Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Solvent: C1CCOC1
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CN4CCCC4)cs3)c2[C@@H]2CCCN12
Reaction time: 96 h
Yield: 44 %

Procedure:
A solution of 1.3 g (0.0032mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 15 ml of tetrahydrofuran was treated with 4 ml (0.048 mol) of pyrrolidine and stirred at 50° for 96 hrs. All volatiles were removed in a water-jet vacuum and the residue was taken up with ethyl acetate and water. The organic phase was dried over magnesium sulphate, concentrated and the residue remaining was chromatographed over silica gel with methylene chloride/methanol 95:5 as the eluent. After recrystallization from ethyl acetate there was obtained 0.62 g (44%) of (S)-8-chloro-1-(4-pyrrolidin-1-ylmethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 213-214° and [α]D20 =-71.2° (MeOH, c=1%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[Cl:11].[S-2:12].[Na+].[Na+].[S]>O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:12][S:12][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[Cl:11])=[C:3]([Cl:11])[CH:4]=1
Reactant: [S-2]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [S]
Solvent: O
Product: Nc1ccc(SSc2ccc(N)cc2Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
76.8 g (0.4 mol) of 1,2-dichloro-4-nitrobenzene, suspended in 120 ml of water, were heated to 90° C. and treated with a solution of 62.4 g (0.8 mol) of sodium sulfide and 12.8 g (0.4 mol) of sulfur in 200 ml of water.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[N:11](CC2C=CC=CC=2)[C@@H:10]([C:19]([O:21]CC2C=CC=CC=2)=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([C@H:8]1[CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)N1
Yield: 94 %

Procedure:
267 mg (0.7 mmol) of stereochemically pure transor cis-N-benzylazetidine-2,4-dicarboxylic acid benzyl t-butyl ester, 50mg of 10% Pd/C, and 20 ml of methanol are hydrogenated under 3 atm of hydrogen in a Parr shaker for 4 hours. The catalyst is filtered off and thoroughly washed, and the solution evaporated to dryness and dried in vacuo to afford as off-white solids the trans- or cis-azetidine-2,4-dicarboxylic acid mono-t-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:11][CH3:12])[CH:5]=1.CCN(CC)CC.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=2[Cl:21])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(F)ccc2Cl)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A dry, 3-L, 3-necked, round-bottomed flask equipped with a thermometer and addition funnel was charged a solution of 33 (96 g, 0.53 mol, 1.0 equiv.) and Et3N (88 ml, 0.64 mol, 1.2 equiv.) in dichloromethane (1.2 L). The solution was cooled to 0° C. by an ice bath and 2-chloro-5-fluoro-benzoyl chloride (110 g, 0.57 mol, 1.05 equiv.) was added drop-wise over 40 min at 0° C. After the addition, the reaction mixture was stirred at 0° C. for further 1.5 h. The organic layer was washed with brine three times, dried over MgSO4, filtered, and evaporated to yield 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid methyl ester 34 as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.84 (s, 1H), 8.61 (d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.45 (dd, 1H), 7.20-7.13 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H). MS (ES) m/z 338.0 (MH)+.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=2)[N:12]=[C:11]([CH3:23])[CH:10]=1>C1(C)C=CC=CC=1>[CH3:5][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=2)[N:12]=[C:11]([CH3:23])[CH:10]=1
Reactant: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COc1cc(C)nc2ccc(NC(C)=O)cc12
Temperature: 25 °C

