Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:40]=[C:11]2[C:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[C:13]([CH3:29])[C:14]([C:16]3[N:20]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[N:19]=[CH:18][CH:17]=3)=[CH:15][N:10]2[N:9]=1.[CH3:42][O:43]S(C1C=CC=CC=1)(=O)=O.[CH3:53]C(C)=[O:55]>>[CH:42]([O-:43])=[O:55].[C:25]([C:24]1[CH:23]=[CH:22][C:21]([N:20]2[C:16]([C:14]3[C:13]([CH3:29])=[C:12]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=4)[C:11]4[N:10]([N:9]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][N+:2]([CH3:53])([CH3:1])[CH3:41])[N:40]=4)[CH:15]=3)=[CH:17][CH:18]=[N:19]2)=[CH:28][CH:27]=1)#[N:26]
Reactant: COS(=O)(=O)c1ccccc1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CC(C)=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCC[N+](C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: O=C[O-]
Temperature: 55 °C

Procedure:
To a solution of 4-{5-[2-(4-dimethylamino-butylamino)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 30, 44 mg, 0.079 mmol) in acetone (0.4 mL) was added methylbenzenesulfonate (12 μL, 0.087 mmol) at ambient temperature. The reaction mixture was heated at 55° C. under N2 for 2.5 hrs. A further quantity of methylbenzenesulfonate (3.2 μL) was added and the mixture was heated at 55° C. for 1 hr. Once cooled the volatiles were evaporated in vacuo and the residue azeotroped with diethyl ether. The resultant residue was subjected to preparative C18 HPLC, eluting with a gradient of 20-70% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (10 mg).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[CH3:24][CH:25](Cl)[O:26][C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28].C(OCC)(=O)C>CN(C=O)C.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH:25]([O:26][C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])[CH3:24])=[O:13])[CH3:3]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=C(C(=O)OC(C)OC(=O)OC3CCCCC3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 50 °C
Yield: 19.2 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.43 g) was dissolved in dry DMF (4.3 ml) and thereto was added triethylbenzylammonium chloride (0.25 g). Thereto was dropped 1-chloroethylcyclohexylcarbonate (0.62 g) and the mixture was stirred under heating to 50° C. One hour later, the mixture was cooled to room temperature and thereto was added ethyl acetate. The mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2→1:3→ethyl acetate only) to give 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.12 g, yield 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19].Cl>ClCCl.CN(C1C=CN=CC=1)C>[C:18](=[O:19])([O:20][CH3:21])[O:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)Cl
Reactant: COc1cc(C)ccc1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
2-methoxy-4-methylphenol (250 mmol) was dissolved in dry dichoromethane (500 ml) with pyridine (392 mmol) and DMAP (N,N-dimethyl-4-aminopyridine, 4.26 mmol). Methyl chloroformate (317 mmol) was added slowly to this solution and the reaction was stirred at room temperature for 3 hours. The reaction mixture was then poured onto a 2M HCl solution (120 ml), and the aqueous layer was extracted twice with dichloromethane (50 ml). Then the combined organic layers were washed twice with water (100 ml), dried over MgSO4 and filtered. The solvent was evaporated and the residue distilled under reduced pressure (120-140° C., 0.4 mbar) to give 38 g (186 mmol, 74% yield) of pure 2-methoxy-4-methyl-phenyl methyl carbonate.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:9]=1[CH2:17][C:18]#N.[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:18](=[O:2])[CH2:17][C:9]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH3:6])[CH3:21]
Reactant: COc1cccc([N+](=O)[O-])c1CC#N
Reactant: O=S(=O)(O)O
Reactant: CCO
Product: CCOC(=O)Cc1c(OC)cccc1[N+](=O)[O-]
Yield: 72 %

