Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[I:6][C:7]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:9]([CH:10]=O)[C:8]=1[OH:19].C(N(CC)CC)C>C(Cl)Cl>[O:3]=[S:1]1(=[O:4])[N:2]=[CH:10][C:9]2[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=[C:7]([I:6])[C:8]=2[O:19]1
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(I)c(O)c(C=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Temperature: 20 °C
Yield: 13.7 %

Procedure:
To a solution of sulfamoyl chloride (13.8 g, 0.12 mole) in anhydrous methylene chloride (75 ml) is added a solution of 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (6 g., 0.02 mole) and triethylamine (12.1 g, 0.12 mole) in anhydrous methylene chloride (100 ml.) dropwise with stirring at 20° C. Upon completing the addition, the resulting reaction mixture is stirred at 20° C. for 3 days. Removal of the solvent in vacuo leaves a tacky residue which is partitioned between ether and 2 N hydrochloric acid. After separating the phases, the organic phase is washed with water and saturated brime, dried over sodium sulfate and filtered. Evaporation of the filtrate leaves an oily residue (6 g.) which is chromatographed on silica gel (300 g.) with benzene. Elution with benzene (840 ml.) gives recovered 3-iodo-5-(1,1-dimethylethyl)salicylaldehyde (2.2 g., 37% recovery), m.p. 76°-78° C. Continued elution with benzene (500 ml.) provides an impure solid (2.4 g.) which is triturated with hexane (20 ml.) and filtered to afford the title compound as a pale yellow solid (1.0 g, 14%), m.p. 130°-134° C. Crystallization from hexane benzene (9.1; viv) gives an analytical sample of 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine, m.p. 135°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.S(Cl)(Cl)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: c1c[nH]cn1
Solvent: O=S(Cl)Cl
Product: Brc1ccc2c(c1)CCC=C2n1ccnc1

Procedure:
Analogously to Example 1, 2.25 g of 6-bromo-1-tetralone are reacted with 1.36 g of imidazole and 0.873 ml of thionyl chloride, yielding the title compound, which is purified by column chromatography (SiO2, hexane/ethyl acetate 9:1 to 1:1) and crystallisation from hexane/ether; m.p. 58°-64°, 1H-NMR (CDCl3): δ (ppm)=0.43 (m, 2H), 2.9 (m, 2H), 6.12 (t, 2H), 6.63 (d, 1H), 7.02 (d, 1H), 7.18 (d, 1H), 7.28 (dd, 1H), 7.36 (d, 1H), 7.61 (s, 1H).
Reaction SMILES: [Cl-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]([CH3:5])=[O:4].[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3[CH:40]=O)[C:30]=2[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[C:31]2[C:32](=[O:43])[N:33]([CH3:42])[CH2:34][C:35]3[N:36]([CH:37]=[N:38][C:39]=3/[CH:40]=[CH:2]/[C:3](=[O:4])[CH3:5])[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1Cc2c(C=O)ncn2-c2cccc(Cl)c2C1=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)/C=C/c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.3 g (29 mmol) of acetonyltriphenylphosphonium chloride are suspended in 100 ml of tetrahydrofuran under argon. 3.3 g (29.4 mmol) of potassium tert.-butylate was added thereto and the mixture was thereafter stirred at room temperature for a further 30 minutes. After cooling to 10° 4.0 g (14.5 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde was added thereto and the mixture was stirred at 20° for 1 hour and under reflux for 6 hours. The reaction mixture was evaporated, the residue was partitioned between methylene chloride and water, the organic phase was washed with water and subsequently dried over magnesium sulphate, filtered and evaporated. After chromatography of the residue on silica gel with methylene chloride/ethyl acetate (8:2, 7:3 and 1:1) and subsequent recrystallization of the combined pure fractions from ethyl acetate/hexane there was obtained 7-chloro-4,5-dihydro-3-[(E)-3-oxo-1-butenyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals of melting point 235°-237°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([OH:21])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reaction time: 4 h

