Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[CH2:31](I)[CH3:32].CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH2:31][CH3:32])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Reactant: CCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1nc(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2-(1H)pyrimidone (14.2 g) in N,N-dimethylformamide (1.42 ml) were added potassium hydroxide (5.5 g) and ethyl iodide (6.0 ml) and the mixture was stirred at ambient temperature for 2.5 hours. To the reaction mixture were added additional potassium tert-butoxide (5.0 g) and ethyl iodide (3.0 ml) and the mixture was stirred at ambient temperature for more 2 hours. The mixture was poured into ice-water (150 ml). The resulting precipitates were collected by filtration, air-dried and subjected to column chromatography on silica gel using a mixture of dichloromethane and methanol as an eluent to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-ethoxy-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.135 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:6]([CH3:24])=[N:5][N:4]=1.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>N1C=CC=CC=1>[S:25]([O:1][CH2:2][C:3]1[N:7]([C:8]2[S:9][C:10]([CH2:22][CH3:23])=[CH:11][C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:6]([CH3:24])=[N:5][N:4]=1)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CO)s1
Solvent: c1ccncc1
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2COS(=O)(=O)c2ccc(C)cc2)s1
Reaction time: 8 h

Procedure:
To a solution of 4.5 g of 3-hydroxymethyl-4-(3 -o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole in 50 ml of pyridine is added 2.5 g of tosyl chloride, and the mixture is allowed to stand at room temperature overnight. The solvent is distilled off, and the residue to which water is added is made alkaline with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer is dried over anhydrous sodium sulfate and the solvent is distilled off to give 3-tosyloxymethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole as a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:35])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH:27]C(OC(C)(C)C)=O)=[CH:10][CH:9]=1)([CH3:6])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:35])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH2:27])=[CH:12][CH:13]=1)([CH3:6])=[O:5])[CH3:2]
Reactant: CCOP(C)(=O)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(C)(=O)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reaction time: 2 h

Procedure:
To a solution of [4-(2-tert-butoxycarbonylamino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-methyl-phosphinic acid ethyl ester (500 mg, 0.972 mmol) in DCM (10 mL) was added TFA (5 mL, 64.9 mmol). After 2 h, the solvent was removed, and to the residue was added EtOAc and sat. NaHCO3. The aqueous fraction was extracted further with EtOAc, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The material was used without further purification. 1H NMR (DMSO-d6) δ 9.69 (br s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.44 (m, 1H), 7.39 (dd, J=7.9, 2.0 Hz, 1H), 7.33 (dd, J=5.0, 1.8 Hz, 1H), 7.27 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (dd, J=3.5, 1.0 Hz, 1H), 7.02 (dd, J=5.0, 3.5 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 5.13 (s, 2H), 3.97-3.88 (m, 2H), 3.40-3.25 (m, 2H), 1.32 (d, J=13.8 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H). MS: cal'd 415 (MH+), exp 415 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH3:46])[C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH3:46])[C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(CCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-propylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1>C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C1CCC(Oc2ccc(Br)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 0 °C

Procedure:
Sodium borohydride (77.3 mg, 2.04 mmol) was added to a solution of 4-(4-bromophenoxy)cyclohexanone (500 mg, 1.86 mmol) in ethanol (10 mL) at room temperature. After 20 minutes the reaction was cooled to 0° C. and quenched by the addition of 1 N HCl (aq). The reaction was concentrated and the resulting residue was partitioned between ether and 1 N HCl (aq). The layers were separated, the organic layer was washed with water then dried (Na2SO4), filtered and concentrated.
Reaction SMILES: [CH2:1]([N:5]([CH2:31][CH2:32][CH2:33][CH3:34])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:13][CH:14]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][C:36]([CH3:39])([O-])[CH3:37].[K+]>CN(C=O)C>[CH2:1]([N:5]([CH2:31][CH2:32][CH2:33][CH3:34])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:13][CH:14]=[CH:35][C:36]2[CH:39]=[CH:39][C:36]([CH:35]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=3)[C:9]3[CH:10]=[CH:11][C:6]([N:5]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)=[CH:37][CH:37]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C(=CC=O)c2ccc(N(CCCC)CCCC)cc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C(=CC=Cc2ccc(C=CC=C(c3ccc(N(CCCC)CCCC)cc3)c3ccc(N(CCCC)CCCC)cc3)cc2)c2ccc(N(CCCC)CCCC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
In 100 ml of DMF were dissolved 2.21 g of 3,3-bis(p-dibutylaminophenyl)acrolein and 1.0 g of p-xylene-α,α'-diylbis(diethyl phosphonate), and then 0.59 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent: benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.42 g (yield 58.8%) of red crystals having a melting point of from 107.0° C. to 111.5° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH2:5]1[O:14][C:8]([CH2:10][CH2:11][CH2:12]Cl)([CH3:9])[O:7][CH2:6]1>CO>[CH2:5]1[O:14][C:8]([CH2:10][CH2:11][CH2:12][O:2][CH3:1])([CH3:9])[O:7][CH2:6]1
Reactant: C[O-]
Reactant: CC1(CCCCl)OCCO1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COCCCC1(C)OCCO1

