Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=c1cc(Cl)cn[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-c2cn[nH]c(=O)c2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
A mixture of 5-chloropyridazin-3(2H)-one (2.94 g, 22.5 mmol), 4-tert-butylphenylboronic acid (8 g, 44.9 mmol), dioxane (100 ml), 2M aqueous sodium carbonate solution (25 ml) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (0.5 g) was degassed (N2), then heated at 100° C. for 18 hours under nitrogen. After cooling to room temperature and standing 24 hours, ethyl acetate (250 ml) was added. The mixture was filtered and the collected solid washed with ethyl acetate to give the title compound 2.36 g. The layers of the filtrate were separated, the aqueous phase extracted with ethyl acetate (100 ml) and the combined organic phases evaporated. Ethyl acetate (100 ml) was added to the residue and the mixture left to stand. A second crop of crystals (2.26 g) was collected and washed with ethyl acetate, giving a combined yield of 4.62 g, 90%.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[NH:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[NH2:11]>CCO>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)([CH3:8])[CH3:1]
Reactant: NNc1cccnc1
Reactant: CC(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(N)n(-c2cccnc2)n1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
Using the procedure described in Example 308A Step 1, to a solution of 4-methyl-3-oxopentanenitrile (303 mg, 2.7 mmol) prepared as described in Example 122A Step 1, in anhydrous EtOH (13 ml) was added 3-hydrazinylpyridine hydrochloride (450 mg, 3.1 mmol) and the reaction mixture was heated at 80° C. overnight to afford 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (179 mg, 28%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.25 (d, J=7 Hz, 6H), 2.90-2.99 (m, 1H), 3.93 (brs, 2H), 5.50 (s, 1H), 7.36-7.38 (m, 1H), 7.96 (d, J=8 Hz, 1H), 8.49 (d, J=7 Hz, 1H), 8.67 (s, 1H); LC-MS (ESI) m/z 203 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:29][CH2:30]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CN)ccc21

Procedure:
To a cooled (0° C.) solution of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (34 mg, 0.064 mmol) and anisole (70 μL, 0.64 mmol) in DCM (2 mL) was added TFA (148 μL, 1.92 mmol). The solution was allowed to reach room temperature and concentrated after 4 h. The residue was stripped with DCM (2×) and methanol (1×). The TFA salt was dissolved in methanol followed by the addition of acetyl cloride (46 μL, 0.64 mmol). After 10 min the solution was concentrated in vacuo and stripped with methanol (2×) and dichloromethane (2×) to give 1-[5-aminomethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-cyclopropyl-1H-quinazoline-2,4-dione; HCl salt (24 mg, 80%) as an off white solid.
Reaction SMILES: CS([C:5]1[N:17]=[C:8]2[N:9]=[C:10]([CH2:15][CH3:16])[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=1)(=O)=O.[C:18]1([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:15]([C:10]1[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=[C:5]([O:27][CH2:26][CH2:25][N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:28][CH2:29][OH:30])[N:17]=[C:8]2[N:9]=1)[CH3:16]
Reactant: OCCN(CCO)c1ccccc1
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Product: CCc1cc(CC)n2nc(OCCN(CCO)c3ccccc3)nc2n1
Yield: 43 %

Procedure:
The title compound was prepared according to the experimentals described for Example 14 above from 2-methanesulfonyl-5,7-diethyl-[1,2,4]-triazolo[1,5-a]pyrimidine and N-phenyldiethanolamine in 43% yield. EM (calc.): 355.2; MS (ESI) m/e: 356.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1(C)C=CC([S:24]([OH:27])(=[O:26])=[O:25])=CC=1>>[C:11]1([CH3:10])[C:16]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:2][CH2:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NCC(=O)CCC(=O)OCc1ccccc1
Product: Cc1ccccc1S(=O)(=O)O

Procedure:
Prepared from benzyl 5-amino-4-oxopentanoate hydrochloride and p-toluenesulfonic acid using the ion-exchange method, mp 120-125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][C:15](=[O:29])[C@@H:16]([NH:18][C:19]1[N:24]=[C:23](Cl)[N:22]=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=1)[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[NH2:14][C:15](=[O:29])[C@@H:16]([NH:18][C:19]1[N:24]=[C:23]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[N:22]=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=1)[CH3:17]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(C(N)=O)nc(N2CCN(c3ccc(F)cc3)CC2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
A mixture of 1-(4-fluorophenyl)piperazine (112 mg, 0.62 mmol), (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (150 mg, 0.62 mmol) and Cs2CO3 (235 mg, 0.62 mmol) in DMF (3.0 mL) was stirred at 100° C. for 14 hrs. The reaction was worked up with EtOAc and purified by silica gel flash chromatography (DCM/methanol) to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenyl)piperazin-1-yl)pyrimidine-4-carboxamide as a white solid (193 mg, 80%). 1H NMR (CD3OD): 6.90-7.1 (4H, m), 6.55 (1H, s), 4.3 (1H, m), 3.98 (4H, m), 3.10 (4H, m), 1.40 (3H, d, J=7.0 Hz). LC/MS: m/z=388 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([C:22](=[O:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu](I)I.O>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][C:15]2[CH:16]=[C:17]([CH3:25])[C:18]([C:22](=[O:24])[CH3:23])=[C:19]([CH3:21])[CH:20]=2)=[CH:3][CH:4]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COCCCOc1ccc(Br)cc1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COCCCOc1ccc(Oc2cc(C)c(C(C)=O)c(C)c2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 21.1 %

