Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:16])[C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N1CCCCC1>CN(C=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:16])[C:13]([CH:14]=[C:22]4[S:18][C:19](=[O:24])[NH:20][C:21]4=[O:23])=[C:9]3[N:8]=[C:7]([CH3:17])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc(NC2CC2)n2nc(C)c(C=O)c2n1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(NC2CC2)n2nc(C)c(C=C3SC(=O)NC3=O)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-(cyclopropylamino)-2,5-dimethylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (0.25 mmol) in DMF was added thiazolidine-2,4-dione (88 mg, 0.75 mmol) and piperidine (25 μl, 0.25 mmol). The mixture was stirred at room temperature overnight. Mixture was prepared by HPLC to yield 5-((7-(cyclopropylamino)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=330)
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:10]=1)[CH2:2]2.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]3)[N:12]=2)=[CH:32][CH:31]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
A suspension of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.4 mmol), 4-aminophenylboronic acid, pinacol ester (0.69 g, 3.2 mmol), and tetrakis(triphenylphosphine)palladium (0.28 g, 0.24 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound.
Reaction SMILES: [SH:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([SH:11])[CH3:10].N.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.Cl>CO>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:1][C:2]([CH3:14])([CH3:13])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]([CH3:12])([S:11][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:10])=[CH:20][CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(S)CNCCNCC(C)(C)S
Agent: Cl
Agent: N
Solvent: CO
Product: COc1ccc(CSC(C)(C)CNCCNCC(C)(C)SCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of N,N'-bis(2-mercapto-2-methylpropyl)ethylene diamine (11.23 g, 47.5 mmol; see, DiZio et al., 1991, Bioconjugate Chem 2: 353 and Corbin et al., 1976, J. Org. Chem. 41: 489) in methanol (500 mL) was cooled in ice/water bath and then saturated with gaseous ammonia over 45 min. To this was added 4-methoxybenzyl chloride (17.0 mL, 125 mmol, 264 mol %). The reaction was allowed to warm to room temperature overnight with stirring under argon. The solution was concentrated to a paste and then partitioned between diethyl ether (150 mL)and 0.5M KOH (200 mL). The aqueous layer was further extracted with diethyl ether (2×50 mL). The combined organic layers were washed with NaCl solution and concentrated to a clear colorless oil. The oil dissolved in diethyl ether (200 mL)and then acidified with 4.0M HCl in dioxane until no further precipitation was seen. The white precipitate was collected by filtration and washed with diethyl ether. The white solid was recrystallized from hot water at a pH of ~2. The product was collected by filtration to afford 29.94 g as a mix of mono- and di- HCl salts. The HCl salts were partitioned between 1M KOH (100 mL)and ethyl acetate (100 mL). The aqueous was extracted with ethyl acetate (2×30 mL)and the combined organic layers were washed with NaCl solution, dried with Na2SO4 and concentrated to give pure product as the free base as a light yellow oil (18.53 g, 82% yield). Nuclear magnetic resonance characterization experiments yielded the following molecular signature: 1H NMR (300 MHz, CDCL3): δ7.25 (d, 4H, J=9), 6.83 (d, 4H, J=9), 3.78 (s, 6H), 3.67 (s, 4H), 2.63 (s, 4H), 2.56 (s, 4H), 1.34 (s, 12H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:7]2[N:8]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:39]=[N+:40]=[N-:41])(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:41][N:40]=[N:39][N:34]=3)=[CH:25][CH:26]=2)[C:7]2[N:8]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 38.8 %