Procedure:
To a solution of sodium methoxide prepared by the addition of 0.8 g of sodium to 35 mL of methanol was added 5-chloro-2-pentanone ethylene ketal (3 g, 180 mmol). The mixture was heated in a steel bomb at 100° C. for 18 hours. The methanol was removed by evaporation under reduced pressure and the residue was extracted into 20 mL of ether. The ether extract was washed with water, saturated saline solution and dried over magnesium sulfate. Evaporation of the ether yielded 1.6 grams of 5-methoxy-2-pentanone ethylene ketal. This was stirred in 10 mL of 75% formic acid for 24 h at room temperature. The mixture was neutralized with sodium bicarbonate and extracted with 50 mL of ether. The ether extract was washed with water, saturated saline solution and dried over magnesium sulfate. Evaporation yielded 1.2 g of the desired ketone as an oil. Step B: Preparation of 1-(R)-(3,4-dihydroxyphenyl)-2-(1-methyl-4-methoxybutylamino)ethanol oxalate salt
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].[OH-:17].[Na+]>CO>[C:10]1([CH:8]2[O:7][N:6]=[C:5]([C:3]([OH:17])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1=NOC(c2ccccc2)C1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazolecarboxamide (i.e. the product of Example 12, Step A) (60.0 g, 275 mmol) in methanol (300 mL) was added an aqueous sodium hydroxide solution (44 g of 50 wt. % aqueous NaOH in 50 mL of water) dropwise over 30 minutes while maintaining the temperature of the reaction mixture at 45° C. The reaction mixture was allowed to cool to room temperature and stirred overnight. The resulting mixture was concentrated under reduced pressure, and treated with 200 mL of water. The pH of the reaction mixture was adjusted using concentrated hydrochloric acid to about 1.0. The crude product was extracted into ethyl acetate (200 mL). The ethyl acetate solution was concentrated under reduced pressure, and the residue was triturated with hexanes. The resulting precipitate was filtered, washed with hexanes (2×20 mL), and dried under vacuum to give 46.5 g of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1.[O:19]1[CH2:24][CH2:23]OCC1>>[CH3:18][C:4]1[C:5]([CH3:17])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:19][C:24]2[CH:23]=[CH:6][CH:5]=[CH:4][CH:18]=2)[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCO)c1C
Reactant: C1COCCO1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCO)c1C
Reaction time: 8 h

Procedure:
4-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butan-1-ol (20.00 g, 93.07 mmol) and additional dioxane (˜30 mL) were added. The reaction mixture was heated at reflux for 3 hours and then allowed to stand at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and then extracted with ethyl acetate (300 mL). The extract was washed with water (2×100 mL) then with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide an oil. The oil was purified by flash chromatography (600 mL of silica gel, eluting initially with 2000 mL 1:3 ethyl acetate:hexanes, then with 2000 mL 1:1 ethyl acetate:hexanes and finally with 1000 mL 3:1 ethyl acetate: hexanes) to provide 13.46 g of 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butan-1-ol as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(N)c1N