Procedure:
Dimethyl sulfate (294 g, 2.33 mol) was charged to a suspension of hydroxyquinoline 4 (287 g, 1.33 mol) in toluene (1.5 L) and the mixture was refluxed for 6 h. After cooling to ambient temperature, the resulting dark yellow solids were collected by filtration and washed with toluene. The dry solid was dissolved in water (2.5 L) and the pH adjusted to 14 using 35% aqueous NaOH (290 g). The resulting tan precipitate was collected by filtration, washed with copious amounts of water and dried in vacuo at 60° C. to give methoxyquinoline 5 as light tan solid (259 g, 85% yield); 1H NMR (DMSO) δ 10.18 (s, 1H), 8.46 (s, 1H), 7.76 (m, 2H), 6.84 (s, 1H), 3.99 (s, 3H), 2.55 (s, 3H), 2.09 (s, 3H); 13C NMR (DMSO) δ 168.36, 160.99, 158.07, 144.86, 135.87, 128.27, 122.78, 119.26, 108.80, 101.20, 55.69, 25.08, 23.97.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:16])=[C:11]([CH3:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:16])[CH2:7][C:6]([NH:17][C:18]([C:20]1[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=1)=[O:19])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cc(C)c(C)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1C)CC(NC(=O)c1cccc3c1CCCC3)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
The mixture of 5,6-dimethyl-2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (78) (438 mg, 1.11 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (79) as a pale brown solid (390 mg, 97%).
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:10]\[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)/[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]>CO>[CH3:9][O:8][C:6](=[O:7])[C@@H:5]([CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)/C(=C/c1ccc2ccccc2c1)NC(C)=O
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(C)=O
Reaction time: 2 h
Yield: 102.9 %

Procedure:
A solution of methyl (Z)-2acetamido-3-(2-naphthyl)propenoate (0.3 g, 1.11 mmol) and the catalyst (I) (7 mg, 0.011 mmol, 1.0 mol %) in degassed methanol (10 ml) was placed in a 50 ml Parr pressure reactor purged with nitrogen. The vessel was then purged with hydrogen (×3) and charged to 4.13 MPa (600 psi) of hydrogen. After stirring for 2 h, the solution was evaporated to give (R)-N-acetyl-3(2-naphthyl)alanine methyl ester (0.31 g, quantitative yield, 77.5% ee).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:20][O:19][B:18]([OH:21])[C:17]=2[CH:22]=1)(=[O:11])=[O:10].[N:23]([CH2:26][CH3:27])=[C:24]=[O:25]>CN(C=O)C.C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:20][O:19][B:18]([OH:21])[C:17]=3[CH:22]=2)(=[O:10])=[O:11])=[C:2]([NH:1][C:24]([NH:23][CH2:26][CH3:27])=[O:25])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(N)c1
Reactant: CCN=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
To a solution of 2,4-diamino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.0 g, 3.13 mmol) in DMF (15 ml) was added isocyanatoethane (0.5 g, 7.0 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with H2O, brine. The organic fraction was then dried (MgSO4) and concentrated in vacuo. The residue was purified by Prep-HPLC to give the title compound as a white powder (0.3 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.87 (s, 1H), 9.17 (s, 1H), 7.99 (s, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.12 (dd, J=2.0, 8.4 Hz, 1H), 7.02 (t, J=5.2 Hz, 1H), 6.08 (dd, J=2.0, 8.4 Hz, 1H), 5.88 (s, 2H), 4.87 (s, 2H), 3.04˜3.11 (m, 2H), 1.07 (t, J=7.2 Hz, 3H); MS (ESI) m/z=389 (M−1, negative); HPLC purity: 93.6% (MaxPlot 200-400 nm), 90.3% (220 nm).
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH2:15][CH2:14][CH:13]=[C:12]2[C:11](=[O:17])[NH:10][C:9](=[O:18])[CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.O1CCOCC1.[Pd]>[C:1]1([C@@:7]23[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:11](=[O:17])[NH:10][C:9](=[O:18])[CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1CC2(c3ccccc3)CCCC=C2C(=O)N1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C1C[C@]2(c3ccccc3)CCCC[C@H]2C(=O)N1

