Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:18][O-:19].[Na+]>CS(C)=O>[ClH:2].[CH3:18][O:19][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)C2CCNCC2)cc1

Procedure:
A solution of 1.12 g (0.0038 mole) of 4-[(4-chlorophenyl)sulfonyl]piperidine monohydrochloride and 0.0152 mole of sodium methoxide in 60 ml of dimethylsulfoxide was heated at 90° C. for 2 hrs. The reaction mixture was quenched in water and diluted mixture was extracted with methylene chloride. The methylene chloride phase was dried over sodium sulfate and the solvent was removed on the rotary evaporator. The residue (the free base of the title compound) was dissolved in methanol and the solution was treated with an excess of ethereal hydrogen chloride. The resulting hydrochloride salt was recrystallized from methanol-diethyl ether to give white crystalline solid, m.p. 275°-276° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)O[C:15](C)([CH3:19])[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:13](=[O:21])[CH2:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:9]#[C:10][CH3:11])[CH3:19]
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Solvent: c1ccncc1
Product: CC#CC(CC(=O)OCC)c1ccc(O)cc1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
Phenol 1.2 (1.2 g, 4 mmol) was dissolved in pyridine (3 mL) and ethanol (1 mL). The mixture was heated to 90° C. for 16 h and then concentrated to an oil which was purified by column chromatography (elution with 1-3% MeOH in dichloromethane). Phenol 16 (0.88 g, 91%) was obtained as an oil. 1H NMR (500 MHz)(acetone-d6) δ 8.24 (s, 1H); 7.21 (d, 2H, J=9.5 Hz); 6.78 (d, 2H, J=9.0 Hz); 4.06 (m, 2H); 3.98 (m, 1H); 2.68-2.59 (m, 2H); 1.78 (d, 3H, J=2.5 Hz); 1.75 (t, 3H, J=7.0 Hz). MS ESI (pos.) m/e: 233.1 (M+H); 255.1 (M+Na).
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[CH2:14](I)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:21]O>>[CH2:14]([N:1]1[C:5]([C:6]([O:8][CH3:21])=[O:7])=[CH:4][N:3]=[CH:2]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1cnc[nH]1
Reactant: CCCCCCI
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCCCn1cncc1C(=O)OC
Yield: 7.5 %

Procedure:
Imidazole-5-carboxylic acid (10.0 g, 89 mmol) was dissolved in methanol (185 ml) and concentrated sulphuric acid (10 ml) was added dropwise. The mixture was heated under reflux for two days. After cooling in ice and neutralising with dilute sodium hydroxide solution the solvents were removed by evaporation. The white solid produced was suspended in methanol (70 ml) and hexyl iodide (26.3 ml, 178 mmol) in methanol (30 ml) was added. After heating under reflux overnight, the mixture was cooled and filtered through a pad of diatomaceous earth, washing well with methanol. The filtrate was concentrated and the residue purified by column chromatography, eluting with 1.5% methanol/dichloromethane (v/v), to give methyl 1-hexylimidazole-5-carboxylate (1.4 g; 7.5% yield), as an oil;
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[CH:59]([C:61]1[CH:62]=[C:63]([CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH:64]=[C:65]([F:68])[C:66]=1[F:67])=[CH2:60].S([O-])([O-])=O.[Na+].[Na+].[OH2:82]>CC(O)(C)C>[OH:82][C@@H:59]([C:61]1[CH:62]=[C:63]([CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH:64]=[C:65]([F:68])[C:66]=1[F:67])[CH2:60][OH:22]
Reactant: C=Cc1cc(CCC(=O)OCC)cc(F)c1F
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CO)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A solution of AD-mix-α (66.0 g), t-BuOH (340 mL), and H2O (380 mL) was stirred until no solid was observed and then cooled to 0° C. Ethyl 3-(3-ethenyl-4,5-difluorophenyl)propanoate (16.3 g, 68.0 mmol) in t-BuOH (45 mL) and H2O (5 mL) was added and the reaction stirred at 0° C. for 6 h and then warmed to room temperature overnight. Sodium sulfite (84 g) was added and the reaction stirred at room temperature for 5 h. The reaction was diluted with H2O and extracted two times with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Column chromatography (2-90% ethyl acetate:hexane) afforded the desired product (17.76 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[ClH:23].[H][H]>[OH-].[OH-].[Pd+2].CCO>[ClH:23].[ClH:23].[NH2:8][CH2:7][C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]2
Reactant: [H][H]
Reactant: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Temperature: 25 °C
Reaction time: 66 h
Yield: 96 %

