Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([S:16]([CH2:18][CH2:19][CH2:20][CH3:21])=[O:17])=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]2[CH:22]=[CH:23][CH:24]=[CH:25][C:5]1=2)(=[O:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([N:4]1[CH2:11][C:10]2[CH:12]=[CH:13][C:14]([S:16]([CH2:18][CH2:19][CH2:20][CH3:21])=[O:17])=[CH:15][C:9]=2[CH2:8][CH2:7][C:6]2[CH:22]=[CH:23][CH:24]=[CH:25][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCCCS(=O)c1ccc2c(c1)C=Cc1ccccc1N(C(C)=O)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCS(=O)c1ccc2c(c1)CCc1ccccc1N(C(C)=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a solution of compound Example 287B (8 mg, 0.023 mmol) in MeOH (5 mL) was added Pd(OH)2/C (26 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The solution was filtered through a nylon membrane filter, concentrated and purified by preparative HPLC to give the title compound (3 mg, 37%). HPLC Rt=3.517 min. m/z=356(M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.CC1C=CC(CC)=CN=1.O>C1(C)C(C)=CC=CC=1.C(O)(=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCc1ccc(Cl)cc1
Agent: CCc1ccc(C)nc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccnc1NCc1ccc(Cl)cc1

Procedure:
A solution of 26.5 g of 2-chloro-3-nitropyridine, 23.7 g of 4-chlorobenzylamine and 25 ml of 2-methyl-5-ethylpyridine in 200 ml of xylene is refluxed for 12 hours. The reaction mixture is then cooled, water and acetic acid are added and the resulting mixture is then extracted with ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated under vacuum to give an oil which crystallizes from isopropyl ether. The crystals are filtered off and then dried to give 27 of 2-(4-chlorophenylmethylamino)-3-nitropyridine in the form of crystals melting at 100° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Nc2ccc(C(F)(F)F)cn2)nn1-c1ncccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Nc2ccc(C(F)(F)F)cn2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
855 mg (2.15 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-5-carboxylate were dissolved in 10.0 ml of ethanol, and 248 mg (2.79 mmol) of 45% strength aqueous sodium hydroxide solution were added. After 24 hours of stirring at room temperature, the mixture was diluted with water and acidified with dilute hydrochloric acid. The aqueous phase was extracted repeatedly with ethyl acetate and dried over magnesium sulphate. The solvent was distilled off under reduced pressure, which gave 758 mg (92% of theory) of 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-5-carboxylic acid. (logP: 2.79; MH+: 384.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 7.28 (m, 1H), 7.38 (m, 1H), 7.55 (m, 1H), 7.89 (m, 1H), 8.05 (m, 1H), 8.51 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:24][C:23]([C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[O:33])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:24][C:23]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:8](=[O:10])[CH3:9])[CH2:36][CH2:35]3)=[O:33])=[N:22]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCNCC3)cc2-c2ccccn2)cn1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCN(C(C)=O)CC3)cc2-c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., triethylamine (0.205 mL) and acetyl chloride (0.0447 mL) were added to a solution of 4-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]piperazine hydrochloride (0.185 g) obtained in Example 81 in methylene chloride (5.0 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and chloroform. The aqueous layer was further extracted with chloroform, and the organic layers were combined, followed by washing with saturated brine and drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (0.147 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH3:24])[C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:12][N:11]=[C:10]([S:21][CH3:22])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc(-c2ccccc2C)c(NC(=O)OC(C)(C)C)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: CSc1ncc(-c2ccccc2C)c(N(C)C(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 2.45 g (7.40 mmol) (2-methylsulfanyl-5-o-tolyl-pyrimidin-4-yl)-carbamic acid tert.-butyl ester in 30 ml N,N-dimethylformamide 0.44 g (11.09 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.74 ml (11.83 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was distributed between 75 ml H2O, 75 ml brine and 75 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 75 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 2.50 g (98%) methyl-(2-methylsulfanyl-5-o-tolyl-pyrimidin-4-yl)-carbamic acid tert.-butyl ester as a colorless oil, MS (TSP): 345 (M+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46]O)[CH:44]2[CH2:48][CH:41]1[CH:42]=[CH:43]2)=[O:39])#[N:35].[F:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1>CN(C)C=O>[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46][S:56][C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)[CH:44]2[CH2:48][CH:41]1[CH:42]=[CH:43]2)=[O:39])#[N:35]
Reactant: Fc1ccc(S)cc1
Reactant: N#CCNC(=O)C1C2C=CC(C2)C1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1C2C=CC(C2)C1CSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of triphenylphosphine (120 mg, 460 μmol) in dimethylformamide (1.0 mL) was cooled to 0° C. Diisopropyl azodicarboxylate (83 μL, 420 μmol) was added and the reaction mixture was stirred for 2 min. (1R/S,2R/S,3R/S,4S/R)-N-(cyanomethyl)-3-(hydroxymethyl)-bicyclo[2.2.1]hept-5-ene-2-carboxamide (79 mg, 380 μmol) and 4-fluorothiophenol (45 μl, 420 μmol) were added and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and 1:1 water:saturated aqueous sodium chloride (10 mL). The product was extracted into ethyl acetate, dried with anhydrous sodium sulfate and concentrated. Chromatography of the residue on silica gel eluting with 4:96 methanol:dichloromethane provided (1R/S,2R/S,3R/S,4S/R)-N-(cyanomethyl)-3-{[(4-fluorophenyl)sulfanyl]methyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide as a colorless syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:19]([C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1)#[N:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=2)=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2cccnc2)nc1Cl
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(-c2cccnc2)nc1Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 14d (1.0 g; 3.79 mmol), 3-cyanophenol (0.587 g; 4.93 mmol) and Cs2CO3 (4.93 g; 15.13 mmol) in CH3CN (25 mL) was stirred at room temperature for 2 h. The suspension was poured into ice-water and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over MgSO4 and concentrated to afford Compound 14e. 1H NMR (300 MHz, CDCl3): δ 9.40 (s, 1H), 9.25 (s, 1H), 8.70 (d, 1H), 8.45 (m, 1H), 7.45-7.65 (m, 4H), 7.35 (m, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 347.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:10]=[CH:11][CH:12]=1>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:10]=[CH:11][CH:12]=1
Reactant: OCCCC#Cc1cccc(C#CCCCO)c1
Agent: [Pd]
Solvent: CO
Product: OCCCCCc1cccc(CCCCCO)c1
Reaction time: 12 h
Yield: 88.8 %

