Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].[CH2:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[CH2:16]([OH:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: C=O
Reactant: C=CCCCCCCCCCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCO
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
This example illustrates a synthesis of 1-(11,12-Oxidododecyl)-3,7-dimethylxanthine (inventive compound no. 2518). To a suspension of magnesium (6.4 g, 265 mmol) and a crystal of iodine in tetrahydrofuran (40 mL) was added 10-undecenyl bromide (12.25 g, 53.0 mmol, available from MTM) in tetrahydrofuran (30 mL) over 30 minutes and the reaction stirred for a further 30 minutes after the addition was complete. The solution was added via a canula over 5 minutes to a suspension of paraformaldehyde (1.80 g, 60.0 mmol) in tetrahydrofuran (40 mL) and stirred at 25° C. for 16 hours. Saturated ammonium chloride (80 mL) is added and extracted with diethyl ether (2×100 mL). The combined organic extracts are dried using magnesium sulfate and evaporated to give a residue which is distilled at 2 mm Hg to yield 6.53 g (67% yield, b.p. 105-107° C.) of 11-dodecenyl alcohol as a clear liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:34]=[CH:33][C:21]4[CH2:22][CH2:23][N:24](C(=O)C(F)(F)F)[CH2:25][CH2:26][C:20]=4[CH:19]=3)[C:12](=[O:35])[CH:11]=2)=[N:6][CH:7]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:34]=[CH:33][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[C:12](=[O:35])[CH:11]=2)=[N:6][CH:7]=1
Reactant: O=C(N1CCc2ccc(CCn3ccc(OCc4ccc(F)cn4)cc3=O)cc2CC1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1cc(OCc2ccc(F)cn2)ccn1CCc1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 350 mg (0.72 mmol) 4-(5-fluoro-pyridin-2-ylmethoxy)-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (preparation 23.10a) in 10 mL MeOH is added 1.1 mL (1.10 mmol) 1 M aqueous NaOH-solution. The reaction mixture is stirred overnight at RT. After filtration is the residue purified via reverse HPLC chromatography (Waters Xbridge; water (0.3% NH4OH)/acetonitrile (0.3% NH4OH) 95:5 to 5:95).
Reaction SMILES: [C:1]([CH:5]1[NH:19][C:18](=[O:20])[CH:17]([CH2:21][N:22]([O:25]CC2C=CC=CC=2)[CH:23]=[O:24])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:33])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH:5]1[NH:19][C:18](=[O:20])[CH:17]([CH2:21][N:22]([OH:25])[CH:23]=[O:24])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C1NC(=O)C(CN(C=O)OCc2ccccc2)CCCC=CCCCCNC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)C1NC(=O)C(CN(O)C=O)CCCCCCCCCNC1=O

Procedure:
The cyclic compound 14 (50.0 mg) was dissolved in ethyl acetate and methanol (1:1, 10 mL) and 20 mg of 10% Pd/C as added. The mixture was exposed to 1 atm of hydrogen until all the starting material was consumed. The charcoal was removed by filtration and the filtrate was concentrated to give the desired compound quantitatively. 1H NMR (250 MHz, CDCl3) δ 9.39 (brs, 1H), 8.37 (brs, 0.27H),7.86 (brs, 0.73H), 7.40 (d, J=8.7 Hz, 0.27H), 6.94 (brs, 1H), 6.57 (brs, 0.73H), 4.33 (m, 1H) 3.81 (m, 2H), 3.43 (m, 1H), 2.87 (m, 2H), 1.64 (brs, 2H), 1.45–1.23 (m, 16H), 0.96 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 175.0, 173.3, 171.2, 170.9, 157.2, 61.1, 60.4, 52.7, 44.5, 38.5, 34.6, 29.8, 28.0, 27.8, 27.5, 26.8, 26.5, 25.2, 21.1, 14.2. HRESI-MS: C19H35N3O4Na+ ([M+Na])+calc'd 392.2520, found 392.2504. HPLC analysis showed a purity of ˜96% (FIG. 1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2OCC3=O)CC1
Temperature: 110 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.522 g, 1.50 mmol), benzyl alcohol (0.186 mL, 1.80 mmol) and triphenylphosphine (0.590 g, 2.25 mmol) in toluene (6 mL) was added with a 40% solution of diethyl azodicarboxylate in toluene (0.980 g, 2.25 mmol), and the mixture was stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-{[6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.259 g, 39%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)[CH2:3]1.[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2)=[C:18]=[O:19]>>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:18]([NH:17][C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[CH:25]4)=[O:19])=[CH:11][CH:10]=2)[CH2:5]1
Reactant: CC1CN(c2ccc(CN)cc2)CC(C)O1
Reactant: O=C=Nc1cccc2cnccc12
Product: CC1CN(c2ccc(CNC(=O)Nc3cccc4cnccc34)cc2)CC(C)O1

