Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:13]1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:48]1[C:52]2[CH:53]=[C:54]([O:57][CH3:58])[CH:55]=[CH:56][C:51]=2[S:50][C:49]=1[C:59]([O:61][CH3:62])=[O:60]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:58][O:57][C:54]1[CH:55]=[CH:56][C:51]2[S:50][C:49]([C:59]([O:61][CH3:62])=[O:60])=[C:48]([CH3:13])[C:52]=2[CH:53]=1
Reactant: COC(=O)c1sc2ccc(OC)cc2c1Cl
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1C
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Methyl boronic acid (120 mg), potassium phosphate (849 mg), water (0.30 ml), palladium acetate (22 mg), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl (95 mg) were added to a solution of methyl 3-chloro-5-methoxy-1-benzothiophene-2-carboxylate (257 mg) in 1,4-dioxane (3.0 ml), and the reaction solution was stirred at 100° C. for 12 hours. The reaction solution was diluted with ethyl acetate and washed successively with an aqueous ammonium chloride solution, an aqueous sodium bicarbonate solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain methyl 5-methoxy-3-methylbenzo[b]thiophene-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:16][C:14]1[CH:15]=[C:10](/[CH:9]=[CH:8]/[C:4]2[CH:3]=[C:2]([NH:1][C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:11]=[N:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(/C=C/c2cncc(Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cncc(Br)c2)c1
Yield: 32.3 %

Procedure:
A mixture of 3-[(E)-2-(3-aminophenyl)vinyl]-5-bromopyridine (3.5 g), 2-chloro-3-nitropyridine (2.22 g) and potassium carbonate (2.64 g) in 1,4-dioxane (30 ml) was stirred under reflux for 22 hours. The mixture was filtered and the filtrate was concentrated. The resultant solid was washed with ethanol to give 2-[3-[(E)-2-(5-bromo pyridin-3-yl)vinyl]phenylamino]-3-nitropyridine (1.63 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.N>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[NH2:1])[O:14][N:13]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(-c3cccnc3)no2)c1
Agent: N
Product: Nc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 46 using the product of Example 40. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.60 (s, 2H), 6.84-6.93 (m, 1H), 7.24-7.33 (m, 2H), 7.41 (d, J=1.7 Hz, 1H), 7.60-7.67 (m, 1H), 8.38-8.45 (m, 1H), 8.81 (dd, J=5.1, 1.7 Hz, 1H), 9.23 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 239 (M+H)+, 256 (M+NH4)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]2(=[O:17])=[O:16])[CH2:26][CH2:25]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mole o& 2-(4-bromobutyl)-1,2-benzoisothiazol-3-(2H)-one 1,1-dioxide and 0.02 mole of 1-(2-pyrimidyl)piperazine are stirred with 0.02 mole of K2CO3 in 150 ml of absolute dimethylformamide (DMF) at 100° C. for 1 hour. The mixture is then concentrated. Water is added and the organic substance is taken up in methylene chloride (CH2Cl2). The dried CH2Cl2 phase is applied to a silica gel column and eluted with CH2Cl2 /CH3OH (95:5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CN(C=O)C.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][C:32]([F:31])([F:42])[F:43])=[CH:35][CH:36]=3)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c([N+](=O)[O-])cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3ccc(OC(F)(F)F)cc3)c([N+](=O)[O-])cc2F)CC1
Yield: 80.3 %

Procedure:
8 g of 4-(2,5-difluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (23 mmol) and 3.82 g potassium carbonate (27.65 mmol) were suspended in 80 ml DMF under stirring and then treated dropwise within 10 min with a solution of 5.29 g of 4-trifluoromethoxy-benzylamine (27.65 mmol) in 30 ml DMF. The reaction mixture was then stirred for 48 h at rt, diluted with 500 ml dichloromethane and 1 liter of water. After separation, the organic phase was washed with brine (500 ml). The two aqueous phases were then reextracted with 2×250 ml dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The solid residue was stirred with 150 ml heptane/ethylacetate 4:1. After 10 minutes the suspension was diluted with 100 ml heptane, and after additional 10 min stirring, filtered. After drying in vacuo, 9.5 g of 4-[2-fluoro-4-nitro-5-(4-trifluoromethoxy-benzylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid (80%). MS(ISP): 515.3 (M+H)+.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:23])[CH2:18][C:19](OC)=[O:20])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CO>O1CCCC1>[C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][OH:20])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)CC(=O)CCCCCNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCCCCC(O)CCO)OCc1ccccc1
Temperature: 25 °C
Yield: 9 %