Procedure:
A 2.5 L Parr reaction vessel was charged with 5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzonitrile (25.00 g, 84.09 mmol), EtOH (8.40 mL, 0.1M), and Pearlmans catalyst (5 g, 20% weight) and purged with nitrogen. Concentrated HCl (70.08 ml, 840.9 mmol) was added to the mixture. The vessel was charged with nitrogen gas (to 30 psi×3) and hydrogen (to 50 psi×3), and the reaction was stirred at ambient temperature for 66 hours. The mixture was filtered through a Celite pad and the pad was washed with EtOH. The filtrate was concentrated under reduced pressure, and the residue was azeotroped with EtOH and toluene to provide light brown solid to provide 30.2 g (96.0%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.72 (d, J=8.61 Hz, 1H), 7.42 (d, J=2.35 Hz, 1H), 7.33 (dd, J=3.13 Hz, 8.61 Hz, 1H), 7.29 (dd, J=2.35 Hz, 8.61 Hz, 1H), 7.12 (dt, J=3.13 Hz, 8.61 Hz, 1H), 6.83 (dd, J=4.70 Hz, 8.61 Hz, 1H), 4.54 (t, J=5.48 Hz, 2H), 4.25 (br s, 2H), 3.98 (t, J=5.48 Hz, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:12])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Reactant: CS(N)(=O)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)NS(C)(=O)=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
3-[(4-Iodo-2-methylphenyl)amino]isonicotinic acid (example 3) (50 mg, 0.141 mmol) was dissolved in 4 ml dry THF followed by the addition of 1,1″-carbonyldiimidazole (CDI) (0.311 mmol, 50 mg), methanesulfonamide (0.169 mmol, 16.1 mg) and DBU (0.169 mmol, 26 mg). The mixture was stirred for 16 h at 40° C. and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 20.3 mg (47 μmol; 33% yield) of pure desired product. LC-MS (method III): rt=2.74 min; m/z [M+H]+ 432.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[O:8][C:9]([C:11]1[NH:33][C:14]2[C:15]3[C:16]([C:29]([O:31]C)=[O:30])=[CH:17][C:18]([C:25]([O:27]C)=[O:26])=[N:19][C:20]=3[C:21](=[O:24])[C:22](=[O:23])[C:13]=2[CH:12]=1)=[O:10].Cl>O>[O:23]=[C:22]1[C:21](=[O:24])[C:20]2[N:19]=[C:18]([C:25]([OH:27])=[O:26])[CH:17]=[C:16]([C:29]([OH:31])=[O:30])[C:15]=2[C:14]2[NH:33][C:11]([C:9]([OH:10])=[O:8])=[CH:12][C:13]1=2
Reactant: COC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C(=O)c1cc(C(=O)OC)[nH]c1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(C(=O)O)c2c(n1)C(=O)C(=O)c1cc(C(=O)O)[nH]c1-2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of potassium carbonate (about 439 g, 3.18 mol) in water (about 4.5 L), 4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid trimethyl ester (about 200 g, 0.53 mol) is added at about 25° C. The reaction mixture is allowed to stir at about 80° C. over a period of about 12 hours. Completion of reaction is monitored by HPLC. Thereafter, the reaction mixture is acidified (pH: 2.0) with 1N hydrochloric acid to precipitate the product [4,5-Dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid] as dark red solid (about 160 g, 91%). 1H NMR (DMSO-d6, 300 MHz): 7.21 (s, 1H), 8.60 (s, 1H), 13.42 (s, 1H); LC-MS (ESI): 329 (M-H), Purity by HPLC: 98%.
Reaction SMILES: [C:1]([C:5]1[N:10]2[C:11]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:12]=3[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:14][CH2:15][C:9]2=[N:8][C:7](=[O:28])[CH:6]=1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:2][CH2:1][C:5]1[N:10]2[C:11]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:12]=3[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:14][CH2:15][C:9]2=[N:8][C:7](=[O:28])[CH:6]=1
Reactant: COC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=c1cc(CO)n2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 37, 1-carbomethoxy-9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one was reduced with lithium aluminum hydride to give 1-hydroxymethyl-9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: CC1NC(C)=CC=1C1C=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[N:25]([CH3:27])[CH3:26])[CH:14]=2)[N:8]=1.[CH2:29](O)[CH3:30].Cl.[NH2:33]O.Cl>O>[CH3:27][N:25]([CH3:26])[CH:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[CH2:19][C:15]1[CH:14]=[C:13]([C:9]2[N:8]=[C:30]([NH2:33])[CH:29]=[CH:11][CH:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NO
Reactant: CCO
Reactant: Cc1cc(-c2cccc(-c3cccc(CC4CCCC4N(C)C)c3)n2)c(C)[nH]1
Agent: Cl
Solvent: O
Product: CN(C)C1CCCC1Cc1cccc(-c2cccc(N)n2)c1
Yield: 83 %