Procedure:
4a-Phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (3.0 g, 12.45 mmoles) from Ex. 1B was dissolved in 100 ml of glacial acetic acid and 50 ml of dioxane. The catalyst, 5% palladium on carbon (700 mg), was added and the mixture was hydrogenated under 40 psi of hydrogen for 24 hours in a Parr shaker. The catalyst was then filtered off and the filtrate evaporated. The white crystalline 4a-phenyl-1,3-diketo-trans-decahydroisoquinoline was recrystallized from ethanol, mp 180°-182.5°.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([N:27]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:28])(=[O:26])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[C:24]([N:27]([C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)[CH3:28])(=[O:26])[CH3:25]
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C([O-])(O)=O.[Na+].[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[NH:16][S:15](=[O:18])(=[O:17])[CH2:14][C:13]=2[CH:19]=1)([O-:8])=[O:7].I[CH3:21]>O>[CH3:21][N:16]1[C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:19][C:13]=2[CH2:14][S:15]1(=[O:18])=[O:17]
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2c(c1)CS(=O)(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1c2ccc([N+](=O)[O-])cc2CS1(=O)=O
Temperature: 80 °C
Yield: 62.3 %

Procedure:
NaHCO3 (0.2 g, 2.4 mmol) is dissolved in H2O (3 mL) and 5-Nitro-1,3-dihydro-2H-2,1-benzisothiazole-2,2-dione (1) (0.41 g, 1.9 mmol) is added with stirring. The mixture is heated to 80° C. for 0.5 hrs and a yellow solid formed. The mixture is cooled to 0° C. and filtered. The solid is washed with cold H2O (5 mL) then with cold EtOH (15 mL). The yellow solid thus obtained is dried under high vacuum then dissolved in dry DMF (3.5 mL). Iodomethane (0.15 mL, 2.1 mmol) is added and the solution heated to 100° C. for 2 hrs. The solution is cooled to room temperature then poured into ice water (50 mL). The solid is collected by filtration and gave crystals (0.27 g, 62%) after recrystallization from EtOH. Mp 214-6° C. HRMS (FAB) calcd for C8H8N2O4S +H1 229.0283, found 229.0280.
Reaction SMILES: C[Mg]Br.[CH2:4]1COCC1.[N:9]1[CH:10]=[CH:11][N:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]3[CH:40]=[CH:39][C:24]([O:25][C:26]4[N:30]([CH2:31][C:32](=[O:34])[CH3:33])[C:29]5[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=5[N:27]=4)=[CH:23][CH:22]=3)[C:13]=12.O>C1COCC1>[N:9]1[CH:10]=[CH:11][N:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]3[CH:22]=[CH:23][C:24]([O:25][C:26]4[N:30]([CH2:31][C:32]([CH3:4])([OH:34])[CH3:33])[C:29]5[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=5[N:27]=4)=[CH:39][CH:40]=3)[C:13]=12
Reactant: CC(=O)Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2ccccc21
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: O
Product: CC(C)(O)Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of cerium chloride(III) (296 mg) in THF (4 ml) was added dropwise 1 M methylmagnesium bromide-THF solution (1.2 ml) at −78° C. After stirring for 10 min, a solution of 1-{2-[4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenoxy]-1H-benzimidazol-1-yl}propan-2-one (338 mg) obtained in Example 10 in THF (20 ml) was added dropwise at −78° C., and the obtained mixture was warmed to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane/ethyl acetate), purified by HPLC (L-Column 2 ODS, 10 mM aqueous hydrogen carbonate ammonium-containing acetonitrile solution) and recrystallized from methanol/water to give the title compound (44.0 mg).
Reaction SMILES: Br[C:2](C)([C:6]1[C:7](=[C:11](C)[CH:12]=[CH:13][CH:14]=1)[C:8]([O-])=[O:9])C([O-])=O.[OH:17][C:18]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=1[C:20]#[N:21].C(N(CC)CC)C>C(#N)C.C(=O)(O)[O-].[Na+]>[CH3:27][O:26][C:23]1[CH:22]=[C:19]2[C:18](=[CH:25][CH:24]=1)[O:17][C:2]1[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8](=[O:9])[NH:21][C:20]2=1
Reactant: Cc1cccc(C(C)(Br)C(=O)[O-])c1C(=O)[O-]
Reactant: COc1ccc(O)c(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2oc3c4ccccc4c(=O)[nH]c3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
α-Bromodimethylhomophthalate (20a) (1.16 g) and 2-hydroxy-5-methoxy-benzonitrile (0.6 g, 4 mmol, 1 eq) were dissolved by warming in acetonitrile (6 mL). Triethylamine (5.6 mL, 10 eq) was then added and the reaction was heated at reflux for 48 h under inert atmosphere, then cooled to room temperature. The reaction mixture was diluted with saturated sodium bicarbonate (40 mL) and the resulting suspension was allowed to stir for 2 h, and was then filtered. The filtercake was washed sequentially with 1 N HCl (2×50 mL), acetonitrile (2×50 mL) and dichloromethane (50 mL), then dried in a vacuum oven at 50° C. fot three days to provide Compound 22a as an white solid. Yield=0.81 g (76%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]1[CH:13]([C:14]([OH:16])=[O:15])[C:12](=[O:17])[CH2:11][CH2:10][N:9]1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>C(O)(C)(C)C>[CH3:7][CH:8]1[C:13]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[Br:26])([C:14]([OH:16])=[O:15])[C:12](=[O:17])[CH2:11][CH2:10][N:9]1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1Br
Reactant: CC1C(C(=O)O)C(=O)CCN1C(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1N(C(=O)c2ccccc2)CCC(=O)C1(Cc1ccccc1Br)C(=O)O
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of potassium t-butoxide (16.8 g, 0.15 mol) in t-butanol (300 ml) was added methyl 1-benzoyl-4-oxo-3-piperidinecarboxylic acid (36.1 g, 0.146 mol) according to the method of G. Stork, J. Am. Chem. Soc. 68, 1053 (1946). The mixture was stirred 1 hour and 2-bromobenzyl bromide was added dropwise in a solution of t-butanol. The reaction was heated to reflux for 2 days, cooled and filtered. The salts were washed with ether and the organic filtrate was washed with 5% hydrochloric acid (100 ml), saturated sodium bicarbonate (100 ml), water (100 ml) and saturated sodium chloride (100 ml). The organic layer was dried (MgSO4), filtered, and concentrated to yield a crude oil. The material was recrystallized from isopropyl ether to yield a pale yellow solid (23.4 g, 37%) An additional recrystallization produced the title compound a white solid, mp 105°-107° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]1[CH2:8][CH2:7]1)=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C1C=CC=CC=1>CO>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:8][CH2:7][N:23]1[CH2:22][CH2:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)([OH:26])[CH2:25][CH2:24]1)=[O:5]
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccccc1Br)N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1Br