Procedure:
The product from Example 67A and the product from Example 61A were processed as described in Example 66C to provide a waxy material which was purified by chromatography (95:5 CH2Cl2-MeOH, eluant) to provide the title compound as a white solid. The corresponding di-hydrochloride salt was prepared using methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.67 (s, 1H), 8.53 (d, J=6.1 Hz, 1H), 8.31 (dd, J=7.6 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.57-7.62 (m, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.92-6.95 (m, 3H), 4.26 (d, J=5.7 Hz, 2H), 3.68 (m, 2H), 3.54-3.57 (m, 2H), 2.21 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); MS (ESI+) m/z 391 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.C[O:10][C:11](=[O:36])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20](=[O:35])[CH2:21][O:22][CH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=1)=[O:25]>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([NH:19][C:20](=[O:35])[CH2:21][O:22][CH2:23][C:24](=[O:25])[NH:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:33]=2)=[C:12]([CH:17]=1)[C:11]([OH:36])=[O:10]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)NCc1cccc(Br)c1
Reactant: OB(O)c1ccsc1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2ccsc2)c1

Procedure:
Using the same method as in Example 19-(ii), 3-thiopheneboronic acid was reacted with the 2-[((2-[(3-bromobenzyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid methyl ester to give 5-chloro-2-([(2-oxo-2-([3-(thiophene-3-yl)benzyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 77%).
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+].C(C1[CH:36]([C:37]#[N:38])[CH2:35][CH:34]2[CH2:39][CH:32]1[C:33]2([CH3:41])[CH3:40])(=O)C>C1COCC1>[C:23]([CH:26]1[CH:36]([C:37]#[N:38])[CH2:35][CH:34]2[CH2:39][CH:32]1[C:33]2([CH3:41])[CH3:40])([CH3:24])=[CH2:22]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)C1C(C#N)CC2CC1C2(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C1C(C#N)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium iodide (3.17 g, 7.84 mmol) was suspended in anhydrous THF (20 ml) under an atmosphere of dry N2. To this solution was added a 1.0 M solution of potassium tert-butoxide (7.84 ml) in THF. After the reaction has stirred at ambient temperature for 30 min, a solution of 2-acetyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile (1.00 g, 5.23 mmol), prepared in step A of example 42, dissolved in anhydrous THF (10 ml) was added to the reaction. After stirring for two hours, the reaction was then partitioned between ethyl ether and water. The ethyl ether layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give an oil which was chromatographed on silica gel using a gradient of neat hexanes to 10% ethyl acetate in hexanes to give 490 mg of the titled compound as an oil: C.I. m/z 190 [M+1]; 1H NMR (CDCl3)δ 4.82 (m, 2H), 2.82 (m, 2H), 2.10-2.28 (m, 3H), 1.93 (m, 2H), 1.75 (s, 3H), 1.33 (d, J=9.9 Hz, 1H), 1.23 (s, 3H), 0.93 (s, 3H), 0.80-0.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:30][CH2:31]O)[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[CH2:16]([O:15][C:14]1[C:13](=[O:23])[C:12]([C:24](=[O:29])[C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:11][N:10]2[CH2:30][CH2:31][N:6]([CH2:5][C:4]3[CH:33]=[CH:34][CH:35]=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:8])[C:9]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)c1cn(CCO)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Yield: 50.2 %

Procedure:
To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg) in tetrahydrofuran (3 ml) was added N,N-diisopropylethylamine (0.187 ml) and the mixture was ice-cooled. Methanesulfonyl chloride (0.07 ml) was added at the same temperature over 30 min with stirring. After confirmation of the completion of the reaction by thin layer chromatography, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with brine, aqueous sodium hydrogen carbonate solution and brine, dried and concentrated. The obtained residue was dissolved in dimethylformamide (2 ml) and 60% sodium hydride (50 mg) was added by small portions with stirring at room temperature. After stirring for 30 min, the reaction mixture was ice-cooled and 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate) to give 9-benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (44 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.[Br:13]P(Br)Br.O>C(Cl)Cl>[Br:13][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(CBr)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [5-(trifluoromethyl)pyridin-2-yl]methanol (5.0 g, 28.24 mmol) in DCM (50 ml) was added tribromophosphane (0.58 g, 3.50 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was then poured into water (50 ml) and the organics were extracted with DCM (2×50 ml), washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[CH3:18][C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][NH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:16][C:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][N:9]([C:7]([C:4]2[CH:3]=[C:2]([C:23]3[C:19]([CH3:18])=[N:20][NH:21][CH:22]=3)[S:6][CH:5]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: CC1(C)CCCN(C(=O)c2csc(Br)c2)CC1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1n[nH]cc1-c1cc(C(=O)N2CCCC(C)(C)CC2)cs1
Temperature: 140 °C
Yield: 15.3 %

