Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=[C:5]1[N:14]([CH2:15][C:16]#[N:17])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:19])[C:11]=2[Cl:18])[NH:6]1)#N.C(=O)([O-])[O-:21].[K+].[K+]>C(O)CO>[Cl:18][C:11]1[C:10]([Cl:19])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][N:14]1[CH2:15][C:16](=[O:21])[NH:17][C:5]1=[N:6]2
Reactant: N#CCN1Cc2c(ccc(Cl)c2Cl)NC1=NC#N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 10 ml of ethylene glycol in 0.5 ml (0.005 moles) of cc. hydrochloric acid, warmed to 120° C., 0.28 g (0.001 mole) of (2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetonitrile are added, and the solution is stirred at the same temperature for 20 minutes. Then it is cooled to room temperature and made neutral with 10% potassium carbonate solution. The separated crystals are filtered off. Thus 0.27 g (96.4%) of crude 6,7-dichloro-1, 5-dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 96.3%), which is dissolved in a hot mixture of 7 ml of methanol and 6 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.76 moles/1000 ml) and allowed to crystallize. Then it is cooled, the separated product is filtered off and washed with a slight amount of ethanol.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[C:7]([O:13][CH3:14])=[C:8]([CH:10]=[CH:11][CH:12]=1)N.[BrH:15]>O>[Br:15][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([F:5])[C:7]=1[O:13][CH3:14]
Reactant: COc1c(N)cccc1F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(F)cccc1Br
Temperature: 50 °C
Reaction time: 1 h

Procedure:
NaNO2 (12.0 g, 173 mmol, in 40 mL of water) solution was added dropwise to the mixture of 3-fluoro-2-methoxyaniline (20.0 g, 158 mmol) in 200 mL of hydrobromic acid (47%) and 100 mL of water at −5˜0° C. and stirred for 1 hour. This solution was then added slowly to the suspension of CuBr (45.2 g, 315 mmol) in 50 mL of hydrobromic acid (47%) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour then warmed to 50° C. and stirred for 1 hour. The reaction mixture was poured into ice water and extracted with ether (2×500 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 1-bromo-3-fluoro-2-methoxybenzene.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](OCC)=[O:17].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][OH:17]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
14 grams (50 mmol) of ethyl 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylate was suspended in 400 ml THF, and 9.5 grams (250 mmol) lithium aluminum hydride were added slowly. The mixture was stirred at room temperature for 12 hours, cooled, 250 ml water was added and the resulting mixture was stirred overnight. The solvent was thereafter evaporated, and water (300 ml) was again added. The aqueous suspension was extracted with dichloromethane. The organic extract was evaporated, and the remaining residue was purified by column chromatography on silica gel, using a 9:1 mixture of ethylacetate and methanol as eluent, to yield 4-hydroxy-7-trifluoromethyl-3-(hydroxymethyl)-quinoline (12 grams, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1.[Sn](Cl)Cl.Cl>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)nc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc(N)ccc2Cl)nc1

Procedure:
75 mL of (5-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 935 mg of 2-(2-chloro-5-nitrophenyl)-5-methylpyridine in 5 mL of Sulfuric Acid was slowly added 2.25 g of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 6-(2-chloro-5-nitrophenyl)nicotinic acid. 704 mg of 6-(2-chloro-5-nitrophenyl)nicotinic acid was esterified with 3.1 mL of 4N HCl in Dioxane in 20 mL of MeOH. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 6-(2-chloro-5-nitrophenyl)nicotinate. 681 mg of methyl 6-(2-chloro-5-nitrophenyl)nicotinate was treated with 2.1 g of Tin (II) Chloride and 1 mL of HCl in 25 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 6-(5-amino-2-chlorophenyl)nicotinate. 296 mg of methyl 6-(5-amino-2-chlorophenyl)nicotinate was coupled to 266 mg of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. To 518 mg of methyl 6-(2-chloro-5-(4-(methylsulfonylmethyl)benzamido)phenyl)nicotinate at 0° C. in 20 mL of EtOH was slowly added 640 mg of Sodium Borohydride. The reaction was subsquently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 431.1 (M)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].Cl.Cl.[N:19]1[C:27]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[S:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30].[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:10]([CH:23]1[C:22]2[S:21][C:20]([NH:28][C:29]([NH2:31])=[NH:30])=[N:19][C:27]=2[CH2:26][CH2:25][NH:24]1)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)Cl