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 140 mg (0.375 mmol) 2-(2,5-dimethylpyrrolyl)-6-[3-(2-dimethylamino-cyclopentylmethyl)-phenyl]-pyridine, 9 mL ethanol, 1 mL water, and 261 mg (3.75 mmol) hydroxylamine hydrochloride. The reaction was refluxed 24 hours treated with additional hydroxylamine hydrochloride, and refluxed a further 12 hours. It was then cooled, poured into dilute aqueous hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6N sodium hydroxide solution, and extracted with two portions of ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil (109 mg, 98.5%) was converted to the hydrochloride salt using 1N HCl in ether to afford 115 mg (83%) of a white solid, mp 60-80° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C.O>C1COCC1.[Fe]>[CH3:1][C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: Cc1c([N+](=O)[O-])ccc2nsnc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N)ccc2nsnc12
Temperature: 80 °C
Yield: 92.7 %

Procedure:
4-Methyl-5-nitro-benzo[1,2,5]thiadiazole (1.4 g, 7.18 mmol) was dissolved in THF (10 mL), acetic acid (1 mL) and water (21 mL) and iron powder (1.4 g, 25.0 mmol, 325 Mesh) was added. The reaction mixture was heated at 80° C. for 1.5 h, cooled to rt and filtered though celite to remove the iron powder. The solution was extracted with CHCl3 (2×250 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give compound 839C (1.1 g) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)=[CH:12][CH:13]=2)=[CH:18][CH:19]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccc(C)cc3)cc2)cc1
Yield: 17 %