Procedure:
A mixture of 2.26 parts of 1-(2-bromobenzoyl)aziridine, 2.12 parts of 4-(4-chlorophenyl)-4-piperidinol, 10.8 parts of benzene and 0.8 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled and evaporated. The residue is crystallized from ethyl acetate. The product is filtered off and dried, yielding 2.5 parts of 2-bromo-N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]ethyl}benzamide; mp. 120.6° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].CCN(CC)CC.[NH2:27][CH2:28][CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:27][CH2:28][CH2:29][C:30]2[N:34]=[CH:33][NH:32][CH:31]=2)[N:14]=1)[C:11]#[N:12]
Reactant: NCCc1c[nH]cn1
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CC(c1ccnc(NCCc2c[nH]cn2)n1)c1nc2ccccc2s1
Temperature: 70 °C
Reaction time: 72 h
Yield: 37.2 %

Procedure:
To a suspension of 1 (0.1 g, 0.35 mmol) in dry EtOH (3 ml) was added Et3N (0.05 ml, 0.35 mmol) and histamine (0.078 g, 0.70 mmol). After sonication, the yellow solution was shaken at 70° C. for 3 days. The yellow precipitate formed was filtered off and washed with H2O (2×) then EtOH (3×) and dried under vacuum at 40° C., affording 47 mg (37%) of the title compound as a bright yellow powder: mp 257-258° C., 10 was taken up in a mixture of DCM/TFA. The yellow fluffy solid formed by addition of ether was filtered off, washed with ether (3×) then dried under vacuum at 40° C., affording 36 mg (29%) of the title compound as a yellow powder: mp 247-249° C., MS: 362.0 (M+1); HPLC (Conditions a, 265 nm): 98%, rt. 2.87 min; 1H NMR (DMSO-d6): δ 14.25 (br s, 2H, exchangeable), 11.05 (br s, 1H, exchangeable), 9.03 (s, 1H), 7.94-7.87 (m, 1H), 7.74-7.71 (m, 2H), 7.57-7.52 (m, 2H), 7.42-7.37 (m, 1H), 7.24-7.19 (m, 1H), 6.40 (d, J=7.1 Hz, 1H), 3.97-3.55 (m, 3H), 3.11-3.05 (m, 2H).
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.C1C=CC=CC=1.[C:13]1([CH3:19])[CH:18]=C[CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[C:3]1([CH3:5])[CH:18]=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:16])[CH:2]=1
Reactant: Cc1ccccc1
Reactant: OCC(O)CO
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: Cc1cc(C)cc(C)c1