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(=O)C1NCCc2nc(NC(=N)N)sc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisopropylethylamine (0.22 mmol) and then pentanoyl chloride (0.11 mmol) are added to a stirred suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine-dihydrochloride (0.1 mmol) in dimethylformamide (0.7 ml) and the reaction mixture is stirred for another 16 hours at room temperature. After the addition of 2M caustic soda solution (1 ml) extraction is carried out with ethyl acetate. The combined organic phases produce the pure title compound after drying over sodium sulphate and concentrating to dryness.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[N+:20]([C:23]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[O:33])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O-:22])=[O:21].C(O)(=O)C>O1CCCC1>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][C:29]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[O:33])=[CH:30][C:23]=1[N+:20]([O-:22])=[O:21])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CC(=O)OCC
Reactant: Cc1ccc(C(=O)Nc2ccc(C=O)c([N+](=O)[O-])c2)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1ccc(NC(=O)c2ccc(C)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of diisopropylamine (0.11 ml, 0.82 mmole) in tetrahydrofuran (2 ml) at -78° C. was added under the argon atmosphere 1.5N butyllithium (0.51 ml, 0.77 mmole), and the mixture was stirred for 30 minutes. Next, to this reaction mixture were added ethyl propiolate (93 μl, 0.92 mmole) followed by a solution of 2-nitro-4-(p-toluoylamino)-benzaldehyde (144.5 mg, 0.51 mmole), and the mixture was further stirred at -78° C. for 1 hour. After a solution of acetic acid (90 μl, 1.58 mmole) in tetrahydrofuran (1 ml) was added to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitro-4-(p-toluoylamino)-phenyl)-2-butynoate as an oil (176 mg). The product thus obtained was dissolved in toluene (2 ml), 4-methoxybenzylazide (250 mg, 1.53 mmole), and the mixture was stirred with heating at 100° C for 5 hours. The reaction mixture was cooled to room temperature, the resulting crystalline products were filtered to give the 1 : 1 mixture of ethyl 4-(hydroxy-(2-nitro-4-(p-toluoylamino)phenyl)methyl)-1-(4- methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-i) and ethyl 5-(hydroxy-(2-nitro-4-(p-toluoylamino)phenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2) (103.4 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[N:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[C:6]([CH3:13])([CH3:14])[N:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]=2[N:3]=1
Reactant: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1(C)C
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCN1c2nc(Cl)ncc2N(c2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
To a stirred solution of 2-chloro-7,7-dimethyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one (707 mg, 2.5 mmol) in dichloromethane (50 mL) was added triethylamine (25.0 mmol), cupric acetate (908 mg, 5.0 mmol) and phenylboronic acid (610 mg, 5.0 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 48 h at room temperature with an air balloon. Then the reaction mixture was filtered over celite. The filtrate was washed with aqueous saturated sodium bicarbonate (2×30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (Eluent: 2% methanol in dichloromethane) to give titled product (yield; 46%). 1HNMR (300 MHz, CDCl3): δ 1.0 (s, 3H), 1.02 (s, 3H), 1.61-1.65 (m, 9H), 3.64 (q, J=5.1 Hz, 2H), 7.06 (s, 1H), 7.18-7.21 (m, 2H) and 7.48-7.57 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[C:4]1[CH2:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)=[O:22])[CH3:2].C([N:31](C(C)C)CC)(C)C.Br[CH:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(#N)C>[CH2:42]([O:41][C:39](=[O:40])[CH:38]([N:24]1[CH2:25][CH2:26][CH2:27][C@@H:23]1[C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[CH2:15][CH2:14][C:4]1[N:3]([CH2:1][CH3:2])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([C:12](=[NH:31])[NH2:13])[CH:10]=2)=[O:22])[CH3:44])[CH3:43]
