Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.O.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-c1ccc(C(F)(F)F)cc1
Yield: 43.4 %

Procedure:
To a solution of 2-bromo-1,3-dimethyl-5-nitrobenzene (2.7 g, 11.7 mmol) in toluene (36 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.36 g, 1.17 mmol), 4-(trifluoromethyl)phenylboronic acid (4.46 g, 23.5 mmol), and potassium fluoride hydrate (3.31 g, 43 mmol). The reaction was purged with nitrogen three times. Water (9 mL) was added and the reaction was refluxed overnight. The reaction was diluted with saturated ammonium chloride and the layers were separated. The organic layer was washed with water (3×40 mL) and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 2,6-dimethyl-4-nitro-4′-(trifluoromethyl)biphenyl (1.5 g, 43%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.99 (s, 2H), 7.75 (d, 2H), 7.26 (s, 1H), 7.25 (s, 1H), 2.10 (s, 6H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2)(=O)[CH3:2].[C:11](CC(O)=O)#[N:12].[OH-].[NH4+].[CH3:19]N(C)C=O>C1C=CC=CC=1>[C:11]([CH2:2][C:1](=[C:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2)[CH3:19])#[N:12]
Reactant: CN(C)C=O
Reactant: CC(=O)C1CC2C=CC1C2
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(CC#N)=C1CC2C=CC1C2
Yield: 31 %

Procedure:
A stirred solution of 100 g (0.72 mol) of 2-acetyl-5-norbornene (Aldrich Chemical Co.), 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide; and 170 ml of benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hr.). Upon completion the reaction was cooled and the solvent removed under reduced pressure. The residue oil was distilled under vacuum to give 36 g (31% yield) pf 2-(2-cyano-1-methylethylidene)-bicyclo[2.2.1]hept-5ene: b.p. 73-84° C/1 mm; ir 3060, 2255, 2225, 1450, 1420, 1330, 905, 730, 715: nmr 1.2-2.2 (m), 2m7-3.4 (m), 5.0-6.1 (m, vinylic H ); ms 159.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.C1(S([C:25]2[N:34]=[C:33]3[C:28]([C:29](=[O:48])[C:30]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:31][N:32]3[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:27][C:26]=2[F:49])(=O)=O)C=CC=CC=1.C(OCC)C>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:25]2[N:34]=[C:33]3[C:28]([C:29](=[O:48])[C:30]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:31][N:32]3[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:27][C:26]=2[F:49])[CH2:5]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)(=O)c3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 86.6 %

Procedure:
In 3 ml of ethanol was suspended 120 mg of 3-aminopyrrolidine dihydrochloride, and 250 mg of triethylamine was added thereto to form a solution. Subsequently, 300 mg of ethyl 7-benzenesulfonyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-caboxylate was added to the solution, and the resulting mixture was subjected to reaction at 45° to 50° C. for 4 hours. To the reaction mixture was added 10 ml of diethyl ether, and crystals were collected by filtration and washed with 12 ml of water to obtain 230 mg (yield 86.6%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 64.
Reaction SMILES: [H][H].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH2:12](O)[CH2:13][OH:14]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:4][C:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:14][CH2:13][CH2:12][O:5]1
Reactant: CC(=O)c1ccccc1
Reactant: OCCO
Reactant: [H][H]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC1(c2ccccc2)OCCO1

Procedure:
Utilising known reaction conditions compounds of Formula 1, where R and R1 are hydrogen or R is hydrogen and R1 is a C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, aryl or C1-8 alkylaryl fragment, readily catalyse the ketalisation of ketones. Standard conditions were used to conduct these reactions. For example heating under a Dean and Stark apparatus acetophenone and an excess of ethylene glycol in benzene or toluene in the presence of compounds of Formula 1 where R and R1 are hydrogen gave the desired product 2-methyl-2-phenyl-1,3-dioxolane in quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC(S(O)(=O)=[O:21])=CC=1.O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:21][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 95.9 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 46.2 g (0.24 mol) of p-chlorobenzenesulfonic acid (produced by Tokyo Chemical Industry Co., Ltd.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.8 g of 1-benzyl-3,4-epoxypyrrolidine (yield 95.9%) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH:8]=[C:9]([CH2:15][C:16](=[O:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][NH:5][N:4]=1)[CH3:2].[C:19]([O-:22])(=O)[CH3:20].[Na+].C([O-])(O)=O.[Na+].[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:5]1[C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][C:16]=2[O:18][C:19](=[O:22])[CH3:20])[C:3]([CH2:1][CH3:2])=[N:4]1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)C(=Cc1c[nH]nc1CC)CC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc(OC(C)=O)c2c(c1)c(CC)nn2C(C)=O
Temperature: 25 °C
Yield: 34 %