Procedure:
A mixture of 1-(2-tetrahydropyranyloxy)-4-hydroxy-5-(4-fluorophenoxy)-trans-2-pentene (23.6 g., 0.08 mole), acetic anhydride (9.2 g., 0.09 mole), and pyridine (7.9 g., 0.1 mole) is heated at 55°-60° for 4 hours and then at 95° for an additional 4 hours. The solution is cooled, diluted with ether and washed with ice-cold saturated sodium carbonate solution, ice water (3 ×) and brine, and dried over sodium sulfate. Removal of solvent under vacuum leaves the title compound as a residual orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cc(CO)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine*.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Si:17]([O:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A solution containing 3 g (18 mmol) of 4-nitrophenethyl alcohol, 5.2 ml (20 mmol) of tert-butylchlorodiphenylsilane, 3.05 g (45 mmol) of imidazole and 438 mg (3.5 mmol) of N,N-dimethylaminopyridine in dimethylformamide (20 ml) was stirred under a nitrogen atmosphere at room temperature for 3 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (40 ml) and 2M hydrochloric acid (40 ml). The ethyl acetate layer was separated, washed with saturated aqueous sodium bicarbonate (40 ml), dried over magnesium sulfate, filtered and evaporated to give 6.56 g of 4-[2-(tert-butyldiphenylsilyloxy) ethyl]nitrobenzene as a yellow gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.500 g, 2.67 mmol) in DCM (6.7 mL) was cooled to 0° C. and charged with triethylamine (0.45 mL, 3.20 mmol), methanesulfonyl chloride (0.23 mL, 2.90 mmol), and 4-dimethylaminopyridine (3.0 mg, 0.03 mmol) and stirred at rt for 6 h. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3 and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a pale yellow oil. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 2.06-2.39 (m, 2H), 3.05 (s, 3H), 3.38-3.82 (m, 4H), 5.27 (t, J=4.4 Hz, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]([N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:27]=2)=[CH:22][C:21]1=[O:39])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.Cl>C(Cl)(Cl)Cl.O1CCOCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]([N:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[N:27]=3)=[CH:22][C:21]2=[O:39])[CH2:10][CH2:9][OH:8])=[CH:13][C:14]=1[F:19]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@H](CCO)c1ccc(Cl)c(F)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
(R)-1-(3-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.056 g, 0.098 mmol) was dissolved in chloroform (1 mL), and 4M HCl in dioxane was added. After agitating for 30 minutes, the mixture was evaporated and dried in vacuo to give (R)-1-(1-(4-chloro-3-fluorophenyl)-3-hydroxypropyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.045 g, 0.098 mmol, quantitative yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=5.0 Hz, 1H), 8.37 (d, J=5.0 Hz, 1H), 7.42 (t, J=5.0 Hz, 1H), 7.36 (s, 1H), 7.28-7.10 (m, 4H), 6.77 (d, J=5.0 Hz, 1H), 6.45 (m, 1H), 4.25 (br s, 1H), 4.20-4.00 (m, 2H), 3.80-3.42 (m, 9H), 2.55 (m, 1H), 2.20 (m, 1H), 2.02 (m, 2H), 1.82 (m, 2H); m/z (APCI-pos) M+1=459.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)[CH:8]=2)[N:3]=1.[Cl-].[OH:34][NH3+:35]>CO.N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:35][OH:34])[CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cccc(C(=NO)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
To a solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.090 g, 0.213 mmol, prepared as Example 15, Step 1) in MeOH (4.0 mL) was added hydroxyammonium chloride (0.044 mL, 1.063 mmol) followed by 3 drops of pyridine. The reaction mixture was brought up to reflux for 41 h until the conversion was completed, determined by LCMS. The reaction mixture was cooled to RT and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone oxime as a off-white solid. MS (ESI, pos. ion) m/z: 439 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:12][CH3:13])=[O:3].[C:14]([O:19][CH2:20]C)(=[O:18])[C:15]([O-])=[O:16].C[O-].[Na+:24].[Na]>CO.CCOCC>[Na+:24].[CH3:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=1[C:2]([O-:3])=[CH:1][C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: COc1cccc(OC)c1C(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 8 h