Reactant: CCOC(=O)C(C)Br
Reactant: CCn1c(CC[C@@H]2CCCN2C(=O)[C@H]2CCCN2)cc2ccc(C#N)cc21
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(C)N1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC
Temperature: 70 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
300 mg (0.823 mmole) of 1-ethyl-2-[2-[(S)-1-[((R)-pyrrolidin-2-yl)carbonyl]pyrrolidin-2-yl]ethyl]indole-6-carbonitrile was dissolved in 15 ml of acetonitrile, and 0.29 ml (1.646 mmole) of diisopropylethylamine and 0.22 ml (1.646 mmole) of ethyl 2-bromopropionate were added thereto. The reaction mixture was heated to 70° C., stirred for 4 hours, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(20:1)] to obtain 310 mg of the title compound as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)[O:6][N:5]=1.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C=O)C>[C:24]([S:26][CH2:2][CH2:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)[O:6][N:5]=1)(=[O:27])[CH3:25]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCCl)no1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2.44 g of 3-(2-chloroethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 40 ml of DMF was added 1.69 g of potassium thioacetate. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The resultant mixture was extracted with benzene and the organic phase was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel using benzene to yield 2.62 g of 3-(2-acetylthioethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a light brown oil. It was crystallized from diisopropyl ether to give colorless needles, m.p. 56°-57° C.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:35])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)Cl.[CH2:39]([O:41][C:42]([C:44]1[CH:45]=[C:46]([N:50]2[C:54]([SH:55])=[N:53][N:52]=[N:51]2)[CH:47]=[CH:48][CH:49]=1)=[O:43])[CH3:40].S(Cl)(Cl)(=O)=O>ClCCl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[C:33]([S:55][C:54]2[N:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[CH:45]=3)[N:51]=[N:52][N:53]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:35])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)c1cccc(-n2nnnc2S)c1
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1ccc2ccccc2c1O
Agent: ClSCl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)OCC)c2)c2ccccc2c1O
Reaction time: 5 h
Yield: 77.5 %

Procedure:
22.8 g of 2-(2-tetradecyloxyphenyl)carbamoyl-1-naphthol was dissolved in 100 ml of dichloromethane and to the solution was added dropwise at room temperature a dichloromethane solution of the sulfenyl chloride prepared from 25 g of 1-(3-ethoxycarbonylphenyl)-5-mercaptotetrazole and 13.5 g of sulfuryl chloride. After the completion of the addition, the mixture was stirred for 5 hours and the dichloromethane solution was washed with an aqueous solution of sodium hydrogencarbonate and then with water. The dichloromethane was distilled off under reduced pressure and the residue was crystallized from methanol to obtain 26.9 g of 2-(2-tetradecyloxyphenyl)carbamoyl-4-[1-(3-ethoxycarbonylphenyl)-5-tetrazolylthio]-1-naphthol. Yield: 74.3%. Melting Point: 88° to 90° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:23]=O>C(O)(=O)C>[F:22][C:2]([F:21])([F:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][C:12]2[N:17]3[C:18](=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:23]1)=[O:4]
Reactant: O=C(NCCCCNCc1cccc2nccn12)C(F)(F)F
Reactant: C=O
Solvent: CC(=O)O
Product: O=C(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 3860 mg (12.28 mmol) of 5-[N-(4-trifluoroacetamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 15 ml of acetic acid was added 13.8 ml (184.21 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water. To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 150 ml of dichloromethane. The organic layer was washed with 200 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 2890 mg of the desired compound (72.0%, a white solid).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]([NH2:32])([CH3:31])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[N:21]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:32][C:25]([C:22]3[N:21]=[C:20]([CH3:19])[O:24][N:23]=3)([CH3:31])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Agent: Cl