Procedure:
A solution of crude ethyl 2-[(3-ethyl-1H-pyrazol-4-yl)methylene]-4-oxopentanoate (4 g, 15.8 mmol) in acetic anhydride (10 mL), sodium acetate (2.6 g, 32 mmol) was added at room temperature and the mixture was heated at reflux for 4 h. The reaction mixture was cooled to room temperature, basified (pH ˜9) using aqueous NaHCO3 solution and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (25 mL), saturated aqueous NaCl (25 mL), dried over anhydrous Na2SO4 and concentrated to obtain the crude product; which was purified by column chromatography (60-120 mesh silica gel) using 2-3% ethyl acetate in pet-ether as eluents to afford ethyl 1-acetyl-7-(acetyloxy)-3-ethyl-1H-indazole-5-carboxylate (1.7 g, 34%) as brown solid. 1H NMR (CDCl3) δ 8.44 (s, 1H), 8.24 (s, 1H), 4.58 (q, 2H), 3.2 (s, 3H), 2.9 (s, 3H), 2.58 (s, 3H), 1.6 (t, 3H).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH2:5]([OH:7])[CH3:6].[Cl:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([Cl:17])[CH:10]=1>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([O:3][CH2:2][CH3:1])[C:14]([C:15]#[N:16])=[CH:13][N:12]=1.[Cl:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([O:7][CH2:5][CH3:6])[CH:10]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: CC[O-]
Reactant: CCO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(Cl)c(C#N)cn1
Product: CCOc1cc(Cl)ncc1C#N
Reaction time: 3 h
Yield: 6 %
Yield: 58 %

Procedure:
A solution of NaOEt in ethanol (1.93M, 18.8 mL, 36.3 mmol) was added over 10 minutes to a solution of 4,6-dichloro-nicotinonitrile (6.29 g, 36.3 mmol) in dimethylformamide (60 mL) at room temperature. The reaction was stirred for 3 hours, diluted with water (600 mL) and extracted with EtOAc (4×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (20% ethyl acetate/hexanes) to give the title compound as a white solid (3.82 g, 58%) and 4-chloro-6-ethoxy-nicotinonitrile (0.41 g, 6.0%) as a white solid.
Reaction SMILES: [Br:1]Br.CO[C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9](OC)[C:10]=1OC.O>C(O)C>[Br:1][CH2:16][C:15]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=1)=[O:17]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: BrBr
Solvent: CCO
Solvent: O
Product: O=C(CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Bromine (160 mg, 1 mmol) was added dropwise to a stirred solution of an 1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL) and the solution was stirred at 0° C. for 1 h and then poured into water to form a precipitate. This was recrystallized from ethanol to give bromoacetophenone (70%) and used directly for next step. A mixture of bromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol) in ethanol was refluxed for 1 h. The reaction mixture was concentrated in vacuo and purified with flash column to give 2i (167 mg, 51.1%). 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s, 1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([O-:8])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=2)[N:21]=1>C(Cl)(Cl)Cl>[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][C:24]([CH2:27][NH:28][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:25][CH:26]=2)[N:21]=1
Reactant: NCc1ccc(-c2csc(N)n2)s1
Reactant: COc1cc(C(=O)[O-])cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)NCc2ccc(-c3csc(N)n3)s2)cc(OC)c1OC
Reaction time: 4 h