Procedure:
Commercially available 2-amino-4-methyl-3nitropyridine (10.0 g, 65.3 mmol) was suspended in ethanol (450 mL) and the flask was filled with argon. 10% palladium carbon (13.9 g, 50% water-containing) was added to the mixture and stirred at room temperature overnight under the flow of hydrogen. Solids were filtered through Celite and this was washed with ethanol. The filtrate was concentrated under reduced pressure to obtain Compound P12 (7.81 g, 63.3 mmol, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:14](=[O:25])[N:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:16]=[C:17]([Cl:19])[N:18]=1
Reactant: Nc1ccc(Br)cc1Br
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(CC)n1cc(Cl)nc(Nc2ccc(Br)cc2Br)c1=O
Yield: 44.7 %

Procedure:
2,4-Dibromoaniline (500 mg), toluene (8 mL), and sodium hydride (60% in oil, 398 mg) were stirred for 10 minutes at room temperature and then 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone (468 mg, Example 1, part B) was added. The reaction was heated at reflux 3 hours, cooled, and quenched with water (50 mL). The mixture was extracted with ethyl acetate (100 mL), which was washed with brine, then dried and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:19) affording 400 mg of material, which was crystallized from ether/hexane to give the title compound (240 mg). Elemental analysis: calcd. for C15H16N3OClBr2 : C, 40.07; H, 3.597; N, 9.356; Cl, 7.895; Br, 35.55. Found: C, 40.41; H, 3.49; N, 9.34; Cl, 8.27; Br, 35.71.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([OH:32])[N:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:46]([O:48][C:49]([C:51]1(Br)[CH2:54][CH2:53][CH2:52]1)=[O:50])[CH3:47]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][C:51]3([C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:54][CH2:53][CH2:52]3)[N:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-{(S)-5-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-pentanoyl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of DMF, 119 mg of cesium carbonate and 76 mg of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with DCM. The solvents were removed under reduced pressure and the residue was dissolved in 1 ml of DCM, 0.2 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:12]=1)[CH:10]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[F:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])[CH:12]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(F)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(F)ccc1C
Reaction time: 1 h

Procedure:
A mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100 ml) was treated at room temperature dropwise with a solution of 5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml) and stirred at the same temperature for 1 hour. Acetone was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and concentrated under reduced pressure to obtain 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][N:16]=[C:15]([N:19](O)[C:20](=[NH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]2=[O:31])=[CH:9][CH:8]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][N:16]3[N:29]=[C:20]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=[C:15]3[C:14]2=[O:31])=[CH:9][CH:8]=1
Reactant: N=C(COc1ccccc1)N(O)c1nccn(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2nc(COc3ccccc3)nn2ccn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 6.3 %

Procedure:
Phosphorus oxychloride (0.28 mL, 3.0 mmol) was added to a solution of N-[4-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-N-hydroxy-2-phenoxy-acetamidine (0.35 g. 1.51 mmol) in THF (8 mL) at 0° C. The reaction was stirred at 100° C. for 5 minutes under microwave irradiation. The reaction mixture was basified with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 1/99 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo and treated with DIPE to yield 7-(4-fluoro-phenyl)-2-phenoxymethyl-7H-[1,2,4]triazolo[1,5-a]pyrazin-8-one (32 mg, 6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 5.33 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.07 (d, J=7.8 Hz, 2H), 7.26-7.36 (m, 2H), 7.36-7.44 (m, 2H), 7.45 (d, J=6.1 Hz, 1H), 7.50-7.62 (m, 2H), 8.03 (d, J=5.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N:14]([CH3:20])[C:15](=O)[O:16]CC)=[CH:4][CH:3]=1.[O-]CC.[Na+].[Na]>C(O)C.O>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:15](=[O:16])[N:14]([CH3:20])[C:8]=23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N(C)c1c(Oc2ccc(N)cc2)ccnc1N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cn1c(=O)[nH]c2nccc(Oc3ccc(N)cc3)c21
Temperature: 100 °C
Yield: 33.8 %