Procedure:
A mixture of 95.0 mg (0.213 mmol) of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-6-methyl-5-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step F), 158 mg (0.769 mmol) of trimethyltin azide, and 2.0 ml of toluene was stirred at reflux under N2 for 24 hours. The mixture was concentrated in vacuo, and the residue was treated with 3 ml of dry MeOH and 1.0 g of silica gel. The resulting mixture was stirred at room temperature in a stoppered flask overnight. The solvent was removed by rotary evaporation in vacuo to give a dry powder, which was added as a slurry in CH2Cl2 to the top of a column of silica gel (26×2.5 cm) packed in CH2Cl2. Gradient elution of the column with 1.5% MeOH in CH2Cl2 and concentration of the product fractions yielded 40.4 mg (37%) of the title compound as a yellow gum, which, upon trituration with ether, was transformed to a tan solid (28 mg, 25%), mp 207°-208° C.; homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: COCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccc2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 2-methoxyethyl chloroformate to give the title compound. LC/MS (M+H)+: 637. Ret. time: 1.91 min. (Condition I); analytical HPLC Ret. time: 8.66 min (Condition H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([Br:16])=[N:11][NH:10][C:9]2=[O:17])=[O:5])[CH3:2].[H-].[Na+].Br[CH:21]([CH3:24])[CH2:22]O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([Br:16])=[N:11][N:10]([CH:21]([CH3:24])[CH3:22])[C:9]2=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(Br)n[nH]c(=O)c2c1
Reactant: CC(Br)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Bromo-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid ethyl ester (6 g, 0.02 mol) was dissolved in dimethylformamide (DMF) (60 ml). To this was added NaH (60%, 0.97 g, 0.024 mol) as a DMF suspension (5 ml). The mixture was stirred at room temperature for 30 minutes then 2-bromo-propanol (3.7 g, 0.03 mol) was added in one portion as a solution in DMF (5 ml). The reaction mixture was stirred for 48 hours whereupon LC-MS showed complete consumption of starting material. The DMF was removed under vacuum and the resulting residue was partitioned between DCM (100 ml) and water (100 ml), the organic layer was dried (MgSO4), filtered and concentrated under vacuum. The resulting yellow oil was recrystallised from methanol to give the title compound (2.3 g, 34% yield) as a white solid. MS (ESI+)=(M+H)+ 339 & 341
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:21])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:21][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cccc(N)c1-c1nnnn1Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Reaction time: 8 h
Yield: 63.8 %

Procedure:
2-(1-Benzyl-1H-tetrazol-5-yl)-3-methoxyphenylamine (Intermediate 13, 0.115 g) was dissolved in pyridine (0.16 mL) and DCM (2 mL). Benzenesulfonyl chloride (0.08 g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM and washed with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless solid (0.11 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[CH3:32][Li].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26]([OH:31])([C:27]([CH3:28])([CH3:30])[CH3:29])[CH3:32]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)(C)C)c2)cc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(C)(O)C(C)(C)C)c2)cc1
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-2,2-dimethylpropan-1-one (275 mg) in THF (5 mL) was added a solution (1.1 M, 1.7 mL) of methyllithium in diethyl ether at −78° C., and the mixture was stirred for 16 hr while allowing the temperature to gradually rise to room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (182 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:4]=1[CH:5]=O.C([CH2:18][S:19]([CH2:22][S:23]([CH2:26][C:27](O)=O)(=[O:25])=[O:24])(=[O:21])=[O:20])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:4]=1/[CH:5]=[CH:18]/[S:19]([CH2:22][S:23](/[CH:26]=[CH:27]/[C:4]1[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])(=[O:24])=[O:25])(=[O:20])=[O:21]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Solvent: CC(=O)O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)c(OC)c1
Yield: 68 %

Procedure:
A solution of 2,4,6-trimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 68% yield. m.p. 140-142° C.
Reaction SMILES: COC(=O)[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[C:23]=1Br.[Cl:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:19]([NH:20][CH3:21])=[O:22])[CH:10]=[N:9][N:8]2[C:23]=1[C:31]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=1
Reactant: CNC(=O)c1cccc(-c2cnn3c(Br)c(NC(=O)OC)nc3c2)c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)c(N)nc3c2)c1

Procedure:
[3-Bromo-7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester (1 eq, 0.159 mmol, 65 mg) and 2-chloropyridine-4-boronic acid (1.2 eq, 0.191 mmol, 30.1 mg) are dissolved in DME (3 ml) and water (0.75 ml) and Na2CO3 (3 eq, 0.478 mmol, 50.6 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.59 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 50 min. At the completion of this time the solvent is evaporated and the reaction mixture is dissolved in MeOH, filtered and the solvent is removed in vacuo to yield 3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo -[1,2-b]-pyridazin-7-yl]-N-methyl benzamide as a yellow solid; [M+H]+=379
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1cccc(F)c1
Temperature: 80 °C
Yield: 54 %