Procedure:
A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyl oxalate in 520 ml of anhydrous MeOH is added slowly to a solution of sodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrous MeOH. The reaction mixture is heated to reflux for 7 hours and left overnight at RT. It is poured into 2 liters of iso ether and left stirring for minutes. The expected product is obtained by filtration, washing with iso ether and drying under vacuum, m=120 g, m.p.=178° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)[N:9]2[C:23]=1[CH3:24])=[O:5])C.O.Cl>[OH-].[K+]>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:14]=3)[N:9]2[C:23]=1[CH3:24])([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(S(C)(=O)=O)ccc3n2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)nc2c(=O)[nH]c3cc(S(C)(=O)=O)ccc3n12
Temperature: 80 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
A suspension of 2-ethoxycarbonyl-1-methyl-7-methylsulfonylimidazo[1,2-a]quinoxalin-4(5H)-one (430 mg, 1.23 mmol) in 2M potassium hydroxide (15 ml) was stirred at 80° C. for 6 h. The reaction mixture was added water (10 ml) and pH adjusted to pH 7 with 1N hydrochloride acid. The precipitate was filtered off and washed with water to give 100 mg (25%) of the title compound as the potassium salt. M.p. 228° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.00 g (3.46 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-yl)butyl]thiazolidine-2,4-dione and 0.31 ml (3.46 mmol) of n-butyraldehyde in 25 ml of ethanol, 0.03 ml (0.35 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.08 g (90.8%, light yellow oily substance) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].N1CCCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]2[CH2:15][CH2:16][CH2:13][CH2:12]2)=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1Cl)N1CCCC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
4-Bromo-2-chloro-benzoic acid (30 g, 127.4 mmol) was placed in a 3 L round bottom flask and 1.5 L of EtOAc was transferred into it. Triethylamine (25.8 g, 255 mmol), pyrrolidine (18 g, 255 mmol), and T3P (48.6 g, 152.9 mmol, 50 wt % in EtOAc) were then added. After 1 hr, the reaction was quenched with 200 mL of 1N NaOH and stirred for 10 min. The layers were separated and after 2 more extractions of the aqueous phase with EtOAc (2×500 ml), the combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a viscous oil. Flash chromatography using a 330 g ISCO™ column and 50%, 80% EtOAc/Hexanes yielded the title compound as a light yellow colored viscous oil (35.4 g. 96% yield) Rf=0.25 (50% EtOAc/Hexanes), LRMS m/z Calcd for C11H11BrClNO, 288.6, found, 289.9 (M+H) APCI; 1H-NMR (CDCl3) δ 7.56 (d, J=1.7 Hz, 1H), 7.43 (dd, J=1.7, 8.3 Hz, 1H) 7.17 (d, J=8.3 Hz, 1H), 3.63 (b apt t, J=6.6 Hz, 2H), 3.17 (B apt t, J=6.6 Hz, 2H), 2.00-1.84 (m, 4H). 13C-NMR (CDCl3) δ 166.0, 13.6, 132.6, 131.3, 130.7, 128.9, 123.3, 48.0, 45.8, 261, 24.7.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[O:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]=1[C:12]([C:14]1[CH:15]=[C:16]([Br:22])[C:17]([OH:21])=[C:18]([Br:20])[CH:19]=1)=[O:13].C1COCC1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>C([O-])(O)=O.[Na+]>[Br:22][C:16]1[CH:15]=[C:14]([C:12]([C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:3]=2[CH2:2][CH3:1])=[O:13])[CH:19]=[C:18]([Br:20])[C:17]=1[O:21][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCc1oc2ccccc2c1C(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1oc2ccccc2c1C(=O)c1cc(Br)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(Br)c1
Reaction time: 18 h
Yield: 39.1 %