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)F)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid;hydrochloride (example 145d) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer A) (example 124b) as starting materials and isolated (16 mg, 20%); MS (ESI, m/z): 445.3 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([NH:5][S:6]([C:9]1[CH:20]=[C:13]2[C:14]([O:16]C(=O)[NH:18][C:12]2=[CH:11][CH:10]=1)=O)(=[O:8])=[O:7])[CH2:3][CH3:4].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)C.C(OCC)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:14](=[O:16])[C:13]2[C:12](=[CH:11][CH:10]=[C:9]([S:6](=[O:7])(=[O:8])[NH:5][CH:2]([CH2:3][CH3:4])[CH3:1])[CH:20]=2)[NH2:18])[CH2:24][CH2:23]1
Reactant: CCC(C)NS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCOCC
Product: CCC(C)NS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-[N-(2-butyl)-sulfamoyl]-isatoic anhydride with 1-methylpiperazine yields 5-[N-(2-butyl)-sulfamoyl]-anthranilic acid (4-methyl)-piperazide with a melting point of 130°-132° (from an ethanol/diethyl ether mixture). The hydrochloride melts at 246°-248°.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10](SC)=[CH:9][CH:8]=1.O[O:19][S:20]([O-:22])=O.[K+].[CH2:24]1COCC1>C(O)C>[Br:1][C:2]1[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:20]([CH3:24])(=[O:22])=[O:19])=[CH:9][CH:8]=1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Agent: [K+]
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 mg of 4-bromo-2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone was dissolved in 15 ml THF and 15 ml ethanol, to which was added 178 mg of OXONE. The mixture was stirred overnight at room temperature. Then the solvent was removed in vacuo. The resulting residue was extracted with 50 ml water and methylene chloride (50 ml×3). The organic layer was concentrated under reduced pressure and the resulting residue was subjected to column chromatographic separation (hexane/ethylacetate=2:1) to afford 45 mg of desired 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 196-196.5° C. NMR: δ1.57 (s, 6H), 3.11 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 8.40 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1703, 1559, 1270, 1148, 1076, 847. MS (EI): 346 (m).
Reaction SMILES: [CH3:1]N(C(N=NC(N(C)C)=O)=O)C.[CH2:13]([O:15]CC)[CH3:14].O.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:14][C:13](=[O:15])[CH2:20][CH2:21][CH2:22][C:23](=[O:19])[CH3:1]
Reactant: CCOCC
Reactant: CN(C)C(=O)N=NC(=O)N(C)C
Reactant: C1CCOC1
Solvent: O
Product: CC(=O)CCCC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (42 g, 431 mmol) was added to a dichloromethane (500 ml) solution of glutaryl chloride (25 ml, 196 mmol) at room temperature, and pyridine (95 ml, 1.18 mol) was dropped under ice-cooled condition. After being stirred at room temperature for 2 hours, the reaction mixture was celite filtered. The filtrate was concentrated under reduced pressure, and diethyl ether (300 ml) was added. The mixture was celite filtered again, and concentrated under reduced pressure to give a Weinreb diamide product. The Weinreb diamide product was dissolved in tetrahydrofuran (500 ml), and a 3 M diethyl ether solution (160 ml, 0.470 mol) methylmagnesium bromide was slowly dropped under ice-cooled condition. After being stirred at room temperature for 4 hours, the mixture was brought back to ice-cooled condition, and water was slowly added. After extraction with ethyl acetate, the reaction liquid was washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was then purified by silica gel column chromatography to give heptane-2,6-dione (20.3 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][S:19][C:13]=3[CH:12]2[CH2:20][CH2:21][CH2:22][CH3:23])=[O:7])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH2:20]([CH:12]1[C:13]2[S:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][N:11]1[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:25][CH:24]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC1c2sccc2CCN1CCNC(=O)c1ccc(N)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCC1c2sccc2CCN1CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Yield: 80 %

Procedure:
Prepared by Method F using the aminobenzene from Example 15 and methanesulfonyl chloride. The product was isolated as a white solid after flash silica gel chromatography using CH2Cl2 /Methanol/NH4OH (97.5/2.25/0.25 to 95.75/4/0.25). This material was recrystallized from EtOAc/ether to afford the title compound as an near-white solid (80%); mp 98°-105° C.; IR (KBr) 3420, 2930, 1635, 1610, 1553, 1505, 1340, 1310 and 1155 cm-1.