Procedure:
To a solution of ethyl 2-(3-fluorophenyl)acetate (I8) (10.1 g, 55.0 mmol) in CCl4 (250 mL), NBS (9.70 g, 55.0 mmol) is added and the mixture refluxed for 2 hours at 80° C. (LC-MS monitoring: complete conversion). The solvent is evaporated and the resulting crude is dissolved in DCM and purified by filtration on a silica bed in order to obtain 7.80 g of (I9) as a colorless oil (54% yield).
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.ClCCl.C[Al](C)C.C[O:26][C:27](=O)[NH:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([O:37][CH3:38])[N:30]=1>C1(C)C=CC=CC=1>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH:17][C:27]([NH:28][C:29]2[N:30]=[C:31]([O:37][CH3:38])[N:32]=[C:33]([O:35][CH3:36])[N:34]=2)=[O:26])(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)N1CCC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N2CCC2)nc(OC)n1
Yield: 23.8 %

Procedure:
In a dry flask under nitrogen was placed 1.20 gram of 2-(azetidin-1-ylsulfonyl)benzenesulfonamide, 50 ml of dry dichloromethane and 2.48 ml of 2M trimethylaluminum in toluene. To this was added 0.885 g of 4,6-dimethoxy-1,3,5-triazin-2-ylcarbamic acid methyl ester and the resultant solution was heated to reflux for 12 hours. The solution was washed with 50 ml of a water/acetic acid/1N HCl solution (40:10:0.4). The organic fraction was concentrated and chromatographed on silica gel (ethyl acetate/methylene chloride (15:85)). The slower moving portions were collected, treated with ethyl acetate and dried to give 0.45 g of a solid, m.p. 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[C:2]([Cl:1])=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:20])[C:6]=3[CH:14]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1cccc(Cl)c1CN1CCNc2ncc(I)cc21
Reactant: OB(O)c1ccnc(Cl)c1
Product: Clc1cc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)CCN3)ccn1
Yield: 31 %

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (511 mg) was reacted with 2-chloropyridine-4-boronic acid as in General Procedure 4B to give the title compound as a yellow solid (31% yield). M.p.=194° C., LCMS: m/z=405.56 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.17 (2H, t, J=4.8 Hz), 3.53 (2H, m), 4.62 (2H, s), 5.12 (1H, bs), 7.06 (1H, s), 7.42 (4H, m), 7.68 (1H, m), 7.81 (1H, d, J=1.8 Hz), 8.35 (1H, d, J=5.1 Hz).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:24][C@@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)=[O:18])[CH:14]=[C:13]([N:27]3[CH2:31][CH2:30][CH2:29][S:28]3(=[O:33])=[O:32])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44]>CO>[CH3:47][N:46]([CH3:48])[S:43]([C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[CH2:35][NH:34][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:20][C@@H:21]([CH3:26])[O:22][C@H:23]([CH3:25])[CH2:24]3)=[O:18])[CH:14]=[C:13]([N:27]3[CH2:31][CH2:30][CH2:29][S:28]3(=[O:33])=[O:32])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4])(=[O:45])=[O:44]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Reactant: COC(=O)c1nc2n(CC(=O)N3C[C@@H](C)O[C@H](C)C3)cc(N3CCCS3(=O)=O)n2c(=O)c1O
Solvent: CO
Product: C[C@@H]1CN(C(=O)Cn2cc(N3CCCS3(=O)=O)n3c(=O)c(O)c(C(=O)NCc4ccc(F)cc4S(=O)(=O)N(C)C)nc23)C[C@@H](C)O1
Yield: 43 %