Procedure:
5-[3-(5-Hydroxy-pent-1-ynyl)-phenyl]-pent-4-yn-1-ol (3.40 g, 14.03 mmol) was dissolved in methanol (60 mL) and 10% Pd/C (2.5% w/w) was added. The resulting mixture was hydrogenated on a Parr hydrogenation apparatus (45 psi) for 12 hrs. The catalyst was removed by filtration through a Celite pad. The filter cake was rinsed with methanol, and the combined organic liquors were concentrated under reduced pressure. The crude product was purified by column chromatography (chloroform:methanol 20:1) to afford 3.12 g of the title compound. Yield: 89%. 1H NMR (300 MHz, CDCl3) δ 1.30-1.45 (m, 4H), 1.50-1.72 (m, 8H), 2.59 (t, J=7.8 Hz, 4H), 3.62 (t, J=6.6 Hz, 4H), 6.99 (m, 3H), 7.18 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 25.7, 31.5, 32.8, 36.1, 63.0, 125.8, 128.3, 128.7, 142.5 ppm.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:17]([CH2:19]Cl)=[O:18]>[N+](C)([O-])=O>[CH2:1]([C:3]1[N:7]([CH2:19][C:17](=[O:18])[NH:16][C:10]2[C:9]([CH3:8])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:15])[CH2:6][CH2:5][N:4]=1)[CH3:2]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CCC1=NCCN1
Solvent: C[N+](=O)[O-]
Product: CCC1=NCCN1CC(=O)Nc1c(C)cccc1C

