Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[S:14][C:13]([CH:15]=[N:16][OH:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:11]1[CH:12]=[C:13]([CH:15]=[N:16][OH:17])[S:14][C:10]=1[N+:7]([O-:9])=[O:8])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(C=NO)s1
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(C=NO)sc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Potassium tertiary-butoxide (960 mg, 8.6 mmol) was dissolved in N,N-dimethylformamide (10 ml) and the solution cooled to −30° C. A solution of 5-nitro-2-thiophenecarboxaldehyde oxime (400 mg, 2.86 mmol) and ethyl chloroacetate (356 mg, 2.86 mmol) was added dropwise in dry N,N-dimethylformamide (5 ml) over 5 minutes. The reaction mixture was stirred at −30° C. for 30 minutes then quenched with 2M HCl (50 ml), diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using hexane/diethyl ether (1:2) as eluent to give 200 mg of ethyl-5-[(hydroxyimino)methyl]-2-nitro-3-thiopheneacetate as a tan solid. MS(ES): m/e 227 [M+H].
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]#[N:24])=[CH:17][C:16]=2[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35]C)=[C:31]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[CH:30]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:35][C:32]1[CH:33]=[CH:34][C:29]([C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]#[N:24])=[CH:17][C:16]=3[CH2:25][CH:26]([CH3:27])[CH3:28])=[CH:14][C:9]=2[CH2:5][CH:6]([CH3:8])[CH3:7])=[CH:30][C:31]=1[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2CC(C)C)cc1Cc1cccc2ccccc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(-c2ccc(O)c(Cc3cccc4ccccc34)c2)c(CC(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
1.02 ml (1.02 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 192.9 mg (0.34 mmol) 3-(2′,2″-Diisobutyl-4-methoxy-3-naphthalen-1-ylmethyl-[1,1′:4′, 1″]-terphenyl-4″-yl)propionitrile (76) in 20 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 12 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 117.9 mg (0.21 mmol, 62.85%) 3-(4-Hydroxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′, 1″]terphenyl-4″-yl)propionitrile (32) as a colorless oil. Rf (hexanes/EtOAc (2+1))=0.37. 1H-NMR (500 MHz, CDCl3): δ=0.59 (d, 6H, J=6.62 Hz, 2*CH3), 0.70 (d, 6H, J=6.78 Hz, 2*CH3), 1.50 (m, 1H, CH), 1.65 (m, 1H, CH), 2.32 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.25 Hz, CH2), 2.62 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.94 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.47 (s, 2H, CH2Naphthyl), 4.80 (s, 1H, OH), 6.86 (d, 1H, J=8.36 Hz), 6.98-7.16 (m, 9H), 7.38 (m, 1H), 7.43-7.48 (m, 2H), 7.73 (dm, 1H, J=8.73 Hz), 7.83 (m, 1H), 8.06 (m, 1H). MS (EI): m/z=552 (30), 551 (65), 446 (21), 419 (21), 178 (19), 155 (15), 149 (24), 142 (18), 141 (100), 128 (28), 97 (23), 85 (26), 83 (25), 71 (39), 69 (30), 57 (74), 55 (35). HR-MS (EI): Calcd. for C40H41NO: 551.318814. Found: 551.318768.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].O>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[C:2]2[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CNc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(F)c(NC(=O)OC(C)(C)C)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloro-5-nitropyrimidin-4-yl thiocyanate (2.73 g, 12.6 mmol) and sodium hydrogen carbonate (2.76 g, 32.9 mmol) in tetrahydrofuran (80 mL) was added a solution of tert-butyl [2-fluoro-5-(methylamino)phenyl]carbamate (2.63 g, 11.0 mmol) produced above in tetrahydrofuran (20 mL), and the mixture was stirred for 1.5 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {2-fluoro-5-[methyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCNCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: OCCN(CCO)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
From diethanolamine and trityl chloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:10])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9].[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18]([NH:10][C:4]2[S:5][C:6]([CH2:7][CH2:8][CH3:9])=[C:2]([CH3:1])[N:3]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCCc1sc(N)nc1C
Product: CCCc1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C
Yield: 46 %

Procedure:
The title compound was prepared from 4-methyl-5-propyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 110 mg (46% yield): HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (344.0403).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[C:7]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[NH:8][NH2:9]>CO>[O:4]1[CH2:5][CH2:6][C:2](=[N:9][NH:8][C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: O=C1CCOC1
Reactant: NNC(=O)OCc1ccccc1
Solvent: CO
Product: O=C(NN=C1CCOC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105 %

Procedure:
3-oxotetrahydrofuran (5.70 g) was dissolved in methanol (150 mL), and benzyl carbazate (10 g) was added to the solution. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated. 14.8 g of a residue was obtained as a crude purified product. This was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18]Br.O>C(O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC#CCOC1CCCCO1
Reactant: Sc1ccccc1
Solvent: CCO
Solvent: O
Product: C(#CCSc1ccccc1)COC1CCCCO1