Procedure:
(5-Bromo-thiophen-3-yl)-(4,4-dimethyl-azepan-1-yl)-methanone (0.105 g, 0.33 mmol) together with 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (83 mg, 0.4 mmol), caesium carbonate (0.150 g, 0.46 mmol), and palladium tetrakis(triphenylphosphine) (0.057 g, 0.05 mmol) in DME (3 mL), IMS 1 mL) and water (0.5 mL) was degassed then heated by microwave irradiation to 140° C. for 20 minutes. Further quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.035 g), caesium carbonate (0.054 g), and palladium tetrakis(triphenylphosphine) (19 mg) were added and the mixture was heated by microwave irradiation to 140° C. for 20 minutes before diluting with water and extracting with DCM (×3). The organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by chromatography on a silica II cartridge, eluting with 10-60% ethyl acetate in cyclohexane and then was further purified by HPLC using a phenyl hexyl column, eluting with 15%-95% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried then taken up as a solution in methanol and dried to give the title compound as a colourless semi-solid (0.016 g). LCMS m/z 318.28 [M+H]+ R.T.=9.29 min (Analytical Method 2).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:10]=1[C:26]([CH3:29])([CH3:28])[CH3:27])C1C=CC=CC=1.C[Si](I)(C)C>C(#N)C>[C:26]([C:10]1[CH:11]=[C:12]([C:22]([O:24][CH3:25])=[O:23])[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:9]=1[OH:8])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(C)cc2)c(O)c(C(C)(C)C)c1
Temperature: 50 °C
Yield: 36 %

Procedure:
5.4 g (14 mmol) of methyl 6-benzyloxy-5-tert-butyl-4′-methyl-3-biphenylcarboxylate (Example 1, d) are dissolved in 100 mL of acetonitrile. 6 mL (41 mmol) of trimethylsilyl iodide are added and the mixture is heated at 50° C. for 24 hours. After extraction, the residue obtained is subjected to esterification conditions similar to those of Example 1 b, and the residue obtained is purified by chromatography. A white solid is obtained (m=1.6 g, yield=36%; m.p.=105° C.).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][NH:15][CH3:16].O.ON1C2C=CC=CC=2N=N1.CN(C=O)C>>[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][N:15]([CH3:16])[C:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: CNCC(OC)OC
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN(C)C(=O)[C@H]1CC[C@H](O)CC1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-4-hydroxycyclohexanecarboxylic acid (1.00 g, 6.94 mmol), 2,2-dimethoxy-N-methylethanamine (0.909 g, 7.63 mmol), and 1-Hydroxybenzotriazole hydrate (1.17 g, 7.63 mmol) in DMF (25 mL, 320 mmol) was added N-(3-Dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (1.46 g, 7.63 mmol) at ambient temperature, and the solution was stirred at ambient temperature overnight. Most of the DMF was evaporated in vacuo, and the residue was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (4×25 mL), saturated with NaCl, and extracted again with EtOAc (5×25 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as yellow oil that was used without further purification in the next step. 1H NMR (400 MHz, CDCl3): δ=4.48 (t, J=5.4 Hz, 1H, major rotamer), 4.39 (t, J=5.4 Hz, 1H, minor rotamer), 3.70-3.61 (m, 1H), 3.45-3.42 (m, 2H), 3.43 (s, 6H, minor rotamer), 3.40 (s, 6H, major rotamer), 3.11 (s, 3H, major rotamer), 2.97 (s, 3H, minor rotamer), 2.56 (tt, J=11.6, 3.8 Hz, 1H, minor rotamer), 2.46 (tt, J=11.8, 3.4 Hz, 1H, major rotamer), 2.11-2.00 (m, 2H), 1.86-1.74 (m, 2H), 1.71-1.55 (m, 3H), 1.36-1.23 (m, 2H). MS (ES+): m/z=268.11 (87) [MNa+], 246.15 (42) [MH+], 214.13 (100) [MH+−MeOH]. HPLC: tR=2.36 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:15]([O:19][C:20]([C:22]([C@@H:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:25]([NH:27][N:28]([CH2:33][CH:34]([CH3:36])[CH3:35])[S:29]([CH3:32])(=[O:31])=[O:30])=[O:26])=[CH2:23])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:15]([O:19][C:20]([C@H:22]([C@@H:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:25]([NH:27][N:28]([CH2:33][CH:34]([CH3:35])[CH3:36])[S:29]([CH3:32])(=[O:31])=[O:30])=[O:26])[CH2:23][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21])([CH3:16])([CH3:18])[CH3:17]
Reactant: C=C(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Reactant: Sc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](CSc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
0.183 g of thiophenol and 0.356 ml of triethylamine were added to a solution of 0.500 g of 2(R)-[1(tertbutoxycarbonyl)vinyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in 20 of toluene and stirring under a nitrogen atmosphere was continued for 48 hours. A further 0.183 ml of thiophenol was added to the mixture and stirring was continued for 48 hours at 60° C. The mixture was then cooled to room temperature and diluted with ethyl acetate. The mixture was washed in succession with 1M aqueous hyrochloric acid, 1M aqueous sodium hydroxide and brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. Trituration with hexane gave 0.307 g of 2(R)-[1(S)-(tertbutoxycarbonyl)-2-(phenylthio)ethyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([N:21](C)[C:22](=O)OCC4C=CC=CC=4)[C:16]3=[O:33])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][CH3:22])[C:16]3=[O:33])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](N(C)C(=O)OCc4ccccc4)C3=O)CC2)nc1
Agent: [Pd]
Solvent: CO
Product: CCc1cnc(N2CCC(N3CCC[C@H](NC)C3=O)CC2)nc1
Reaction time: 8 h
Yield: 59.1 %