Procedure:
In a manner similar to Ex. IA react 47.7 gm. (0.486 M) of 2-ethyl-2-imidazoline and 19.21 gm. (0.097 M) of 2-chloro-2',6'-acetoxylidide in 200 ml. of nitromethane, to obtain the title compound.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37]>N1C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:34]5[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: O=C1CNCCN1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(N3CCNC(=O)C3)n2)c2cc(-c3cccnc3)ncc21
Temperature: 130 °C
Yield: 30.3 %

Procedure:
The mixture of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine from Example 271 (211 mg, 0.5 mmol) and piperazin-2-one (100 mg, 1.0 mmol) in pyridine (5 mL) was heated at 130° C. for 16 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, eluting with 5% to 30% acetate in heptane to afford 4-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazin-2-one as a yellow oil (76 mg, 30%). ESI MS m/z=501.23 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4](F)[C:3]=1[F:14].[CH3:15][OH:16]>>[F:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([F:1])[C:3]([F:14])=[C:4]([O:16][CH3:15])[C:5]=1[C:11]#[N:12]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: CO
Product: COc1c(F)c(F)c(C#N)c(F)c1C#N

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile was heated under reflux in 40 ml of methanol for 4 hours. The methanol was distilled off in vacuo to approximately one-fifth volume and ice water was then poured to the resultant mixture. The precipitated crystal was collected by filtration and was then washed with water and a small amount of cold methanol. After drying in vacuo, 1.6 g of the desired compound No. 20 was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:31]#[C:30][CH2:29][CH2:28][OH:32])=[CH:22][CH:23]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 5 h
Yield: 86 %

Procedure:
1 g of bis(triphenylphosphine)-palladium(II)-chloride, 3.8 g of copper(II)iodide and 8.7 g of triphenylphosphine were added in succession to a solution of 100 g of 4-bromofluorobenzene in 350 ml of triethylamine. This mixture was heated to the reflux temperature, after which 43.4 g of 3-butynol were added dropwise in the course of 20 minutes at this temperature (about 100° C.). Stirring was continued for a further 5 hours at this temperature. After cooling, the triethylamine was distilled off. The residue was taken up in methyl tertbutyl ether and water. The aqueous phase was extracted twice more with methyl tert-butyl ether and the combined organic extracts were washed in succession with 1N hydrochloric acid and with 10% strength sodium bicarbonate solution and was dried over sodium sulfate. After removal of the solvent, the crude product was distilled under greatly reduced pressure. Yield: 86%.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH:4]=[CH:3][NH:2]1.[Br:15]Br.O>CC(O)=O>[Br:15][C:4]1[C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[C:1](=[O:14])[NH:2][CH:3]=1
Reactant: BrBr
Reactant: O=c1[nH]ccc2sc3ccccc3c12
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cc(Br)c2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of [1]benzothieno[3,2-c]pyridin-1(2H)-one in AcOH (0.52 M) was added Br2 (1.1 equiv) at room temperature. The mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into H2O and stirred for 30 min. The mixture was filtered and washed with H2O to give the title compound.
Reaction SMILES: [CH3:1][C:2]([NH2:11])([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].O>C(Cl)(Cl)Cl>[CH3:3][C:2]([NH2:11])([CH3:1])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[CH:9][CH:10]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of phentermine (1.0 g) in chloroform (20 ml) was added dropwise to sulfuric acid (3.57 ml) at 0° C.; then fuming nitric acid (specific gravity=1.52; 2.8 ml) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h, made alkaline with water and a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 367 mg of the titled compound (yield, 28%).
Reaction SMILES: CO[CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[S:16]>Cl.O>[CH2:4]1[N:5]2[C:6](=[N:7][C@@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9]2)[S:16][CH2:3]1
Reactant: COCCN1CC(c2ccccc2)NC1=S
Agent: Cl
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 1-2(methoxyethyl)-4-phenylimidazolidin-2-thione product of Example VII in the amount of 0.78 g is suspended in 50 ml concentrated aqueous hydrochloric acid and maintained with stirring at 70°-75° C. for four hours. The solution is then cooled at room temperature and diluted with 50 ml water.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:4].[C:20]1([CH2:26][CH2:27][CH:28]=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOC(C)=O>[F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)=[O:4]
Reactant: O=CCCc1ccccc1
Reactant: O=C(NCC=Cc1cccc([N+](=O)[O-])c1)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(NCCCc1cccc(NCCCc2ccccc2)c1)C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-(3-nitrophenyl)allyl)acetamide (1.0 g, 3.6 mmol) and 3-phenylpropanal (0.48 g, 3.6 mmol) in EtOAc was degassed and saturated with argon. 10% Pd/C (500 mg) was added to this solution and the resulting mixture was stirred under H2 at 1 atm for 16 hrs, filtered through Celite, and concentrated under reduced pressure. Purification by flash chromatography (40% to 50% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-(3-phenylpropylamino)phenyl)propyl)acetamide as a colorless semi-solid. Yield (0.54 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (br.s, 1H), 7.30-7.17 (m, 5H) 6.95 (t, J=7.6 Hz, 1H), 6.36-6.34 (m, 3H), 5.50 (t, J=5.6 Hz, 1H), 3.18 (q, J=6.4 Hz, 2H), 2.98 (q, J=6.4 Hz, 2H), 2.67 (t, J=8.0 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 1.82 (quintet, J=7.6 Hz, 2H), 1.73 (quintet, J=7.6 Hz, 2H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1>ClC1C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C)cc1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: Clc1ccccc1
Product: Cc1ccc(CON2C(C)(C)CC(O)CC2(C)C)cc1
Temperature: 140 °C
Yield: 12 %

