Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1>N1C=CC=CC=1>[CH:31]1([CH2:30][O:29][C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])(=[O:14])=[O:15])([CH3:21])[CH3:20])=[O:18])[CH2:33][CH2:32]1
Reactant: OCC1CC1
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C(=O)OCC1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that described in Example 2, paragraph (c), by reacting (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride and hydroxymethylcyclopropane in pyridine there was obtained benzyl rac-α-[[[1-[(cyclopropylmethoxy)carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil; MS: 459 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])O.[Na+].[CH:16](B1OC(C)(C)C(C)(C)O1)=[CH2:17]>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.O.O1CCOCC1>[CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])=[CH2:17]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccccc1C(C)=O
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
A solution of 2′-bromoacetophenone (1.6 mL, 12 mmol), sodium hydrogencarbonate (2.5 g, 30 mmol), vinylboronic acid pinacol ester (3.0 mL, 18 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.60 mmol) in a mixed solvent (50 mL), which consists of water and 1,4-dioxane (1:4), was stirred at 95° C. for 2.5 hours. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate. After the organic layer was filtered with celite and the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (1.2 g) as an orange oil (Yield 69%).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16].[OH-].[Na+]>O(C(C)C)C(C)C>[Br:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CN(C)Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: CC(C)(Cc1c[nH]c2ccc(Br)cc12)[N+](=O)[O-]

Procedure:
5-Bromogramine, 60.0 g., 165 g. of 2-nitropropane, and 10.5 g. of sodium hydroxide pellets were caused to react under the conditions of Procedure 10C. The product was recovered as a dark syrup-like liquid from which the crystalline product was obtained by dissolving in i-Pr2O. The crystalline material was recrystallized from i-Pr2O to yield 48.6 g. of tan crystalline product, m.p. 106°-109°. The structure was confirmed by examination of the NMR spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C.[ClH:10]>CO>[Cl:10][C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1
Reactant: Cl
Reactant: Cc1ccc(O)cn1
Solvent: CO
Product: Cc1ccc(O)c(Cl)n1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
5-Hydroxy-2-methylpyridine (1-014-01) (27.01 g) was dissolved in conc. hydrochloric acid (200 mL) and to the reaction mixture was bubbled chlorine gas at 68 to 74° C. After the reaction mixture was stood overnight, the volatile was removed by bubbling nitrogen gas. The reaction mixture was evaporated under reduced pressure to give the crystal residue. The crystal residue was dissolved in methanol, and treated with active charcoal. After recrystallization, the desired 2-chloro-3-hyroxy-6-methylpyridine (1-014-02) (23.96 g, 67.3%) was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]2=[O:38])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=[O:38])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:43][CH:42]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C1C(S(=O)(=O)c2ccc(F)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Temperature: 100 °C

Procedure:
A Mixture of 3-(4-fluoro-benzenesulfonyl)-1-trityloxy-azepan-2-one prepared from step F (18.9 mg, 0.0357 mmol), 4-methoxy-phenol (19.2 mg, 0.154 mmol) and K2CO3 (38.1 mg, 0.275 mmol) in anhydrous DMA (1.5 mL) was stirred and heated at 100° C. for overnight. The reaction mixture was diluted with EtOAc and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜25% EtOAc in hexane). MS: 656.5 (M+Na)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)c1cccc(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1cccc(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of methyl 4-(6-(dibutylcarbamoyl)pyridin-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (158 mg, 0.30 mmol) in THF (2.0 mL) and MeOH (2.0 mL) was added 2N NaOH (1.5 mL, 3.00 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. At 0° C., the reaction mixture was neutralized to pH 4-5 with 1N HCl. The solution was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (146 mg, 95%). MS(ESI+) m/z 514.4 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[C:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>CCCCC>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:15](=[O:17])[CH3:16])[CH2:23][CH2:22]1)=[O:25]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1OC
Temperature: 100 °C