Procedure:
A stirred solution of sodium ethoxide in ethanol, obtained from 1.3 g of sodium and 50 ml of absolute ethanol was treated dropwise with 5.5 g (0.05 mol) of thiophenol in 15 ml of absolute ethanol. The reaction mixture was refluxed for 1 hour and then treated with 5.84 g (0.025 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether, refluxing the mixture for 2 additional hours. It was then cooled, poured into water and extracted with methylene chloride. The organic extract was washed with water, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, to produce 4-phenylthiobut-2-yn-1-ol tetrahydropyranyl ether, as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cccc(Cl)c1Cl
Product: O=c1cc(N2CCN(Cc3cccc(Cl)c3Cl)CC2)nc[nH]1

Procedure:
6-[4-(2,3-Dichloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,3-dichlorobenzaldehyde. Mass spectrum (ES) MH+=339.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:30][NH:29][CH2:28]2)=[C:22]([CH3:31])[CH:21]=1>O1CCCC1>[F:12][C:9]1[CH:10]=[N:11][C:2]([N:29]2[CH2:30][CH:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=3[CH3:31])[CH2:28]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)cnc1Cl
Reactant: Cc1cc(F)ccc1NC1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cnc1N1CC(Nc2ccc(F)cc2C)C1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
A mixture of methyl 2-chloro-5-fluoronicotinate (D69) (199.85 mg, 1.054 mmol) and potassium carbonate (291 mg, 2.108 mmol) in tetrahydrofuran (2 ml) was stirred under N2 nitrogen 15 min at room temperature. N-(4-fluoro-2-methylphenyl)azetidin-3-amine (D55) (190 mg, 1.054 mmol) was added and the resulting mixture was stirred 1 day at room temperature. The residue obtained after solvent evaporation was purified by Biotage SNAP-Si column eluting with a mixture cyclohexane/ethyl acetate from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D90)(155 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH2:19])=[CH:7]2.CCN(C(C)C)C(C)C.[Cl:29][C:30]1[C:35]([O:36][CH3:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1>C(O)CCC>[Cl:29][C:30]1[N:31]=[CH:32][N:33]=[C:34]([NH:19][CH2:18][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:35]=1[O:36][CH3:37]
Reactant: COc1c(Cl)ncnc1Cl
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1c(Cl)ncnc1NCc1cc2cccc(Cl)c2nc1-c1ccccc1

Procedure:
A mixture of (8-chloro-2-phenylquinolin-3-yl)methanamine (0.035 g, 0.13 mmol) in n-butanol (3 mL) was treated with DIEA (0.046 mL, 0.26 mmol, 2.0 eq) followed with 4,6-dichloro-5-methoxypyrimidine (0.025 g, 0.14 mmol, 1 eq) at 100° C. for 8 h. The reaction mixture was concentrated and purified by column chromatography on a Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to provide 6-chloro-N-((8-chloro-2-phenylquinolin-3-yl)methyl)-5-methoxypyrimidin-4-amine as a white solid. 1H-NMR (DMSO-d6) δ ppm 8.33 (s, 1H), 8.20 (t, 1H), 8.02-8.04 (m, 1H), 7.99 (s, 1H), 7.93-7.95 (m, 1H), 7.70 (d, J=6.60, 1H), 7.46-7.61 (m, 1H), 4.73 (d, J=5.71, 2H), 2.51 (s, 3H), Mass Spectrum (ESI) m/e=412 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[NH2:4].[C:29]([O-])([O-])(OCC)[CH3:30].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]2[N:4]=[C:29]([CH3:30])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Oc1ccc(Oc2ccc(CNc3cccc(F)c3N)cc2)cc1
Reactant: CCOC(C)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1nc2c(F)cccc2n1Cc1ccc(Oc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A mixture of 2-fluoro-6-[4-(4-methylsulfonyloxyphenoxy)benzylamino]aniline (300 mg) and ethyl ortho-acetate (181 mg) was heated at 150° to 160° C. for 24 hours while stirring. The reaction mixture was cooled to room temperature, toluene (100 ml) and a 5% sodium hydroxide solution (50 ml) were added thereto, and the resultant mixture was stirred for 10 minutes The toluene layer was separated, washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to eliminate toluene. The residue was purified by silica gel column chromatography to give 4-fluoro-1-[4-(4-methylsulfonyloxyphenoxy)benzyl]-2-methylbenzimidazole (243 mg) as white crystals m.p., 48°-56° C.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[C:8]1([CH2:14][SH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:16][C:17]1[N:25]=[C:24](Cl)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Cl-].[Na+].O>[NH2:16][C:17]1[N:25]=[C:24]([S:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: SCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCc2ccccc2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (410 mg, 10 mmol, 60% in mineral oil) were added α-toluenethiol (1.7 ml, 14 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 100° C. for 4.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (97 mg, yield 73%).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[CH:13]=[O:14].C1(C)C=CC=CC=1>O>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[C:13]([OH:2])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC1CCCC(C)(C)C1C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCCC(C)(C)C1C(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 40 g of nitric acid (60% aqueous solution) and heated to 55° C. To the solution was added dropwise 95 g (0.62 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde (4) composed of 90% of the trans-form and 10% of the cis-form synthesized in Synthesis Example 2-A) described above over a period of 2 hours. Thereafter, the reaction was carried out for 3 hours at the same temperature. Then, 100 g of toluene and 100 g of water were added to the reaction mixture at room temperature to wash with water and form an organic layer and an aqueous layer separately. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, and 80 ml of the toluene was distilled off under reduced pressure by means of an evaporator, to provide 104 g of crude 2,2,6-trimethylcyclohexanecarboxylic acid (5) composed of 89% of the trans-form and 11% of the cis-form (boiling point: 44° to 54° C.). The mass spectra of the cis- and trans-forms of the acid (5) were the same as those in Synthesis Example 1.
Reaction SMILES: [NH2:1][C:2](=[N:33]O)[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([NH2:28])=[N:26]O)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[NH2:33][C:2](=[NH:1])[C:3]1[CH:32]=[CH:31][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:28])=[NH:26])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: NC(=NO)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(=N)N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
To an acetic acid (150 mL) suspension of 14.9 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-hydroxybenzamidine was added 5.97 mL of acetic anhydride at room temperature, which was then stirred at room temperature for 1 hour and 20 minutes. To this mixture was added 1.50 g of 5% palladium-carbon, which was then stirred under hydrogen atmosphere for 4 hours and 40 minutes. Insoluble matter was filtered off, and 55 mL of 6.0 mol/L hydrochloric acid was then added. The solvent was distilled off under reduced pressure, and ethanol was added to the resultant residue. The solid matter was collected by filtration to provide 14.0 g of 4-{3-[4-(3-{4-[amino(imino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:5].[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2)#[N:19]>C(OCC)(=O)C.Cl>[CH2:11]([C@H:3]([NH:2][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([C:18]#[N:19])=[CH:28][CH:27]=2)=[O:30])[C:4](=[O:5])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CCSC3)cc2c1