Procedure:
Methyl 8-(N-Cbz-amino)-3-oxo-octanoate (3,51.5 g, 0.16 moles) was dissolved in anhydrous tetrahydrofuran (350 mL) in a reaction flask equipped with a magnetic stirbar, reflux condenser, pressure equalizing addition funnel and nitrogen gas inlet. While stirring the mixture under nitrogen sodium borohydride (15.1 g, 0.4 moles) was cautiously added. The mixture was then heated to reflux and methanol was added dropwise over 90 minutes. Stirring was continued at reflux temperature for 60 minutes after the addition was complete. After allowing the solution to cool to ambient temperature, distilled water (78 mL) was added and 3N HCl was added to pH 3. The mixture was evaporated in vacuo to remove the organic solvents, and solid potassium carbonate was added to adjust the pH back to 12. The mixture was then extracted with ethyl acetate (5×100 mL). The extract was washed with saturated sodium chloride (2×50 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in methanol (200 mL) and evaporated again. This was repeated a total of five times. The residue was crystallized from ether (700 mL) giving 8-(N-Cbz-amino)-1,3-octanediol (4,23 g). A second crop was collected on addition of cyclohexane (300 mL) to the mother liquor (6.8 g). Mass Spectrum: (M+H)+ (M+H)+ @m/z 296, (M+H4)+ @m/z 313.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20]1
Reactant: IC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(C4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:38](F)(F)[C:39]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:38]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:39]
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(C(F)(F)F)c1)CCC2
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1F

Procedure:
2-Fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 523.29 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 3-trifluoromethyl-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C[O:14][C:15]([C@H:17]1[CH2:21][CH2:20][C@@H:19]([CH2:22]O)[CH2:18]1)=O>C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:12]=[C:22]([C@@H:19]3[CH2:20][CH2:21][C@H:17]([CH2:15][OH:14])[CH2:18]3)[O:3][N:4]=2)=[CH:7][CH:8]=1
Reactant: N=C(NO)c1ccncc1
Reactant: COC(=O)[C@H]1CC[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@@H](c2nc(-c3ccncc3)no2)C1
Reaction time: 18 h

Procedure:
Sodium hydride (10 mg of a 60% dispersion in oil, 2.5 mmol) was added to a solution of N-hydroxyisonicotinamidine (344 mg, 2.5 mmol) in anhydrous THF (3 ml) and the mixture heated under reflux for 1 h. cis-Methyl-3-hydroxymethylcyclopentane-1-carboxylate (396 mg, 2.5 mmol) was added in one portion and heating was continued for 18 h. After cooling, the solution was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=2.59 min, m/z (ES+)=246.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6]>Cl>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 99 %

Procedure:
In a manner similar to Example 4, Step (b), 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid, methyl ester (1.34 g, 0.00398 mol) was refluxed in 6 M aqueous hydrochloric acid (24 mL) to give 1.27 g of 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid as an 80% pure solid. A portion (0.059 g) of the material was purified by chromatography on silica gel (7 g, 230-400 mesh), eluting with dichloromethane (15×10 mL); dichloromethane-methanol (15:1, 16×10 mL) to give 0.0476 g of pure 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid as an off-white solid; mp 172-174° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=[O:17])[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH2:16][OH:17])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[N:10]=1
Reactant: COc1ccc(C=O)cc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzaldehyde (14.0 g) in tetrahydrofuran (100 mL)-ethanol (30 mL) was gradually added sodium borohydride (1.69 g) at 0° C. After stirring at room temperature for 2 hrs., water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxyphenyl)methanol as pale-yellow crystals (12.87 g, yield 91%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 145-146° C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>O.O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]1[O:17][CH2:8]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Clc1cccc(C2CO2)c1
Reaction time: 0.25 h

Procedure:
A mixture of 42.0 g. of 57% sodium hydride dispersed in oil and 700 ml. of dimethyl sulfoxide is stirred at 70°-75° C. for 1 to 11/2 hours. The solution is diluted with 700 ml. of dry tetrahydrofuran and cooled to 0° C., under nitrogen. A 200 g. (1.0 mole) sample of trimethylsulfonium iodide is added in portions, maintaining the temperature between 0°-5° C. The mixture is stirred for 15 minutes and then a solution of 70.4 g. (0.50 mole) of m-chlorobenzaldehyde in 300 ml. of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred at room temperature for 4 hours, poured into water and extracted with ether. The extract is washed with brine, dried and evaporated in vacuo to leave m-chlorostyrene oxide.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[CH2:18][C:19]([OH:21])=[O:20]>>[C:19]([CH2:18][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:22](=[O:23])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:21])=[O:20]
Reactant: NC(CC(=O)O)C(=O)Nc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)Nc1ccccc1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-amino-N-phenyl-succinamic acid to provide the title compound in good yield. LCMS m/z 414 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]3[N:15]=[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][N:17]4[C:18](=[O:21])[C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][Cl:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:38].[CH3:20][C:19]1[C:18](=[O:21])[N:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=[N:15][C:14]=1[O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[CH:29][CH:28]=2)=[CH:9][CH:10]=1
Reactant: ClCc1ccncc1
Reactant: Cc1c(OCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccccn2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(OCc4ccncc4)cc3)cc2)nc2ccccn2c1=O
Yield: 68.1 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (96 mg), 4-picolyl chloride hydrochloride (89 mg) and potassium carbonate (178 mg) in DMF (7 ml) was stirred at room temperature for 13 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol =20:1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (87 mg).
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11](N(CC)CC)[CH3:12].[CH3:18][C:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20]>O.C(O)C.CO>[CH3:18][C:19]([CH2:21][C:22]([OH:24])=[O:23])=[O:20].[CH2:11]([C:9]1[CH:8]=[CH:7][C:6]([CH2:18][CH2:19][OH:20])=[N:5][CH:10]=1)[CH3:12]
Reactant: c1ccncc1
Reactant: CCN(CC)CC
Agent: CC(=O)CC(=O)O
Solvent: O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CCc1ccc(CCO)nc1