Procedure:
To a rapidly stirred slurry of aluminum chloride (1.1 g, 8.2 mmol) and 1,2-dimethoxybenzene (3.5 mL) at ambient temperature was added 1-acetylpiperidine-4-carbonyl chloride (0.8 g, 4.2 mmol). The reaction mixture was heated at reflux (100° C.) for 1.5 hours and then poured into 30 mL of ice water, the mixture was extracted with DCM (50 mL) and the organic layer was washed with water and dried over Na2SO4. The solvent was removed in vacuo to give an oil. Trituration of the oil with pentane gave the title product (0.88 g, 2.87 mmol) as a white solid. MS (ESI) m/z 292.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 0.86 min.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:9]=[C:10]([C:14]2[C:15](=[O:26])[C:16]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:32]O>>[CH3:32][O:6][C:5]([C:8]1[CH:9]=[C:10]([C:14]2[C:15](=[O:26])[C:16]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: Cn1cc(-c2cccc(C(=O)O)c2)c(=O)c(-n2cccn2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(-c2cn(C)cc(-n3cccn3)c2=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
24 ml (0.33 mole) of thionyl chloride are added dropwise to 30 g (0.09 mole) of 5-(3-carboxyphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone-sulphuric acid adduct in 100 ml of methanol at 0° C. to 10° C.; when the addition has ended, the mixture is stirred at room temperature for 12 hours and concentrated in vacuo, the oil which remains is taken up in 100 ml of water and the mixture is rendered weakly alkaline with aqueous sodium carbonate solution and extracted three times with 100 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulphate and concentrated in vacuo. The crystals which remain are digested with ether, filtered off with suction and dried. 20 g (91% of theory) of 5-(3-methoxycarbonylphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone of melting point 144° C. are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OB(O)c1ccoc1
Product: O=[N+]([O-])c1cccc(Cc2ccoc2)c1
Yield: 84 %

Procedure:
Using the same method as in Example 19-(ii), 3-furanboronic acid was reacted with the 3-nitrobenzyl bromide to give 3-(3-nitrobenzyl)furan (yield: 84%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1.N1C=CC=CC=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>ClC(Cl)C>[F:19][C:2]([F:18])([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: FC(F)(F)Oc1cccc(NCc2cccnc2)c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-trifluoromethoxyphenyl)pyrid-3-ylmethylamine(0.270 g, 1 mmol) and pyridine were dissolved in dichloroethane (2 ml). The solution was cooled in an ice-bath. To the solution was added 2,2,2-trifluoroethylsulfonyl chloride (0.274 g, 1.5 mmol). The mixture was stirred at room temperature overnight. Upon removing solvent, the residue was dissolved in water and extracted with EtOAc. The organic phase was washed with brine concentrated. The residue was chromatographed to afford the title compound. 1H NMR: 8.42 (d,1H,J=6.4 Hz), 8.20 (d,1H,J=2.0 Hz), 7.57 (d,1H,J=9.8 Hz), 7.40-6.85 (m,5H), 4.81 (s,2H), 3.72 (q,2H, J=7.8 Hz). MS calcd 414.1; MS (M+1) 415.1.
Reaction SMILES: Br[C:2]1C=C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)C(OC)=N[CH:7]=1.Cl[CH2:25][C:26]([N:28]1CC[CH2:31][C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)=[O:27]>>[C:26]([N:28]1[CH2:31][CH:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)(=[O:27])/[CH:25]=[CH:2]/[CH3:7]
Reactant: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Product: C/C=C/C(=O)N1CC(Nc2cc(-c3ccncc3)c[nH]c2=O)C1