Procedure:
1-[2-((2R,6R)-2,6-Dimethyl-morpholin-4-yl)-2-oxo-ethyl]-3-(1,1-dioxo-1lambda*6*-isothiazolidin-2-yl)-6-hydroxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (30 mg, 0.062 mmol) was dissolved in MeOH (1 mL) and 2-aminomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide (22 mg, 0.093 mmol) was added. The reaction was heated at reflux for 24 hours then filtered hot and the filtrate concentrated. The product was recrystalised from methanol and ether and isolated (17 mg, 43% yield) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:15][C:16](=O)[CH3:17].[I-].[Na+]>CO>[NH2:12][C:10]1[N:11]2[CH:15]=[C:16]([CH3:17])[N:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[Cl:13]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: CC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)n2cc(C)nc12
Reaction time: 24 h
Yield: 59 %

Procedure:
A mixture of methyl 2,6-diamino-5-chloronicotinate (Example 2, Step 3, 15 g, 74.4 mmol), bromoacetone (10.4 mL, 112 mmol) and sodium iodide (16.7 g, 112 mmol) in methanol (700 mL) was stirred under reflux for 22 h. Another 2.5 mL (33 mmol) of bromoacetone was added and the stirring was continued for 24 h. The reaction mixture was quenched with saturated aqueous sodium carbonate and removed methanol in vacuo. The residue was extracted with ethyl acetate (250 mL×10) adding a small amount of methanol to dissolve the organic solid. The organic extracts were dried over sodium sulfate and concentrated. Purification by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) gave a dark brown solid, which was washed with ethyl acetate and filtered to afford 10.5 g (43.9 mmol, 59%) of the title compound as a pale brown solid.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@:8]3([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12]4)[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].Cl[CH2:29][O:30][CH2:31]Cl>C1C=CC=CC=1>[CH:1]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21][CH2:29][O:30][CH3:31])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@:8]3([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12]4)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(CC1CCC1)CC3
Reactant: ClCOCCl
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COCOc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(CC1CCC1)CC3

Procedure:
One mole of compound XXVII was placed in 3 liters of benzene. One mole of sodium methoxide was added, followed by the slow addition of 1 mole of chloromethyl ether with stirring. The solution was heated to reflux to yield the title product.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([OH:15])[CH:7]=1)[CH3:2].C(OC(=O)C)(=O)C.Cl.C(Cl)Cl.[N:31]1C=CC=[CH:33][CH:32]=1>>[CH2:32]([NH:31][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:8]=1[OH:15])[CH3:33]
Reactant: c1ccncc1
Reactant: CCCCC(CC)COc1ccc(C(=O)O)c(O)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCCCC(CC)COc1ccc(C(=O)NCC)c(O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
In 30 ml of pyridine was dissolved 3.00 g (11.3 mmol) of 4-(2-ethylhexyloxy)-2-hydroxybenzoic acid (compound 14), and 2.89 g (28.4 mmol) of acetic anhydride was added to the solution dropwise on an ice-water bath. After the dropwise addition, the mixture was stirred for 20 minutes, poured into 120 ml of a 12% aqueous solution of hydrochloric acid, and extracted with 150 ml of ethyl acetate. The organic layer was washed successively with three 150 ml portions of dilute hydrochloric acid, three 150 ml portions of water, and three 100 ml portions of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by concentration. The resulting crude product was dissolved in 10 ml of methylene chloride, and a few drops of DMF were added thereto. To the mixture was further added dropwise 1.57 g (13.2 mmol) of methylene chloride at room temperature, followed by stirring for 15 minutes. The solvent was removed by distillation under reduced pressure, and the oily residue was dissolved in methylene chloride. The solution was added to 10 ml of a 70% aqueous solution of ethylamine on an ice bath. After the inner temperature was raised to room temperature, 300 ml of dilute hydrochloric acid was added thereto, and the mixture was extracted with 300 ml of ethyl acetate. The organic layer was washed successively with three 300 ml portions of water and two 300 ml portions of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was recrystallized from hexane to obtain 2.06 g (62%) of N-ethyl-4-(2-ethylhexyloxy)-2-hydroxybenzamide represented by the following chemical formula (hereinafter referred to as compound 28) as white crystals. The analytical results are shown below. ##STR49##