Procedure:
Bromination of olefin 2 with bromine in a neutral solvent e.g. dichloromethane, carbon tetrachloride, can give 5. Similarly, cyclic sulfate 10a may be prepared via oxidation of cyclic sulfite 10b, which in turn may be obtained form diol 11 by reacting with thionyl chloride, in the presence of bases e.g. pyridine, triethylamine. The formation of diol 11, can be achieved from diacetate 17, by treatment with base in water or methanol or ethanol. Alternatively, one can also prepare diol 11, from the diacetate 17 which in turn can be obtained from N-oxide of 5-ethyl-2-pyridyl-2-ethanol as shown in scheme I. In all the above transformations (Scheme I) upon completion of the reaction, the desired compound is easily isolated from the reaction mixture in a most conventional manner eg. extracting in organic layer, washing with water, drying organic layer, concentrating and purifying/crystallizing the desired final product.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)Cl)=[CH:3][CH:2]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[N:20]=[C:21]([NH2:23])[NH2:22].C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:23][C:21]1[N:20]=[C:12]2[N:13]([C:8](=[N:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:11]2
Reactant: NC(N)=Nc1nc2ccccc2s1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(=Nc2ccccc2)n2c(n1)sc1ccccc12

Procedure:
Phenyl isocyanide dichloride (0.18 g) in dry tetrahydrofuran (5 ml) was added to a stirred solution of 2-benzothiazolylguanidine (0.2 g) and diisopropylethylamine (0.27 g) in dry tetrahydrofuran (10 ml). The mixture was refluxed for sixteen days and on cooling the title compound was obtained as a white crystalline solid (23 mg) mp>250°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([C:15]3[C:16]([CH3:22])=[N:17][O:18][C:19]=3[CH2:20][OH:21])=[CH:13][N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:21][CH2:20][C:19]1[O:18][N:17]=[C:16]([CH3:22])[C:15]=1[C:14]1[C:10]([C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:11][N:12]([CH3:23])[CH:13]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(CO)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(COS(C)(=O)=O)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of (4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone (0.05 g, 0.15 mmol) in DCM (10 mL), was added triethylamine (0.1 mL) and methane sulfonyl chloride (0.05 mL) at room temperature. The mixture was stirred for 2 h at room temperature. DCM (50 mL) and saturated sodium bicarbonate solution (20 mL) were added. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the titled product as yellow oil (0.035 g, 56%). LC/MS m/z 409 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.C([N-]C(C)C)(C)C.[Li+].[I:29]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([I:29])=[CH:10][C:3]=12
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 5A (25 g, 71.2 mmol) in tetrahydrofuran (600 ml) at −78° C. was slowly added lithium diisopropylamide (2M in tetrahydrofuran, 39.1 mL, 78 mmol) and the mixture was stirred at −78° C. for 1 hour. A solution of iodine (19.87 g, 78 mmol) in tetrahydrofuran (100 mL) was added slowly and the mixture was stirred for 3 hours. Saturated aqueous sodium thiosulfate, water and ethyl acetate were added and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to provide the title compound. MS (CI) m/z 477 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:14]=O.N1CCCCC1.C(O)(=O)C>CC(O)C>[CH3:1][O:2][C:3](=[O:9])[C:4]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:14][C:13]1[CH:12]=[C:11]([Cl:10])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)CC(=O)OC
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.00 g (7.68 mmol) of 3-oxovaleric acid methylester and 1.34 g (7.68 mmol) of 3,5-dichlorobenzaldehyde were dissolved in 20 ml of 2-propanol. 65.4 mg (0.768 mmol) of piperidine and 46.1 mg (0.768 mmol) of acetic acid were added and stirred at room temperature for one day. After the solvent was evaporated under reduced pressure, ethyl acetate was added thereto. The reaction mixture was washed with 1 N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:25]([NH2:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:25]([NH:27][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])[CH3:26]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ethylamide (64 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), ethylamine (2 M in THF, 251 uL), HBTU (114 mg), and DIEA (66 uL). LC/MS: m/z 386.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.40 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.72 (d, 1H), 7.57 (bs, 1H), 7.44 (d, 1H), 7.37 (dd, 1H), 3.64 (bs, 3H), 3.30 (q, 2H), 1.13 (t, 3H).