Procedure:
Following Example 1, but using tert-butyl 3-aminoazetidine-1-carboxylate (Example 1 Step 3) and reaction with (E)-but-2-enoyl chloride (Example 1 Step 6) provided the desired compound after purification: 1H NMR (300 MHz, DMSO-d6) 11.83 (br s, 1H), 8.52 (d, J=5.7 Hz, 2H), 7.61 (d, J=5.7 Hz, 2H), 7.25-7.35 (m, 1H), 6.55-6.75 (m, 1H), 6.49 (d, J=2.1 Hz, 1H), 6.26 (d, J=6.6 Hz, 1H), 6.01 (dd, J=15.2, 1.7 Hz, 1H), 4.45-4.65 (m, 1H), 4.20-4.40 (m, 2H), 4.07 (dd, J=8.6, 4.7 Hz, 1H), 3.87 (dd, J=9.9, 4.8 Hz, 1H), 1.82 (dd, J=6.6, 1.5 Hz, 3H); MS (ES) m/z 311 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH3:27])([O-:26])=[O:25]>CO>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]=[CH:27][N+:24]([O-:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1[nH]c2ccccc2c1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: O=[N+]([O-])C=Cc1[nH]c2ccccc2c1Cc1ccccc1

Procedure:
A mixture of 3-benzyl-2-indolecarbaldehyde (7.06 g), ammonium acetate (462 mg) and nitromethane (10.5 ml) in methanol (30 ml) was refluxed for 2 hours. After cooling, precipitates formed were collected and washed two times with chilled methanol (5 ml) to give 3-benzyl-2-(2-nitrovinyl)indole.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([F:31])=[CH:33][C:34]=3[C:40]([F:42])([F:41])[F:43])[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(F)cc2C(F)(F)F)c1=O
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 4-fluoro-2-trifluoromethylbenzyl bromide (455 mg, 1.77 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from hexane gave the title compound (184 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.11 (br. s., 1 H), 7.67 (dd, J=9.09, 2.78 Hz, 1 H), 7.45 (ddd, J=8.40, 2.65 Hz, 1 H), 7.29 (dd, J=8.59, 5.31 Hz, 1 H), 5.13 (s, 2 H), 4.64 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.53-1.73 (m, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.10 (q, J=12.63 Hz, 1 H)
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.[Cl:16][CH:17](Cl)C>>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:17][Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCO)c1ccccc1
Reactant: CC(Cl)Cl
Agent: C=O
Agent: Cl
Product: O=C(OCCOCCl)c1ccccc1
Reaction time: 3 h

Procedure:
A cold (0° C.) mixture of ethylene glycol monobenzoate (166g) and paraformaldehyde (30g) in dry dichloroethane was saturated with dry HCl with stirring for 3 hours. The pinkish red li1uid was dried over calcium chloride and the volatile components removed on a rotary evaporator at 30° C. to give 1-benzoyloxy-2-chloromethoxyethane (215g). The Infra-Red spectrum indicated the absence of a hydroxyl group.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=[CH:15][CH:14]=1>ClCCl>[CH3:12][C:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N+:16]([O-:6])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc2c1CCCC2
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c2c1CCCC2
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A stirred suspension of 3-chloroperoxybenzoic acid (34 g, 197 mmol) in dichloromethane (170 ml) at 0° was treated dropwise with 5,6,7,8-tetrahydro-4-methylquinoline (23.7 g, 161 mmol) in dichloromethane (30 ml), warmed to room temperature, washed with lN-NaOH (3×200 ml), and extracted with dichloromethane (5×150 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give the product (21 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35]([OH:37])=O)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH2:42]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35](=[O:37])[NH:42][CH2:41][C:40]([O:39][CH3:38])=[O:43])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)CN
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Product: COC(=O)CNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 76 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with glycine methyl ester to give 4-(6-bromonaphth-2-ylsulphonyl)-2-[N-(methoxycarbonylmethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 76% yield as a glass;
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(-c3ccccc3)onc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2c(-c3ccccc3)onc12
Yield: 78.1 %