Procedure:
A mixture of 8.60 g (0.1 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 53.09 g (0.5 mol) of p-xylene in 61 mL of chlorobenzene under a nitrogen atmosphere is heated at 140° C. for 56 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10 w/v % ascorbic acid (3×30 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 3.33 g (48% yield) of the title compound as a white solid melting at 92.5-93° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:15]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[O:16])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)COc1ccc(-c2ccc(Cl)cc2)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and 4-chlorophenylboronic acid according to GP4: LC/MS (an10n8): Rt 3.08 min, m/z 432.5 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](Br)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1.C(O)C.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=3)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2-c2cccc(F)c2)c1
Yield: 7.6 %

Procedure:
5-Amino-3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (1.2 g, 29 mmol) was dissolved in toluene (16 ml) and ethanol (18 ml) under argon atmosphere. To the solution Pd(PPh3)4 (157 mg, 0.14 mmol), 3-fluorophenylboronic acid (0.50 g, 35.8 mmol) and 2M solution of Na2CO3 (14 ml) was added. The reaction mixture was refluxed for 1 hour then it was filtered through celite and washed with toluene. The filtrate was tightened in vacuum; water (13 ml) and ethyl acetate (13 ml) were added to the residue. It was separated and the water phase was extracted with ethyl acetate (2×5 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate:hexane=2:1) to yield 0.94 g (76%) of the title compound. The crude product can be purified by stirring with methanol to give a yellow amorphous material. LC-MS: (M+H)+ 428.2. 1H NMR (500 MHz, DMSO-d6, 25° C.): 5.67 (s, 2H); 6.81 (d, J=2.6 Hz, 1H); 7.00-7.07 (m, 2H); 7.35-7.43 (m, 1H); 7.50-7.60 (m, 2H); 7.60-7.64 (m, 1H); 8.20-8.25 (m, 1H); 8.27 (d, J=2.6 Hz, 1H).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>CO.O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=CN1CCN(CCSCc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1csc(CSCCN2CCNCC2)c1
Yield: 89.2 %

Procedure:
1 g (3.7 mM) of N-formyl-N'-[2-(2-thienylmethylthio)ethyl]piperazine was dissolved in 10 ml of methanol. Thereto was added a solution of 178 mg (4.4 mM) of sodium hydroxide in 10 ml of water. The mixture was refluxed for 10 hours with heating, to give rise to a reaction After the completion of the reaction, the solvent was removed under reduced pressure. The residue was subjected to extraction with chloroform. The extract was washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel chromatography to obtain 800 mg of N-[2-(2-thienylmethylthio)ethyl]piperazine at a yield of 89%.