Procedure:
(S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-yl(methyl)carbamate (0.100 g, 0.22 mmol) was dissolved in methanol (5 mL). 10% Pd/C (10 mg) was added and the reaction mixture was stirred under hydrogen balloon pressure overnight. The reaction was filtered and concentrated and purified over silica gel (100% EtOAc) to afford (S)-1′-(5-ethylpyrimidin-2-yl)-3-(methylamino)-1,4′-bipiperidin-2-one (40 mg, 0.13 mmol, 57% yield).
Reaction SMILES: Cl[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:3]2[C:2]([O:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:7][N:6]3[CH:8]=[N:9][N:10]=[C:5]3[C:4]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CO)cc1
Reactant: Clc1ccc(-c2c(Cl)nn3cnnc3c2-c2ccc(Cl)cc2)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: COc1ccc(COc2nn3cnnc3c(-c3ccc(Cl)cc3)c2-c2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 40 h

Procedure:
To round bottom flask was added 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (37.6 mg, 0.10 mmol), 4-methyoxybenzyl alcohol (0.15 mmol), THF (1 ml) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) (30 mg, 0.11 mmol). The reaction was heated to 50° C. and stirred at this temperature for 40 hrs. The solvent was removed and the residue was purified using preparative HPLC to give pure product 7,8-bis(4-chlorophenyl)-6-(4-methoxybenzyloxy)-[1,2,4]triazolo[4,3-b]pyridazine as a solid. HPLC retention time (method C) 7.91 min; LCMS (M+H)=477.10.
Reaction SMILES: [Cl-].[Cl-].[CH3:3][C:4]1[C:8]([Zr+2:10][C:11]2([CH3:20])[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]2[CH3:19])([CH3:9])[C:7]([CH3:21])=[C:6]([CH3:22])[C:5]=1[CH3:23].[C:24]([OH:30])(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:24]([O-:30])(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[C:24]([O-:30])(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[CH3:16][C:15]1[C:11]([Zr+2:10][C:8]2([CH3:9])[C:7]([CH3:21])=[C:6]([CH3:22])[C:5]([CH3:23])=[C:4]2[CH3:3])([CH3:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14]=1[CH3:17]
Reactant: CC(C)(C)C(=O)O
Agent: CC1=C(C)C(C)([Zr+2]C2(C)C(C)=C(C)C(C)=C2C)C(C)=C1C
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)[O-]

Procedure:
To a solution of bis(pentamethylcyclopentadienyl)zirconium dichloride (0.865 g, 2.001 mmol) and pivalic acid (0.685 g, 6.710 mmol) in toluene (30 ml) at 40° C. was added triethylamine (0.726 g, 7.174 mmol) with stirring. A white precipitate formed immediately which was removed by filtration. The title compound was isolated as an off-white powder in 90% by evaporating the solvent and excess pivalic acid under vacuum at 65° C. The title compound such prepared exhibited purity above 98% based on NMR results. 1H NMR (toluene d8) δ1.83 (s, 30H), 1.30 (s, 18H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][OH:34])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:36][CH2:37][O:38][CH3:39]>CN(C=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][O:34][CH2:36][CH2:37][O:38][CH3:39])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(CO)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Solvent: CN(C)C=O
Product: COCCOCc1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
81.6 mg (0.065 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-hydroxymethyl-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 5 mL abs. DMF. At 0° C. 21.9 mg (0.195 mmol) potassium tert.butylate were added. After 5 min 12 μl (0.13 mmol) 1-bromo-2-methoxy-ethane were added and the reaction mixture was allowed to come to room temperature. After 3 h further 12 μl (0.13 mmol) 1-bromo-2-methoxy-ethane were added and the reaction mixture was stirred for 16 h. The solvent was distilled off and the resulting residue was purified by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as a light brown amorphous solid. The title compound was obtained as its formiate. Yield: 12 mg MS (ES+): m/e=543, chloro pattern.