Procedure:
A solution of 23.5 g (0.112 mole) of 7-methyl-3-phenyl-2,1-benzisoxazole in 400 ml of carbon tetrachloride was treated with 20.0 g (0.112 mole) of N-bromosuccinimide and the mixture was heated at reflux with a white light lamp until all solid floated in the solvent. The mixture was filtered and the filtrate deposited a 15 g crop of reasonably pure product. This 15 g of material was dissolved in methylene chloride and washed with diluted sodium hydroxide to remove succinimide. The organic solution was concentrated and the residue was crystallized from isopropanol to give 25.2 g (77%) of yellow needles, m.p. 125.0°-125.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CC(C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and isopropylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.57 Hz, 6H) 2.44 (s, 3H) 4.13 (dd, J=14.15, 6.57 Hz, 1H) 7.66 (dd, J=8.08, 1.52 Hz, 1H) 7.74 (s, 1H) 7.75-7.85 (m, 1H) 8.07-8.28 (m, 1H) 8.45 (dd, J=19.70, 6.82 Hz, 3H) 8.84-8.98 (m, 1H) 12.97-13.37 (m, 1H). MS m/z [M+H]+ 362.2.
Reaction SMILES: C([N:4]([CH:7]([CH3:9])C)[CH2:5][CH3:6])(C)C.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C:18]([N:4]1[CH2:5][CH2:6][CH:12]([CH2:11][CH2:10][OH:17])[CH2:9][CH2:7]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Temperature: 0 °C

Procedure:
A solution of 3-1 (Aldrich) (25 g, 0.94 mol) in THF (400 mL) was treated with diisopropylethylamine (67 mL, 0.388 mol) and cooled to 0° C. under argon. Benzylchloroformate (27.6 mL, 0.194 mol) was added and the reaction was allowed to warm to room temperature. The reaction was concentrated, the residue was diluted with Et2O (300 mL), washed with water, 10% KHSO4 solution and brine, dried (MgSO4), filtered and evaporated to give 3-2 as an oil. Rf (35% EtOAc/Hexanes) 0.08 1H NMR (300 MHz, CDCl3) δ 7.38 (s, 5H), 5.13 (s, 2H), 4.18 (b, 2H), 3.7 (dd, 2H), 2.8 (bt, 2H), 1.78 (bd, 2H), 1.5 (m, 2H), 1.4 (m, 1H), 1.2 (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[CH:16][S:17][C:18]=1[NH2:19])=[O:13])[CH3:10]>C(#N)C.CCOC(C)=O>[NH2:19][C:18]1[S:17][C:16]([Br:1])=[N:15][C:14]=1[C:12]([O:11][CH2:9][CH3:10])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncsc1N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Br)sc1N
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
N-Bromosuccinimide (0.54 g, 3.03 mmol) was added to a solution of 5-aminothiazole-4-carboxylic acid ethyl ester (0.44 g, 2.53 mmol) [prepared according to the procedure described by Golankiewicz et al. (Tetrahedron, 41 (24), 5989-5994 (1985))] in acetonitrile (10 mL), and the mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with 5% K2CO3 aq. solution (25 mL) followed by brine (25mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluted with 15% EtOAc in hexane to give 0.37 g (58% yield) of the titled compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1)(=[O:15])=[O:14]>C(Cl)Cl.C(OCC)(=O)C>[CH3:12][S:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:25])=[O:6])[N:19]=1)(=[O:14])=[O:15]
Reactant: CSc1nccc(COS(C)(=O)=O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1nccc(COS(C)(=O)=O)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
m-Chloroperoxybenzoic acid (75%, 2.4 g, 10 mmol) was added to a solution of 4-methanesulfonyloxymethyl-2-methylthiopyrimidine (2.4 g, 10 mmol, Reference Compound No. 8-2) in anhydrous methylene chloride (30 mL) and the mixture was stirred for 15 minutes under ice-cooling. m-Chloroperoxybenzoic acid (0.29 g, 1.3 mmol) was added thereto and the whole was stirred for 10 minutes under ice-cooling. The reaction mixture was diluted with ethyl acetate (100 mL), washed twice with saturated aqueous sodium hydrogencarbonate solution (30 mL), and then washed with brine (30 mL). The aqueous layer was extracted twice with chloroform (100 mL), then the extract was mixed with the ethyl acetate layer, and the whole was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give 2.2 g of the title Reference Compound as a colorless oil (Yield: 88%).