Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][C:19]#[CH:20])[C:13]([OH:15])=O)[N:11]=1.C[Si](CC(N)=O)(C)C.[NH2:29][CH:30]1[C:40](=[O:41])[N:32]2[C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH2:35][S:36][C@H:31]12.C(=O)(O)[O-].[Na+]>O1CCCC1.O.CN(C)C=O>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:16][O:17][CH2:18][C:19]#[CH:20])[C:13]([NH:29][CH:30]2[C:40](=[O:41])[N:32]3[C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH2:35][S:36][C@H:31]23)=[O:15])[N:11]=1
Reactant: C#CCON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.17 h

Procedure:
Phosphoryl chloride (1.4 g.) was added dropwise to a suspension of 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.7 g.) in tetrahydrofuran (15 ml.) below 7° C., and stirred at the same temperature for 10 minutes. Phosphoryl chloride (1.4 g.), trimethylsilylacetamide (1.3 g.) and N,N-dimethylformamide (0.76 g.) were added to a solution, and stirred for 20 minutes to prepare the activated acids solution. On the other hand, trimethylsilylacetamide (7.8 g.) was added to a suspension of 7-amino-3-cephem-4-carboxylic acid (1.5 g.) in tetrahydrofuran (20 ml.), and stirred at 40° C. for 30 minutes. To the solution was added all at once the activated acid solution obtained above at -20° C., and stirred for 30 minutes at 0° C. After adding water (20 ml.) to the resultant solution at -20° C., the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate and diisopropyl ether in turn, and treated with activated charcoal at pH 5.5. The solution was adjusted to pH 3.0, and the precipitates were collected by filtration and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-cephem-4-carboxylic acid, (syn isomer, 1.47 g.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: Clc1ncccn1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncccn4)CC3)nc3ccccc32)cc1
Yield: 61 %

Procedure:
A mixture of 34.5 parts of 2-chloropyrimidine, 110 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 25 parts of sodium hydrogen carbonate and 1200 parts of ethanol was stirred and refluxed overnight. The reaction mixture was cooled and filtered over Hyflo. The filtrate was evaporated. The residue was purified by HPLC over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 82 parts (61%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(2-pyrimidinyl)amino]-ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 168.4° C. (compound 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1)[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1)[CH3:2]
Reactant: CCc1cc(O)ccc1-c1nc2ncncc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: CCc1cc(OS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 1 from 8-(2'-ethyl-4'-hydroxyphenyl)-purine and methanesulfonic acid chloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])[C:12]([OH:14])=O)#[N:8].O[NH:23][C:24](=[NH:43])[C:25]1[C:26]([CH3:42])=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]2.C(N(CC)CC)C>ClCCl.CN(C=O)C.C(#N)C>[C:7]([C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:23]=[C:24]([C:25]3[C:26]([CH3:42])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][N:30]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:29][CH2:28]4)[N:43]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])#[N:8]
Reactant: Cc1c(C(=N)NO)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.75 h
Yield: 34.1 %

Procedure:
Oxalyl chloride (571 mg, 4.5 mmol) was added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (available from AK Scientific Product Catalog; 800 mg, 3.90 mmol) in dichloromethane (15 ml) followed by DMF (catalytic amount). The reaction mixture was stirred for 45 minutes, further oxalyl chloride (0.1 ml) and DMF (1 drop) were added and stirring continued for 20 minutes. The solvent was evaporated, the residue was co-evaporated with toluene then dried under high vacuum for 30 minutes. The crude acid chloride was dissolved in acetonitrile (10 ml) and added to a suspension of 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 17; 916 mg, 3.00 mmol) and triethylamine (607 mg, 6.00 mmol) in acetonitrile (15 ml). The reaction mixture was stirred at room temperature for 40 minutes then heated under reflux for 24 hours. The reaction mixture was cooled and the solvent evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated to give the crude product (1.3 g). The residue was purified by chromatography, eluting with 8-38% ethyl acetate in cyclohexane, to give the title compound (486 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([N+:19]([O-])=O)[CH:11]=1>CCO.CCOC(C)=O.[Pd]>[NH2:19][C:12]1[CH:11]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:15]=[CH:14][C:13]=1[CH2:16][C:17]#[N:18]
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1N