Procedure:
Sulfuric acid (1 mL) was slowly added to a solution of (2-methoxy-6-nitro-phenyl)-acetonitrile (200 mg, 1.04 mmol) in 95% ethanol (2 mL). The mixture was heated at reflux overnight then quenched into ice cold water and extracted with diethyl ether (10 mL). The organic phase was washed with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (2-methoxy-6-nitro-phenyl)-acetic acid ethyl ester (180 mg, 72%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=2)=[N:4]1)[CH3:2]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:45][C:42]1[CH:41]=[CH:40][C:39]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[N:14]([S:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)(=[O:31])=[O:32])[C:15]([C:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=5)=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:44][CH:43]=1
Reactant: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(N)cc2)n1
Reaction time: 16 h

Procedure:
A solution of 1,1-dimethylethyl 4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (0.46 mmol) in ethyl acetate (5 mL) was purged with nitrogen and palladium(II) hydroxide/Carbon (30 mg of 20 wt. % palladium) added. The reaction was purged with hydrogen gas and allowed to stir vigorously under 1 atm of hydrogen. After 16 h, the reaction was purged with nitrogen and filtered though a pad of Celite (rinsing with ethyl acetate). The filtrate was concentrated under reduced pressure to give the title compound as a yellow foam which was used without further purification. ESMS [M+H]+: 625.6
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1O>CN(C)C=O>[N+:11]([C:9]1[CH:10]=[CH:5][C:2]([C:1]2[O:3][C:6]3[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=3[N:4]=2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: CCO
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1

Procedure:
About 60 grams (0.3 mole) of the 4-nitrophenylchloroxime is mixed with 340 milliliters of ethanol, 60 grams (0.39 moles) of 2-amino-4-nitrophenol and 60 milliliters of dimethylformamide. The mixture is heated to reflux for about 6.5 hours, filtered, washed with methanol and air dried. Approximately 55 grams of 2-(p-nitrophenyl)-5-nitrobenzoxazole are obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.N1C=CC=CC=1.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[S:27]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([NH2:38])=O)(=[O:29])=[O:28]>C(#N)C>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[S:27]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]#[N:38])(=[O:28])=[O:29]
Reactant: NC(=O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: N#CC1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
Oxalyl chloride (5.00 ml) was added dropwise to a solution of dimethylformamide (4.43 ml) in acetonitrile (200 ml) at 0° C. The mixture was stirred for 20 mins. and a suspension of pyridine (9.66 ml) and 1-(1H-benzo[d]imidazol-2-ylsulfonyl-2-piperidinecarboxamide (14.73 g) [see Preparation 17] in acetonitrile (100 ml) was added over a period of 10 mins. The reaction mixture was stirred for a further 20 mins. after which time the solvent was removed under reduced pressure. The residue was diluted with diethyl ether and washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 70:30, by volume, hexane:ethyl acetate to afford 1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidinecarbonitrile (4.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+].ClC1C=C2C(=C(Cl)C=1)CN(C)CC2C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH3:11])=[CH:6][CH:7]=1
Reactant: CN(CC(=O)c1ccc(Br)cc1)Cc1ccc(Cl)cc1Cl
Agent: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Product: CN(Cc1ccc(Cl)cc1Cl)CC(O)c1ccc(Br)cc1
Yield: 86 %

Procedure:
Intermediate 1 was reduced to the corresponding alcohol with 2 equivalents of NaBH4 in analogy to the manner described for intermediate 4, example 1, and the alcohol was isolated in a yield of 86%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH:25]([C@@H:28]1[C:32]([CH3:34])([CH3:33])[O:31][C:30](=[O:35])[NH:29]1)([CH3:27])[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[C@H:28]([CH:25]([CH3:26])[CH3:27])[C:32]([CH3:33])([CH3:34])[O:31][C:30]4=[O:35])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: CC(C)[C@H]1NC(=O)OC1(C)C
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC(C)(C)[C@H]4C(C)C)cc3C)CC2)c(C)c1
Yield: 3.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (867 mg) described in Preparation Example 67 and (R)-(+)-4-isopropyl-5,5-dimethyloxazolidin-2-one (409 mg), the title compound (35 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:14]([NH2:19])[C:15]([NH2:18])=[N:16][N:17]=1)=[CH:7][CH:6]=2.[CH:20]([CH:22]=O)=O.C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:14]3[N:19]=[CH:20][CH:22]=[N:18][C:15]3=[N:16][N:17]=1)=[CH:7][CH:6]=2
Reactant: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)n1N
Reactant: O=CC=O
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2ccc(Cc3nnc4nccnn34)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(3-bromo-quinolin-6-ylmethyl)-[1,2,4]triazole-3,4-diamine (977 mg, 3 mmol), glyoxal (40% solution in water, 5 mL), acetic acid (10 mL) and water (2 mL) was stirred at ambient temperature for 18 hours. After such time the mixture was filtered and the filtrate was concentrated onto silica gel and via flash column chromatography (SiO2 12 g, dichloromethane/CH3OH, 0-10%) to return the title compound a white solid (298 mg, 29%). Analytical data presented in Table 1.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1SC>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:21]2[N:20]([CH3:19])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc2ccccc2n1C
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: Cn1c(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc21