Procedure:
Ethyl 4-(4-aminophenoxy)-2-aminopyridin-3-yl-methyl-carbamate (180 mg, 0.6 mmol) was suspended in a solution of sodium ethoxide in ethanol, obtained from dissolving sodium (480 mg, 21 mmol) in ethanol (9 ml). The suspension was heated under microwave irradiation for 40 minutes (100° C., 150 W). The mixture was cooled at room temperature, diluted with water and evaporated. The residue was triturated with acetone, and the washings discarded. The solid was dissolved in water and the insoluble solid was filtered off. The filtrate was acidified with HCl 1 M to pH 1, then brought to pH 10 with saturated aqueous Na2CO3. The precipitate formed was recovered by filtration, to afford the title compound (52 mg, 34%). 1H-NMR (δ, ppm, DMSO-d6): 3.49 (s, 3H, CH3N), 5.11 (s, 2H, NH2), 6.29 (d, 1H, HPy,6, J=6.0 Hz), 6.63 (d, 2H, Harom,Ph,3+5, J=8.69 Hz), 6.90 (d, 2H, Harom,Ph,2+6, J=8.73 Hz), 7.74 (d, 1H, HPy,6, J=5.96 Hz), 11.53 (s, 1H, NHPy2). LC-MS (m/z): 257 (M+H, 100).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N+:2]=[N-:3].[CH2:16]([Sn:20]([C:29]#[CH:30])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C1COCC1>[CH2:25]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:16][CH2:17][CH2:18][CH3:19])[C:29]1[N:3]=[N:2][N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:30]=1)[CH2:26][CH2:27][CH3:28]
Reactant: [N-]=[N+]=NCCCCCCCCCC(=O)O
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCCCCCCCC(=O)O)nn1
Reaction time: 24 h
Yield: 8.4 %

Procedure:
10-Azidodecanoic acid (2.0 g, 9.5 mmol) in THF (50 mL) is treated with tributylstannyl acetylene (2.99 g, 9.5 mmol) copper(I)iodide (90 mg 0.47 mmol) and triethylamine (256 mg, 2.54 mmol) at room temperature with constant stirring for 24 h. The reaction is then filtered through celite and concentrated in vacuo to a gum, and then chromatographed on silica in a gradient of 10-40% ethyl acetate in petrol. The main fraction is collected and concentrated in vacuo to give 10-(4-tributylstannyl-[1,2,3]triazol-1-yl)-decanoic acid (3.22 g, 0.8 mmol).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14].Cl>CCO>[CH:1](=[C:12]([CH2:13][CH3:14])[CH:11]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCCC=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C=O)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
30.0 mL Benzaldehyde was dissolved in 150 mL EtOH and cooled with an ice bath. Added was 5.01 mL 45% KOH (0.2 equiv.), followed by dropwise addition of 16.5 mL butyraldehyde. The mixture was stirred for 3 days at room temperature, acidified with 1M HCl and extracted with ether. The organic layer was dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum distillation yielded 20.4 g of a yellow fluid (78-82° C., 0.6 mbar) containing 70% of the desired product. This material was used in subsequent steps without further purification. Characteristic signals in 1H NMR (400 MHz, CDCl3): δ 1.15 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 1H), 7.22 (s, 1H), 9.56 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:15]3)[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15]3)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(CCOc2ccc3[nH]c(CCC(=O)OC)cc3c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1cccc(CCOc2ccc3[nH]c(CCC(=O)O)cc3c2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.2 %

Procedure:
To a solution of methyl 3-(5-{2-[6-(methylamino)-2-pyridyl]ethoxy}indolyl)propanoate (0.023 g, 0.65 mmol), as prepared in the preceding step, in methanol (3 mL) was added sodium hydroxide (0.15 g, 3.8 mmol) in H2O (0.5 mL) and the reaction was stirred for 6 hours at ambient temperature. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4–5 with 10% HCl, extracted with a mixture of ethyl acetate and butanol (2×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound as a solid (0.018 g, 82%). 1H-NMR (400 M Hz, CDCl3+CD3OD) δ 7.52 (t, J=7.3 Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 7.14 (d, J=3.1 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.81 (dd, J=8.9, 2.4 Hz, 1H), 6.60 (d, J=7.3 Hz, 1H), 6.38 (d, J=8.6 Hz, 1H), 6.33 (d, J=3.2 Hz, 1H), 4.38 (t, J=7.0 Hz, 2H), 4.24 (t, J=6.6 Hz, 2H), 3.06 (t, J=6.6 Hz, 2H), 2.89 (s, 3H), 2.77 (t, J=6.9 Hz, 2H). Mass spectrum (LCMS, ESI pos.) Calcd. for C19H21N3O3 340.3 (M+H); Found: 340.9.