Procedure:
A suspension of [4-(1,3-benzoxazol-2-yl)-2-nitrophenyl]acetonitrile (100 mg, 0.36 mmol) and Pd/C (20 mg) in EtOH/EtOAc (5:1, 60 mL) was hydrogenated (35 psi) over 2d. The resulting reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The yellow solid obtained was purified by flash chromatography on silica gel eluting with MeOH:CH2Cl2 (1:19) to afford [2-amino-4-(1,3-benzoxazol-2-yl)phenyl]acetonitrile as an orange solid (M.p. 198–199° C.). 1H NMR (CDCl3, 300 MHz) δ 7.77 (m, 1H), 7.71–7.66 (m, 2H), 7.58 (m, 1H), 7.40–7.34 (m, 3H), 3.88 (s, 2H), 3.66 (s, 2H). MS (ESI) 250 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: BrCCCCSc1ccccc1
Product: O=c1ccc2cc(OCCCCSc3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 92 from 6-hydroxy-carbostyril and 4-phenylmercapto-butyl bromide.
Reaction SMILES: OO.[CH3:3][S:4][C:5]1[C:6]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)=[N:9][CH:10]=1.CC(OC(C)=O)=[O:35]>C(Cl)Cl>[CH3:3][S:4]([C:5]1[C:6]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:35]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Agent: OO
Solvent: ClCCl
Product: CS(=O)c1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
The H2O2 (0.32 ml, 3.13 mmole) solution was added to a stirred solution of phenyl 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenylcarbamate (0.54 g, 1.28 mmole), CH2Cl2 (7 ml), Ac2O (0.13 ml), and silica gel (230-400 mesh, 200 mg). The solution was stirred at room temperature for 2-3 hrs, and quenched with NaHSO3(aq) (70 ml), and NaHCO3(aq) (70 ml), the solvent was removed, the residue was chromatographed to give the product (71%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Na].[CH2:13]([O:15][P:16]([CH2:21][OH:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>CN(C=O)C>[CH2:13]([O:15][P:16]([CH2:21][O:22][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([O:17][CH2:18][CH3:19])=[O:20])[CH3:14]
Reactant: CCOP(=O)(CO)OCC
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOP(=O)(COc1ccc(Br)cc1[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-fluoro-5-bromonitrobenzene (1 mmole) in DMF (5 mL) was cooled to 0° C., and treated with a solution of freshly prepared sodium salt of diethylhydroxymethylphosphonate (1.2 mmole) in DMF (5 mL). The mixture was stirred at room temperature for 16 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-bromonitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH3:21])[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2>C(O)(=O)C.Cl>[Cl:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH3:21])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOC(=O)c1cn(C)c2nc3cc(Cl)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reaction time: 4 h
Yield: 92.4 %