Procedure:
Further, the insulating liquid can include a known liquid as the insulating liquid in addition to the fatty acid triglyceride as described above. Specifically, there can be cited silicone oil such as KF96, KF4701, KF965, KS602A, KS603, KS604, KF41, KF54, FA630 (produced by Shin-Etsu Chemical Co., Ltd.), TSF410, TSF433, TSF434, TSF451, TSF437 (produced by Momentive Performance Materials Inc.), or SH200 (produced by Dow Corning Toray Co., Ltd.), aliphatic hydrocarbon such as TSOPAR-E, ISOPAR-G, ISOPAR-H, ISOPAR-L (produced by Exxon Mobil Corp.), Cosmo White P-60, Cosmo White P-70, Cosmo White P-120 (produced by Cosmo Oil Lubricants Co., Ltd.), Dyna Freshia W-8, Daphne Oil CP, Daphne Oil KP, Transformer Oil H, Transformer Oil G, Transformer Oil A, Transformer Oil B, Transformer Oil S (produced by Idemitsu Kosan Co., Ltd.), Shellsol 70, Shellsol 71 (produced by Shell Oil Company, Ltd.), Amsco OMS, Amsco 460 solvent (produced by American Mineral Spirits Company, Ltd.), low-viscosity/high-viscosity liquid paraffins (produced by Waco Pure Chemical Industries, Ltd.), octane, isooctane, decane, isodecane, decalin, nonane, dodecane, isododecane, cyclohexane, cyclooctane, cyclodecane, a resolvent of the fatty acid triglyceride such as fatty acid monoglyceride, fatty acid diglyceride, glycerine, or a fatty acid, a synthetic esters liquid such as Prifer 6813 (produced by UNIQUEMA), benzene, toluene, xylene, mesitylene, fatty acid monoester, and so on, and one species or a combination of two or more species out of these compounds can be used.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=NO)[C:11]=2[CH:12]=1.CC(C)=[O:17]>Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]=2[CH:12]=1
Reactant: CC(C)=O
Reactant: COc1cc2c(cn1)CCCC2=NO
Agent: Cl
Product: COc1cc2c(cn1)CCCC2=O
Temperature: 25 °C

Procedure:
A solution of 3-methoxy-7,8-dihydro-5(6H)-isoquinolinone oxime (1.20 g, 6.25 mmol) in a mixture of acetone (40 ml) and 6M hydrochloric acid (27 ml) was refluxed for 4 h then allowed to cool to room temperature. The mixture was concentrated to remove acetone then basified with sodium carbonate and extracted four times with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated and the residue subjected to column chromatography (silica, ethyl acetate-hexane, 1:4) to afford the title compound (0.81 g) as a white solid m.p. 7981°. MS (ES+) 178 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)ccn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred room temperature solution of 4-bromo-2-methylpyridine (1.72 g, 10 mmol) in carbon tetrachloride at was added N-bromosuccinimide (1.9 g, 10.5 mmol). The mixture was warmed at 90° C. After 30 minutes, the mixture was cooled, and benzoyl peroxide (100 mg) was added and refluxing was continued. After 7 hours, the mixture was cooled to room temperature, washed with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 4-bromo-2-bromomethylpyridine as a brown oil [MS m/z 250/252/254 (MH+)] which was determined to be 75% pure and was used without further purification. The remaining material was determined to be 4-bromo-2-dibromomethylpyridine.