Procedure:
To a solution of 5.4 g of 3,4,5-trimethoxybenzoate in 100 ml of chloroform is added 4.0 g of 2-amino-4-(5-aminomethyl-2-thienyl)thiazole under cooling with ice at -5° C. to 0° C., and stirred at 15° C. to 25° C. for 4 hours. After the resulting mixture is cooled with ice, the precipitated crystals are collected by filtration and recrystallized from methanol to give 2-amino-4-[5-(3,4,5-trimethoxybenzoylaminomethyl)-2-thienyl]thiazole, melting at 217° C. with decomposition.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.C1(S([S:24][CH2:25][CH:26]([N:38]([CH3:40])[CH3:39])[CH2:27][S:28]S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:13]([C:12]1([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)[S:28][CH2:27][CH:26]([N:38]([CH3:40])[CH3:39])[CH2:25][S:24]1)#[N:14]
Reactant: CN(C)C(CSS(=O)(=O)c1ccccc1)CSS(=O)(=O)c1ccccc1
Reactant: N#CCc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CN(C)C1CSC(C#N)(c2ccc(Cl)cc2)SC1
Reaction time: 4 h
Yield: 87 %

Procedure:
To 20 ml of chloroform were added 1.52 g (0.01 mole) of p-chlorophenylacetonitrile and 4.3 g (0.01 mole) of 1,3-bis(benzenesulfonylthio)-2-(N,N-dimethylamino)propane, and then 3.1 g (0.02 mole) of 1,8-diazabicyclo[5,4,0]undeca-7-ene was added thereto at room temperature. After completion of addition, the reaction was allowed to proceed at 40° C. for 4 hours. The reaction mixture was washed with two 20-ml portions of water, dried over anhydrous magnesium sulfate and concentrated to dryness. The crystals thus obtained were heated in 10 ml of toluene for dissolution and the solution was allowed to stand in the cold overnight. The resulting crystalline precipitate was collected by filtration to give 2.6 g (87%) of 2-cyano-2-(p-chlorophenyl)-5-(N,N-dimethylamino)-1,3-dithiane as light-yellow crystals melting at 110°-111° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[CH2:25][N:24]([CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36]
Reactant: CCOC(=O)c1onc(-c2ccncc2)c1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccncc2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
Ethyl 4-(bromomethyl)-3-(pyridin-4-yl)isoxazole-5-carboxylate (1.5 g, 4.82 mmol) was dissolved in 20 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (1.22 g, 4.82 mmol) and potassium carbonate (1.33 g, 9.65 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (100 mL) and water (100 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude was purified by flash chromatography (0-50% EtOAc/hexanes) to give 0.49 g of the title compound. MS: (+) m/z 484.48 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1)#[N:2].[Br:10][CH2:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:10][CH2:11][CH2:12][CH2:13][S:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(S)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(SCCCBr)cc1
Yield: 62.1 %

Procedure:
A mixture of 4-cyanothiophenol (20.8 g, 154 mmol), 1,3-dibromopropane (155 g, 0.77 mol) and K2CO3 (21.3 g, 154 mmol) in MeCN (300 mL) was refluxed overnight. Filtration and evaporation of the solvent gave a brown oil that crystallised when treated with EtOH. The crystals were isolated by filtration to give the sub-title compound (24.5 g, 62%).
Reaction SMILES: O.[CH:2]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](C=O)[C:4]=2[CH:3]=1.S(=O)(O)[O-:13].[Na+]>C(#N)C>[OH:13][C:5]12[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]1[CH2:3][CH2:2]2
Reactant: O=Cc1cccc2c1C=C2
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: OC12C=CC=CC1CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of the thus prepared permonophosphoric acid (18 mL, 1.2M) in acetonitrile was added to a flask equipped with ice bath, stirrer and water-cooled condenser. To the stirred solution was added 3-benzocyclobutene aldehyde (5 g, 0.037 moles) dropwise over a period of 30 minutes. The reaction mixture was stirred for an additional 2 hours and cooled to 0° C. Water (20 mL) was added to the cooled reaction mixture, followed by the addition of sodium bisulfite solution until the reaction mixture was free from permonophosphoric acid, as tested with starch iodide paper. The organic solvent was removed by rotary evaporation, and sodium hydroxide was added until the reaction mixture became alkaline. The reaction mixture was cooled to 0° C., acidified and extracted with ethyl acetate. The organic layer was washed with water, sodium bicarbonate and brine. Drying and removal of the solvent was followed by flash chromatography using 10 percent ethyl acetate in hexanes to afford 3.19 g 3-hydroxybenzocyclobutene as a solid. This represents a yield of approximately 70 percent. The 3-benzocyclobutene phenol was recrystallized from pentane. The 3-benzocyclobutene phenol product has a melting point of 47° C. Product analysis indicated substantially complete conversion of 3-benzocyclobutene aldehyde with the product, other than the desired 3-hydroxybenzocyclobutene, comprising unidentified polymer-like substance with substantially no formation of 3-benzocyclobutene carboxylic acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:10]([S:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=O)[CH2:11][CH3:12]>C(Cl)Cl.C(N(CC)CC)C>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:14][S:13][CH2:10][CH2:11][CH3:12]
Reactant: CCCSCC(=O)c1ccccc1O
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCSC=C(c1ncc[nH]1)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.02 g of imidazole, 1.52 g of triethylamine and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resulting mixture was stirred for 30 minutes, followed by addition of 2.42 g of 2-n-propylthio-2'-hydroxyacetophenone and a solution consisting of 1.16 g of triethylamine and 5 ml of dry methylene chloride. The reaction mixture was stirred at room temperature for further 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The organic, i.e., methylene chloride layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was dissolved in chloroform. The chloroform solution was subjected to chromatography on a silica gel column. Upon concentration of the resulting eluate, 0.2 g of Isomer A (Compound 19; m.p. 191°-192° C.) and 1.1 g of Isomer B (Compund 18; m.p. 127°-128° C.) of 1-(2-hydroxyphenyl)-1 -imidazolyl-2-n-propylthioethylene were obtained respectively as colorless crystals.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.O1CCC[CH2:20]1>>[ClH:1].[C:6](=[O:12])([O:7][CH2:8][CH2:14][NH:13][CH3:18])[O:5][CH2:2][CH3:20]
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Product: CCOC(=O)OCCNC
Product: Cl