Procedure:
A suspension of 15 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 150 cm3 of acetic acid and 150 cm3 of hydrochloric acid as a 17.5% aqueous solution is heated at a temperature close to 100° C., with stirring, for 4 hours. After cooling to a temperature close to 20° C., the product is drained and washed with twice 150 cm3 of ethanol and then twice 100 cm3 of diethyl ether. 12.7 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a beige solid which sublimes at 400°-405° C. and is used for the subsequent steps without further purification.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[N:11][CH:12]=1.[CH:21](OC)=[O:22].C([O-])(O)=O.[Na+]>C1COCC1.CC(C)=O.CCCCCC>[Cl:6][C:7]1[C:8]([CH:21]=[O:22])=[C:9]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[N:11][CH:12]=1
Reactant: Clc1cncc(OCc2ccccc2)c1
Reactant: COC=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(Cl)cncc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a stirred solution of dilsopropylamine (4.5 mL, 31.78 mmol) in anhydrous tetrahydrofuiran (20 mL) under nitrogen atmosphere at −5° C. was added dropwise n-BuLi in hexanes (2.5 M solution, 12.8 mL, 31.78 mmol) maintaining internal temperature of the reaction mixture below 0° C. The reaction mixture was stirred at −10° C. for 10 minutes, then at 0° C. for 30 minutes. This was cooled to −78° C. and a solution of Example 236A (5.8 g, 26.5 mmol) in anhydrous tetrahydroffiran (30 mL) was added slowly. Stirring at −78° C. was continued for 1 hour. Then the reaction was quenched with dropwise addition of methyl formate (5 mL, 79.5 mmol) in anhydrous THF (15 mL) and stirred at −78° C. for 3.5 hours. Internal temperature of the reaction mixture was maintained at or below −74° C. throughout the reaction. After 3.5 hours, the reaction mixture was poured into an ice cold saturated aqueous solution of NaHCO3 (200 mL) and stirred for 15 minutes. The mixture was partitioned with ethyl acetate (250 mL), organic layer was separated and washed with brine (2×60 mL). The dried (MgSO4) organic layer was concentrated under reduced pressure to obtain the crude product (8.5 g). The title compound was obtained in 75% yield (4.2 g) by flash chromatography on silica gel eluting with 6% acetone-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]3)=[N:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:13]([C:12]4[C:2]([Cl:1])=[CH:3][C:4]5[S:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=5[CH:11]=4)=[O:15])[CH2:35][CH2:36]3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white solid (42 mg, 60% yield) following Scheme 3 and in analogy to Example 35 using 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31 mg, 0.12 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [NH2:1][C:2]([CH2:10][CH2:11][CH3:12])=[C:3]([Cl:9])[C:4](OCC)=[O:5].[CH:13]([NH2:15])=O.C[O-].[Na+]>CO>[Cl:9][C:3]1[C:4]([OH:5])=[N:15][CH:13]=[N:1][C:2]=1[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(N)=C(Cl)C(=O)OCC
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1ncnc(O)c1Cl

Procedure:
58.1 g (0.30 mol) of ethyl 3-amino-2-chloro-2-hexenoate are reacted with 47.7 g (1.1 mol) of formamide and 140 ml of sodium methylate solution in 175 ml of methanol and worked up in analogy to Example 9 (reaction time 6 h). Yield: 42.2 g (81.5%)
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([CH3:22])=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].[C:23](O)(=[O:25])[CH3:24]>[Fe]>[C:23]([NH:19][C:17]1[C:16]([CH3:22])=[CH:15][C:3]([O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[CH:18]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c([N+](=O)[O-])cc1C
Agent: [Fe]
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(NC(C)=O)cc1C
Temperature: 0 °C

Procedure:
A mixture of 3.1 g (10 mmol) of the 5-(2,5-dimethyl-4-nitrophenoxy)-2,2-dimethylpentanoic acid, methyl ester (Example 1) and 2.0 g (3.5×10 mg-atom) of iron powder (40 mesh) in 35 mL of glacial acetic acid is stirred at reflux for 1.5 hours and poured into an ice-water mixture (300 mL). After scratching the oil crystallizes and the solid is collected on a filter, washed with water, and dried in vacuo at 40° C. The filtrate is extracted with dichloromethane. The extracts are washed with water, dried (magnesium sulfate), filtered, and evaporated leaving a medium brown oil which partially crystallizes. Recrystallization from 75 mL of isopropyl ether in the presence of charcoal affords 1.0 g of the title compound; mp 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[C:36]=4[CH3:42])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.Cl[CH2:44][O:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:44][O:45][CH3:46])[C:36]=4[CH3:42])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(O)c1C
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc(OCOC)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of EXAMPLE 158B (0.6 g), chloro(methoxy)methane (0.18 g) and cesium carbonate (0.9 g) was suspended in N,N-dimethylformamide (15 mL). After it stirred at room temperature for 30 minutes, the crude product was purified by preparative HPLC using a 250×50 mm C18 column and eluting with 20-100% CH3CN vs. 0.1% trifluoroacetic acid in water.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N+:13]([O-])([O-:15])=[O:14].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1
Reactant: Cc1nc(-c2ccccc2)c[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1