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.41 g) and 1-methyl-2-methylthiobenzimidazole (1.57 g) were fused at 150° C. for 6 hours. The cooled residue was subjected to column chromatography on silica (chloroform:methanol 19:1) to give the title compound as an oil. This was treated with maleic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-1-methylbenzimidazole dimaleate (0.87 g), m.p. 153°-154° C. (recrystallised from isopropanol).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:3]=2[O:2]1.[NH:12]([CH2:19][CH2:20][C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(C)=O.C[O-].[Na+]>CO>[NH:12]([CH:19]=[C:20]([CH2:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)[C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: N#CC(=CNc1ccccc1)Cc1ccc2c(c1)OCO2
Temperature: 5 °C

Procedure:
Piperonaldehyde (45 g.), β-anilinopropionitrile (52 g.) and dimethylsulfoxide (96 ml.) were heated together to 120°C and a solution of sodium methylate (2.5 g.) in methanol (12 ml.) was added over a 5 min. period. The temperature was maintained at 115°-120°C for 1 hr. and the mixture was then poured into ice-water. The resulting gum was collected by decantation and was likewise washed with water (2 × 100 ml.). Methanol (100 ml.) was then added and the mixture was heated until solution was complete. Cooling to 5°C C gave β-anilino-α-piperonylacrylonitrile as crystalline solid which was collected, and washed with cold methanol, ether, and pentane. Wt.=45 g. (54%) m.p. 150.5°-151°C (recrystallised from methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])[CH3:2].C(N(CC)CC)C.Cl.[NH2:37][OH:38]>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:37][OH:38])=[CH:22][CH:21]=1)[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCC)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
The (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester (136 mg) described in example 2.2 was dissolved in ethanol. Triethylamine (712 mg) and hydroxylamine hydrochloride (245 mg) were added and the mixture was stirred for 18 h at room temperature. The mixture was concentrated; the residue was dissolved in CH2Cl2 and washed with water. The product was purified by column chromatography (CH2Cl2/MeOH) to give 87 mg of (RS)-(3,5-diethoxy-2-fluoro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester as a colorless foam. MS: 420 ([M+H]+).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1
Reactant: Clc1nccs1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2nccs2)cc1
Reaction time: 6 h
Yield: 27.8 %

Procedure:
A mixture of 2-chlorothiazole (2.0 g), ethyl 4-hydroxybenzoate (2.8 g), potassium carbonate powder (3.5 g) and dimethylformamide (30 ml) is stirred at 135°-140° C. for 6 hours. The reaction mixture is treated in the same manner as in Example 1. From the eluate of 30% ether-benzene, ethyl 4-(2-thiazolyloxy)benzoate (1.16 g) is obtained. IR νmaxCCl4 1730, 1280 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=O)[CH3:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Cl.[CH3:26][O:27][NH2:28].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[N:28][O:27][CH3:26])[CH3:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: CON
Reactant: COC(=O)c1c(Sc2nc(OC)cc(OC)n2)cccc1C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C(C)c1cccc(Sc2nc(OC)cc(OC)n2)c1C(=O)OC
Temperature: 25 °C
Yield: 60 %