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., ethyl 2-(methylamino)ethyl carbonate hydrochloride (1.10 g) obtained in Reference Example 14 was added. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 2.5 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine (1.44 g) synthesized by the method described in JP-A-63-146882, triethylamine (1.16 mL) and 4-dimethylaminopyridine (0.049 g) were added, and the mixture was stirred at 60° C. for 6 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1). Crystallization from diethyl ether gave the title compound (0.721 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:33]([Br:34])=[CH:32][C:31]([C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[Br:38]>C(#N)C>[Br:34][C:33]1[CH:32]=[C:31]([C:35](=[O:37])[CH3:36])[CH:30]=[C:29]([Br:38])[C:28]=1[O:27][CH2:26][CH2:25][CH2:24][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Br)c1
Yield: 58.7 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.0 mmol), K2CO3 (1.3 g), and 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone (2.65 g, 9.0 mmol) and acetonitrile (50 ml) was heated at reflux for 3 hours. At the end of the reaction, the solvent was evaporated and the residue was extracted into dichloromethane (150 ml). The insolubles were filtered off. The dichloromethane solution was concentrated down to an oil. The purification was done by flash chromatography on a silica gel column (SiO2, 47 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 600 ml). The material thus purified as a colorless oil, solidified on standing. Recrystallization from ethanol gave 1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone as white crystals (2.93 g, 57%), m.p.=102°-103° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([N:23]=[N+]=[N-])=[O:22])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[CH:8]=2)[N:3]=1.[CH2:28]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40]N)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][NH:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([N:14]([CH2:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[NH:11][C:10]3=[O:12])[CH2:15][CH3:16])=[CH:18][CH:19]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCc1nccn1Cc1ccccc1
Reactant: CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)N=[N+]=[N-])cc1
Product: CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCc2nccn2Cc2ccccc2)cc1
Yield: 21 %

Procedure:
Using the process described in Example 5, p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-ethylamino]benzoyl azide was reacted with (1-benzylimidazol-2-yl)methylamine to give N-(1-benzylimidazol-2-yl)methyl-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-ethylamino]benzamide (containing 1.3 equivalents of water) in 21% yield, m.p. 217°-221° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:22]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl N-(piperidin-4-yl)carbamate (2 g, 9.99 mmol, 1.20 equip), dichloromethane (20 mL) and triethylamine (2.53 g, 25.00 mmol, 3.00 equip). To the resulting mixture was then slowly added benzoyl chloride (1.17 g, 8.32 mmol, 1.00 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum to yield tert-butyl N-(1-benzoylpiperidin-4-yl)carbamate as a white solid. (ES, m/z) 305 [M+H]+