Procedure:
(S)-2-Amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one hydrochloride (4.0 mmol) and 5-cyano-1H-indole-2-carboxylic acid (4.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hours reaction time) with the following workup: the reaction mixture was diluted with ethyl acetate and 2 N HCl, the resulting precipitate collected by filtration, washed with 2 N HCl and 2 N NaOH. The crude product was purified by chromatography on silica gel eluted with 30, 40 and 60% ethyl acetate in hexanes. Yield 1.22 g, 75%; HPLC (60/40) 4.74 minutes (97%); PBMS 405 (MH+, 100%);
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
As for Example 2, 1.04 g. of 3-amino-4-carboethoxypyrazole is heated at reflux temperature for 16 hours with 1.18 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 1.30 g. of the product of the example as colorless needles, m.p. 170°-171° C.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12)c1ccccc1

Procedure:
The title compound, MS m/e (%): 391 (M+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and benzoylchloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.F[C:34](F)(F)[C:35](O)=[O:36].ClCCO.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:34][CH2:35][OH:36])[CH2:12][CH2:13]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OCCCl
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(CCO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of (S)-N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.400 g, 0.881 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (7 mL) at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resultant amber syrup combined with 2-chloroethanol (354 μL, 5.27 mmol), potassium carbonate (0.730 g, 5.27 mmol), and acetonitrile (20 mL) and the mixture heated to reflux for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was chromatographed over silica gel (10 g), eluting with 1%, 3%, and then 6% methanol/chloroform, to afford, after concentration of appropriate fractions, 0.067 g (19%) of the title compound as an off-white solid with mp 172°-174° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[N:10]([CH:13]1[CH2:15][CH2:14]1)=[C:11]=[S:12]>CC(O)C>[CH:13]1([N:10]2[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8][NH:9][C:11]2=[S:12])[CH2:15][CH2:14]1
Reactant: NNC(=O)c1cccs1
Reactant: S=C=NC1CC1
Solvent: CC(C)O
Product: S=c1[nH]nc(-c2cccs2)n1C1CC1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a slurry of thiophene-2-carboxylic acid hydrazide (866 mg, 6.09 mmol) in iPrOH (25 ml) was added isothiocyanato-cyclopropane (602 mg, 6.08 mmol). The mixture was stirred at 70° C. for 72 h and then cooled to room temperature. The white precipitate was filtered off and suspended in a MeOH:H2O (9:1, 40 ml) together with aq. NaOH (2%, 5 ml). The reaction mixture was stirred at 70° C. overnight and then cooled to room temperature. The pH was adjusted to around 4 with aq. HCl (1N). The formed white precipitate was filtered off, washed with water and dried under vacuum (829 mg, 61%). 1H NMR (CD3OD), δ (ppm): 7.67 (dd, 1H), 7.63 (dd, 1H), 7.17 (dd, 1H), 3.15 (m, 1H), 1.14 (m, 2H), 0.86 (m, 2H).