Procedure:
At ambient temperature, to a stirred solution of commercial benzbromarone (0.243 g, 0.574 mmol) in 0.5M aq. NaHCO3:THF (8 mnL; 1:1) was added portionwise 4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g, 1.15 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After the addition was complete the reaction was stirred for 18 h. To the reaction was added 4-chlorosulphonyl-2-hydroxybenzoic acid (0.271 g, 1.15 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After 2 h, the reaction was quenched with 2N HCl (25 mL), extracted with EtOAc and concentrated. The crude product was purified by preparative HPLC (C18, eluting with 75% CH3CN/H2O containing 0.1% TFA) and crystallized from EtOAc/hexane to give 0.14 g (39%) of the title compound as a white solid, mp 173° C.; 1H NMR (DMSO-d6) δ1.25 (t, 3H), 2.76 (q, 2H), 7.30 (dt, 1H), 7.36 (dt, 1H), 7.44-7.49 (m, 3H), 7.66 (d, 1H), 8.03 (d, 1H), 8.08 (s, 2H). IR (KBr) 3400, 2950, 1680, 1650, 1400 and 1180 cm−1. mass spectrum (−ESI), m/z 621/623/625 (M−H). Anal. Calcd. for C24H16Br2O8S: C, 46.18; H, 2.58; N, 0.00. Found: C, 46.41; H, 2.64; N, 0.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:30][CH:29]=[CH2:28])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:20][CH:21]=1
Reactant: C=CCBr
Reactant: COc1ccc(C(=O)c2oc3cccc(O)c3c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2oc(C(=O)c3ccc(OC)cc3)c(C)c12

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran (0.60 gm; 2.2 mmoles), potassium carbonate (0.83 gm; 6.0 mmoles) and allyl bromide (0.73 gm; 6.0 mmoles) in acetone (25 mL) was refluxed for a period of 22 hours. The reaction mixture was cooled, filtered through Celite, and concentrated in vacuo. The residue was chromatographed on silica gel using 15% ethylacetate in hexane as eluent to yield 2-(p-methoxybenzoyl)-3-methyl-4-allyloxybenzofuran.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:13]=1)=[O:11].C(N(CC)CC)C.[C:36](Cl)(=[O:39])[O:37][CH3:38]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][N:25]([C:36]([O:37][CH3:38])=[O:39])[CH2:24]2)[CH:13]=1)=[O:11]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1cn([C@H]2CCNC2)c2ncccc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](n2cc(C(=O)Nc3c(Cl)cncc3Cl)c(=O)c3cccnc32)C1
Reaction time: 0.67 h
Yield: 88 %

Procedure:
Then, to a 4 ml anhydrous methylene chloride solution of (S)-N-(3,5-dichloropyridin-4-yl)-1-(3-pyrrolidyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide hydrochloride, 43.6 μl (0.31 mmol) of triethylamine and 9.7 μl (0.125 mmol) of methyl chlorocarbonate were added at room temperature and stirred for 40 minutes. The reaction solution was concentrated under vacuum and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=1/3) to obtain 45 mg (88%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(C)C)(C)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(c2ccc(CO)cc2)CC1
Yield: 61.9 %

Procedure:
To a solution of tert-butyl-[4-(1,4-dioxa-spiro[4.5]dec-8-yl)benzyloxy]dimethylsilane (12.1 g, 33.3 mmol) in acetone (12 ml) and water (1.2 ml) was added pyridinium p-toluenesulfonate (2.51 g, 9.99 mmol) at room temperature. The mixture was refluxed for 3 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=60/40) to afford 4-(4-hydroxymethylphenyl)cyclohexanone as a colorless solid (4.21 g, 20.6 mmol, 62%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18].[OH-].[Na+].[CH2:21](Br)[CH3:22]>CO.O>[CH2:21]([N:4]1[C:5](=[O:17])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:18])[CH3:22]
Reactant: CCBr
Reactant: C=CCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCCCn1cnc2c1c(=O)n(CC)c(=O)n2C
Reaction time: 40 h

Procedure:
20 g of 3-methyl-7-(hex-5-enyl)-xanthine (see Example 22) are added to a solution of approximately 3.3 g of NaOH in 70 ml of methanol/water (1:1) and 9 g of ethyl bromide are added thereto. The mixture is kept at 40° C. under a nitrogen atmosphere for 40 hours. The solvent is then removed under reduced pressure, the residue dissolved in diethyl ether and the pH of the solution is adjusted with aqueous sodium hydroxide solution to a pH-value of 13.5 to remove unreacted 3-methyl-7-(hex-5-enyl)-xanthine. 1-Ethyl-3-methyl-7-(hex-5-enyl)-xanthine recovered from the ether phase is subsequently subjected to column chromatography using silica gel with methylene chloride/acetone (8:2) as eluent followed by distillation under reduced pressure and is obtained as a colourless oil. Yield: 11.2 g (81.3% of theory relative to reacted starting material) of the title compound, nD20 =1.5415.