Procedure:
Ethyl 2-Methyl-2-{4[2-(4-methyl-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(4-methyl-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield 17% of theory; m.p. 214° C.
Reaction SMILES: [Ca].[C:2]([O:6][C:7]([NH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[CH3:26][N:25]([CH3:27])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][CH2:14][C@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:5])([CH3:3])[CH3:4])[CH2:11]2)=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [Ca]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and disopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(+3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer was washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: Cc1cc(Cl)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccc(Cl)cc1C
Yield: 41.4 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (1.24 g, 5 mmol) and 4-chloro-2-methylaniline (1.06 g, 7.5 mmol) in dioxan (5 ml) were heated at reflux for 30 minutes, then allowed to cool. The product was filtered off, converted to free base, and recrystallised from methanol, to give 3-butyryl-4-(4-chloro-2-methylphenylamino)-8-methylquinoline (0.73 g), m.p. 166°-167°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)OCC(C)C.[NH2:27][C:28]1[CH:32]=[C:31]([Br:33])[S:30][C:29]=1[C:34]([NH2:36])=[O:35].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:33][C:31]1[S:30][C:29]([C:34](=[O:35])[NH2:36])=[C:28]([NH:27][C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[CH:32]=1
Reactant: CS(=O)(=O)c1ccc(N2CCC[C@H]2C(=O)O)cc1
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(N2CCC[C@H]2C(=O)Nc2cc(Br)sc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(methylsulfonyl)phenyl]proline (512 mg) and triethylamine (0.314 mL) in tetrahydrofuran (10 mL) was added 2-methylpropyl chlorocarbonate (0.259 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Thereafter, to the reaction system was added 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, and the mixture was stirred at 60° C. for 19 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated organic layer was washed with brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give N-(5-bromo-2-carbamoylthiophen-3-yl)-1-[4-(methylsulfonyl)phenyl]prolinamide as a pale-yellow amorphous solid. To a solution of N-(5-bromo-2-carbamoylthiophen-3-yl)-1-[4-(methylsulfonyl)phenyl]prolinamide produced above in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (2.83 mL), and the mixture was stirred at 70° C. for 10 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (2 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (208 mg) as a pale-yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7](O)([CH3:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17](#[N:19])[CH3:18]>C1C=CC=CC=1>[CH3:18][C:17]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]([CH3:15])([CH3:6])[N:19]=1
Reactant: CC(C)(O)Cc1ccccc1
Reactant: CC#N
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC1=NC(C)(C)Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To conc. sulfuric acid (10 ml) was added a solution of 2-methyl-1-phenylpropan-2-ol (7.0 g) and acetonitrile (1.62 ml) in benzene (7.0 ml) dropwise and the mixture was stirred for 24 hours at room temperature. The mixture was neutralized by adding to a mixture of ice and a saturated aqueous solution of sodium bicarbonate dropwise, and it was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and was concentrated under reduced pressure. The residue was dissolved in ether and was extracted with 1N hydrochloric acid and 2N hydrochloric acid. The extract was washed with ether and to the mixture was added 5N aqueous solution of sodium hydroxide and was extracted with ether twice. The extract was washed with water and a saturated aqueous solution of sodium chloride successively, and dried over anhydrous magnesium sulfate and was concentrated under reduced pressure to give the title compound (2.53 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN([CH:29]=[O:30])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[CH2:15]([O:14][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:29]=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN(C=O)c1ccccc1
Reactant: CCCCCCOc1ccccc1OCCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCOc1ccc(C=O)cc1OCCCCCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1,2-Dihexyloxybenzene (11.14 g; 40 mmol) and N-methylformanilide (5.41 g; 40 mmol) are cooled to 0° C., and phosphorus oxychloride (6.13 g; 40 mmol) is added. Heating is then carried out for 1 hour at 25° C., followed by stirring for 4 hours at 60° C. The reaction mixture is poured onto ice and then adjusted to pH 6. Extraction is carried out with tert-butyl methyl ether (2×200 ml), and washing is carried out with NaHCO3 (2×100 ml). The organic phase is dried over Na2SO4, filtered and concentrated to dryness by evaporation.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[N:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=2)(=[O:11])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: COc1ccc(S(=O)(=O)n2cccc2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)n2cccc2)n[nH]1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
A mixture of 3-methoxy-6-(pyrrole-1-sulfonyl)-pyridazine (0.46 mmol, 112 mg), conc. HCl (1 mL) and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue and the resulting solid was collected to obtain 6-(pyrrole-1-sulfonyl)-2H-pyridazin-3-one (69%, 73 mg); mp 140° C.-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].[CH2:13]([CH2:15][NH2:16])[OH:14].CCN(CC)CC>CCO>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:16][CH2:15][CH2:13][OH:14]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1NCCO

Procedure:
2-Chloro-1,3-difluoro-4-nitrobenzene (5.37 g, 27.7 mmol), ethanolamine (1.69 g, 27.7 mmol) and Et3N (2.80 g, 27.7 mmol) are stirred in EtOH (40.0 mL) at room temperature for 2 hours. The solvent is then evaporated, and the resulting residue is suspended in EtOAc (50.0 mL) and washed with 0.5 N NaOH (50.0 mL). The aqueous phase is extracted 4 times with EtOAc (4×50.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is purified by flash chromatography on silica gel, eluting with mixtures of heptane and EtOAc (5.53 g, 85%). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.39 (dd, J=10.55, 5.27 Hz, 2H) 3.53 (t, J=5.47 Hz, 2H) 4.89 (s, 1H) 6.89 (dd, J=9.37, 8.01 Hz, 1H) 7.19 (t, J=4.69 Hz, 1H) 8.01 (dd, J=9.47, 5.96 Hz, 1H).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:13]([C:23]([OH:25])=[O:24])=[CH:14][C:15]2[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[C:16]=2[CH:22]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].[ClH:28]>>[ClH:28].[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[C:13]([C:23]([OH:25])=[O:24])=[CH:14][C:15]3[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[C:16]=3[CH:22]=2)=[N:9]1)([CH3:7])[CH3:6]
Reactant: Cc1nc2cc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)cc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cc(C(=O)O)c(C3=NC(C)(C(C)C)C(=O)N3)cc2n1C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
A mixture of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-1,2-dimethyl-5-benzimidazolecarboxylic acid (0.330 g, 0.910 mmol) and 2M sodium hydroxide (3.0 mL, 6.0 mmol) is stirred for 2.5 hours at reflux temperature, cooled, acidified to pH 3 with hydrochloric acid and filtered. The filter cake is recrystallized from ethanol to afford the title product as a white solid (0.120 g, 31.5%), mp 256°-258° C.