours. Water (200 mL) was added to the reaction mixture, and extracted with ethyl acetate. The extracted solution was dried, and the solvent was distilled off. The crude product was distilled under reduced pressure to obtain a title compound (13 g, yield 67%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:19]([CH2:20][OH:21])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O.CO>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:19]([CH2:20][OH:21])[CH2:18][CH2:17][C:12](=[O:13])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CCC2(C[C@H]1COCc1ccccc1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC[C@@H](CO)[C@H](COCc2ccccc2)C1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A solution composed of {(7R,8R)-7-[(benzyloxy)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}methanol (33.6 g, 115 mmol) in a mixture of acetic acid (220 mL) and water (80 mL) was heated at 85° C. for 2 h. The solvents were removed by rotary evaporation under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with an additional portion of ethyl acetate and the combined organics were washed with saturated aqueous NaHCO3 and NaCl solutions, and dried over a mixture of Na2SO4 and MgSO4. Concentration in vacuo afforded a yellow syrup that was taken up in methanol (250 mL) and treated with K2CO3 (20 g, 150 mmol) with stirring at rt for 30 min. The methanol was then evaporated and the residue was taken up in ethyl acetate and washed with water, saturated aqueous NaCl solution, and dried a mixture of Na2SO4 and MgSO4. Concentration in vacuo provided (3R,4R)-3-[(benzyloxy)methyl]-4-(hydroxymethyl)cyclohexanone as a thick, yellow syrup. 1H NMR (500 MHz, d6-acetone) δ 7.36 (4H, m), 7.30 (1H, m), 4.56-4.50 (2H, m), 3.70 (1H, m), 3.66-3.60 (2H, m), 3.56 (1H, dd, J= 5.4, 9.3 Hz), 3.54-3.48 (1H, dd, J= 4.0, 9.3 Hz), 2.44-2.26 (4H, m), 2.13-2.07 (2H, m), 1.91 (1H, m), 1.67 (1H, m).
Reaction SMILES: COC(=O)[CH:4]([C:7]1[S:8][C:9]([Br:12])=[CH:10][CH:11]=1)[CH:5]=O.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][NH2:23].[CH3:24][OH:25]>Cl>[Br:12][C:9]1[S:8][C:7]([C:4]2[N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])[N:23]=[C:24]([OH:25])[CH:5]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)C(C=O)c1ccc(Br)s1
Reactant: NNc1ccccc1Cl
Reactant: CO
Agent: Cl
Product: Oc1cc(-c2ccc(Br)s2)n(-c2ccccc2Cl)n1
Yield: 70 %

Procedure:
To a solution of 3-(5-bromo-thiophen-2-yl-3-oxo-propionic acid methyl ester (2.0 g, 7.60 mmol) in 1.2 M HCl in MeOH (20 mL) was added 2-chlorophenylhydrazine hydrochloride (1.43 g, 7.98 mmol). The reaction mixture was heated to reflux for 4 hours and cooled off. The solvent was evaporated and the residue was purified by flash column chromatography with 10% ethyl acetate in hexane. The product 5-(5-bromo-thiophene-2-yl)-1-(2-chloro-phenyl)-1H-pyrazole-3-ol was recovered as a white solid (1.89 g, 70% yield. MS (ES): 355 [M+H]+.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(Cl)(Cl)Cl>CO>[Br:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)=[O:21])=[CH:23][CH:24]=1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of 4-(p-tolyloxy)piperidine (765 mg), 6-bromonicotinic acid (808 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.7 g) were added chloroform (5 mL) and methanol (5 mL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.5 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[C:17]([F:20])=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.[C:40](O)([C:42]([F:45])(F)F)=O>C(Cl)Cl>[F:45][C:42]1[CH:40]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[N:33]4)[CH:27]=3)[CH2:24][C:23](=[O:38])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3ccc(F)cc3F)cc2N1

Procedure:
Prepared from {2′,4′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K90) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (78 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OCCCl)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (100 mg), 1-bromo-2-chloroethane (127 mg), and potassium carbonate (204 mg) were suspended in N,N-dimethylformamide (3 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (107 mg, yield 30%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1C=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]3[N:28]=[C:29]([NH2:31])[N:30]=[C:26]3[N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.N1C=CC=CC=1.[OH-].[Na+].CN1[C:45](=[O:46])N(C)CC1>>[CH3:2][O:4][CH2:5][CH2:6][CH2:7][CH:8]([NH:11][C:45]([NH:31][C:29]1[N:30]=[C:26]2[N:25]=[CH:24][CH:23]=[C:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=3)[N:27]2[N:28]=1)=[O:46])[CH3:9]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCN(C)C1=O
Reactant: COc1ccc(-c2ccnc3nc(N)nn23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COCCCC(C)NC(=O)Nc1nc2nccc(-c3ccc(OC)cc3)n2n1
Temperature: 0 °C

Procedure:
4-nitrophenyl chloroformate (644 mg) was dissolved in DMI (26 ml). Thereafter, while stirring under cooling on ice, 7-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine (the compound obtained in Reference Example 8; 514 mg) and pyridine (347 μl) were added to the solution. The obtained mixture was stirred for 40 minutes under cooling on ice. Thereafter, 4-methoxy-1-methylpropylamine (500 mg) was added thereto, and the obtained mixture was stirred for 1 hour under cooling on ice. Subsequently, the reaction solution was stirred at a room temperature overnight. Thereafter, an ice block and an aqueous 3 M sodium hydroxide solution were added to the reaction solution, followed by extraction with methylene chloride. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under a reduced pressure. The obtained residual solution was further subjected to vacuum distillation to eliminate DMI. Thereafter, the distillation residue was dissolved in ethyl acetate (100 ml), and the organic layer was washed with 1 M hydrochloric acid (30 ml×4) and then dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with 0% to 20% methanol-containing ethyl acetate) to obtain the captioned compound (242 mg).