Procedure:
1.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)thio]-6-acetylbenzoate and 0.5 g of methoxyamine hydrochloride were dissolved in 6 ml of methanol, and the resultant solution was refluxed for 15 minutes. After cooling the mixed liquor to room temperature, 0.8 g of potassium carbonate was added to this liquor and the resultant liquor was heat-refluxed for 3 hours. The reaction liquor was poured into a large amount of water, and an oily product thus precipitated was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and was dried to distill off ethyl acetate under reduced pressure. The residue thus obtained was purified by chromatography to obtain 0.65 g of the aimed compound (refractive index=1.5709) at a yield of 59%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>CN(C=O)C.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][N:6]3[C:5]4[C:9](=[N:10][C:2]([Cl:1])=[N:3][C:4]=4[Cl:11])[N:8]=[CH:7]3)=[CH:27][CH:26]=2)=[O:24])=[CH:33][CH:34]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3nc(Cl)nc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
To a solution of 2,6-dichloropurine (3.25 g) in DMF (34 ml) was added potassium carbonate (2.85 g) as well as 4-(4-chlorobenzoyl)benzyl bromide (5.32 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1-1:3) to provide the title compound (1.37 g, 19%) as colorless (anhydrous) powder. 1H-NMR (CDCl3) δ5.76(2H,s), 7.21-7.85(8H,m), 8.33(1H,s).
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][CH:8]=[CH2:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[OH2:12]>>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:12])[C:2]=1[CH3:11])[CH:8]=[CH2:9]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: O
Product: C=CCC1=C(C)C(O)CC1=O
Temperature: 30 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
Twenty grams of a 300-mesh activated alumina (Wako Junyaku Co.) for use in column chromatography was suspended in 100 ml of a toluene-ether (1:1 by volume) mixture admixed with 2.4 g of water. To the suspension, was added 4.0 g of 4-hydroxy-4-methyl-5-allyl-2-cyclopentenone. The suspension was stirred at 30° C. for 24 hours and the alumina was separated by filtration. The separated alumina was extracted three times with 50 ml of a toluene-ether (1:1 by volume) mixture. The extract solutions were combined with the filtrate and concentrated. The concentrate was fractionally distilled in vacuo to obtain 2.5 g (62.5% yield) of 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone boiling at 155° C./1 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[CH:15]=O.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:15]([C:14]4[CH:17]=[CH:18][C:19]([C:20]([F:23])([F:22])[F:21])=[C:12]([F:11])[CH:13]=4)[CH2:31][NH:30][C:35]3=[O:36])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(C(F)(F)F)c(F)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 3-fluoro-4-(trifluoromethyl)benzaldehyde (0.768 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.585 mL, 4.2 mmol), di-(imidazol-1-yl)methanone (0.681, 4.2 mmol) as described in method 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCNCC3)ccc2S(C)(=O)=O)c1OC
Yield: 2.8 %

Procedure:
A solution of [1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl]-(5-fluoro-2-methanesulfonyl-phenyl)-amine (0.52 g, 1.34 mmol), piperazine (0.23 g, 2.68 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.68 mmol) in acetonitrile was stirred at 80° C. for 24 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield the crude residue which was purified by preparative TLC (0.5% NH4OH/9.5% methanol/dichloromethane) to afford [1-(5-chloro-2,3-dimethoxy-phenyl)-ethyl]-(2-methanesulfonyl-5-piperazin-1-yl-phenyl)-amine (17 mg, 3%). 1H NMR (400 MHz, CD3OD): δ 7.42 (d, 1H), 6.87 (m, 2H), 6.25 (dd, 1H), 5.90 (s, 1H), 4.87 (m, 1H), 3.85 (s, 1H), 3.81 (s, 1H), 3.05-3.2 (m, 4 H), 3.78 (m, 4H), 1.49 (d, 3H). MS (ESI) m/z: Calculated: 453.98; Observed: 454.4 (M+H+); 476.4 (M+Na+); 930.8 (2M+Na+). Mol. Wt.: 453.98 (C21H28ClN3O4S).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[C:22]1([CH2:28]C[Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C.O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN(C)C(CCc1ccccc1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (21.93 g, 97 mmol) in abs. THF (180 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of phenylethylmagnesium chloride in THF (242 ml, 242 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.