Procedure:
Prepared by nitrogenation of 2-methyl-4-phenyl-imidazole (melting point: 154-156° C.)) in concentrated sulphuric acid with ammonium nitrate analogously to Example D.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[CH:12].N>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: C#Cc1ccccc1F
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Fc1ccccc1-c1cc(-c2cccnc2)no1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-2-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.34-7.56 (m, 2H), 7.58-7.74 (m, 3H), 8.02 (td, J=7.6, 1.7 Hz, 1H), 8.47 (dt, J=7.9, 2.0 Hz, 1H), 8.77 (dd, J=4.9, 1.5 Hz, 1H), 9.23 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29].[OH-].[Na+]>CO>[O:1]=[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: COC(=O)CCCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)nc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75.3 %

Procedure:
A mixture of methyl 2-oxo-4,5-diphenyl-1(2H)-pyrimidinenonanoate (4.70 g, 11 mmol), 5N NaOH solution (7.40 mL, 36 mmol) and methanol (80 mL) was stirred at room temperature for 75 minutes and than at reflux for 75 minutes before being cooled and concentrated. The residue was diluted with water and 2N HCl was added until pH=2. The mixture was extracted with CH2Cl2, the extracts combined, dried over sodium sulfate and the solvent evaporated to leave an oil that crystallized. Recrystallization from a mixture of diethyl ether and CH2Cl2 afforded 2-oxo-4,5-diphenyl-1(2H)-pyrimidinenonanoic acid (3.35 g, 73%), m.p. 120°-123° C.
Reaction SMILES: [S:1]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[S:1]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH:19][C:20](=[O:22])[CH3:21])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCCCC1S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: CC(=O)NC1CCCCC1S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Alternatively, compound 9 is reductively aminated with ammonium acetate and sodium cyanoborohydride to provide for intermediate 11 which, upon removal of the lauroyl groups, affords 2-aminocyclohexyl 1-thio-β-D-galactopyranoside, B2. Compound B2 can then be acylated with acetic anhydride to give 2-acetamidocyclohexyl 1-thio-β-D-galactopyranoside, C2. Alternatively, intermediate 11 can be acylated with phthalic anhydride to provide for intermediate 12 which affords 2-(2-carboxybenzamidocyclohexyl 1-thio-β-D-galactopyranoside, D2, by removal of the lauroyl groups using the conditions described above.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25]>CS(C)=O.O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
44.5 g (280 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 750 ml of anhydrous dimethyl sulphoxide, and 33.4 g (298 mmol) of potassium tert-butoxide are added a little at a time at room temperature. The suspension is stirred at this temperature for 1 h, 38.5 g (280 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are then added and the reaction solution is heated at 80° C. for 20 h. The solution is allowed to cool and carefully diluted with water. The resulting crystalline precipitate is filtered off, washed with a little water and dried under reduced pressure. This gives 62 g (80% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>C(#N)C>[CH2:34]([N:31]1[C:32]2[N:33]=[C:14]([CH2:13][C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[N:8][CH:7]=3)[NH:26][C:27]=2[C:28](=[O:40])[N:29]([CH3:39])[C:30]1=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc2cncc(CC(=O)O)c2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C

Procedure:
A suspension of (6-methoxy-isoquinolin-4-yl)-acetic acid (3.5 g, 13.82 mmol) in acetonitrile (70 ml) is treated sequentially with Hunig's base (6.15 ml, 36 mmol), O-(7-benzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.29 g, 16.6 mmol) and 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (3.22 g, 15.2 at mmol) while the solution is stirred at room temperature. The reaction is stirred at ambient temperature for 2 h, prior to evaporation of the solvent. The residue is tritruated with ethyl acetate (50 ml) filtered and washed with ethyl acetate and then dried at 50° C. under reduced pressure. The resulting intermediate is suspended in a mixture of methanol (30 ml) and 4M aqueous sodium hydroxide (60 ml) and heated at 80° C. for 45 minutes. This suspension is neutralised with acetic acid and cooled to 0-5° C. overnight. The resultant solid is collected by filtration, and washed with methanol/water 1:9 (30 ml) followed by methanol (30 ml). Drying under high vacuum at 50° C. affords 3-isobutyl-8-(6-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 394.5.