Procedure:
A mixture of 1-bromo-4-isopropoxybenzene (21-2, 0.85 g, 3.9 mmol), 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 1.10 g, 6.71 mmol), N,N-dimethylglycine HCl salt (0.21 g, 1.5 mmol), copper iodide (0.12 g, 0.60 mmol), and cesium carbonate (2.90 g, 8.91 mmol) in dioxane (15.0 mL) was stirred at 120° C. for 48 h. The reaction mixture was cooled to room temperature, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, concentrated, and purified by flash column chromatography on silica gel (EtOAc:hexanes=1:5 as eluant) to give 1-{4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}ethanone (21-3, 0.27 g) as yellow oil in 21% yield: 1H NMR (CDCl3) δ 6.96 (dd, J=4.5, 2.2 Hz, 2 H), 6.89 (dd, J=4.3, 2.4 Hz, 2 H), 6.57 (s, 2 H), 4.05 (m, 2 H), 3.57 (t, J=6.2 Hz, 2H), 3.36 (s, 3 H), 2.66 (s, 3 H), 2.20 (s, 6 H), 2.05 (t, J=6.2 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:17][C:18]([OH:20])=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NCc2ccccc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 102.1 %

Procedure:
A solution of tert-butyl (3R)-3-{3-[(benzylamino)carbonyl]-1,2,4-oxadiazol-5-yl}6-cyclohexylhexanoate (Preparation 16b) (173 mg, 0.38 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a beige solid (155 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C1([Mg]Br)C=CC=CC=1.[C:17]([C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[C:2]1([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:25]2[O:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[OH:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)c2ccccc2)on1
Reactant: Brc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cc(C(O)(c2ccccc2)c2ccccc2)on1
Yield: 79.2 %

Procedure:
From 31.4 grams (0.2 mole) bromobenzene and 4.86 grams (0.2 mole) magnesium turnings in 150 ml ether there was prepared a solution of phenylmagnesium bromide which was added dropwise at -5°C to a solution of 18.7 grams (0.1 mole) 5-benzoyl-3-methylisoxazole. Heating was effected slowly, followed by boiling under reflux for one hour and poured onto ice. After acidification with 25 ml hydrochloric acid, the ethereal phase was separated; washing with bicarbonate solution was effected, followed by drying and concentration. The residue was crystallized with ether/petroleum ether. 21 grams bis-phenyl-(3-methylisoxazol-5-yl)-carbinol of the melting point 116°-118°C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:25][CH2:26][CH3:27])[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:25][CH2:26][CH3:27])[N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCn1nc(-c2ccc(OC)c(F)c2)c2cccc(-c3ccccc3)c21
Agent: BrB(Br)Br
Product: CCCn1nc(-c2ccc(O)c(F)c2)c2cccc(-c3ccccc3)c21
Yield: 57.7 %

Procedure:
Prepared according to Method D step C from 3-(3-Fluoro-4-methoxyphenyl)-7-phenyl-1-propyl-1H-indazole (0.28 g, 0.78 mmol), BBr3 (0.073 mL, 0.78 mmol) gave title compound as a white solid (0.156 g, 0.45 mmol, 58%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH:5]([C:8](=O)[CH2:9][CH3:10])[C:6]#[N:7].O.[NH2:18][NH2:19]>CCO>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[C:8]([CH2:9][CH3:10])=[N:18][NH:19][C:6]=1[NH2:7]
Reactant: CCC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 20 h
Yield: 39.4 %

Procedure:
To a solution of 2-(2,3-dichlorobenzyl)-3-oxopentanenitrile (1.2 g, 4.7 mmol) in EtOH (10 mL) was added hydrazine hydrate (285 mg, 5.7 mmol) and stirred at 90° C. for 20 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (PE:EA=10:1) to give the titled compound (500 mg, 36% over two steps); LC/MS: MS (ES+) m/e 270 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 1.16 (t, J=7.5 Hz, 3H), 2.53 (q, J=7.5 Hz, 2H), 3.78 (s, 2H), 4.26 (s, 2H), 6.94-6.97 (m, 1H), 7.10 (t, J=7.8 Hz, 1H), 7.32-7.35 (m, 1H).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[NH:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:18]([CH3:20])=[O:19].Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:27]([C:24]3[CH:23]=[CH:22][C:21]([NH:17][C:18](=[O:19])[CH3:20])=[CH:26][CH:25]=3)(=[O:29])=[O:28])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.43 g of 4-acetamino-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.60 g of N-{4-[4-(3-nitro-phenyl)-thiazol-2-ylsulphamoyl]-phenyl}-acetamide separated as yellowish crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=O)(=[O:3])[CH3:2].CC([O-])=O.[Na+].Cl.[NH2:24][OH:25]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=[N:24][OH:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A soln. of 2-(3,5-dichloro-2-formylphenoxy)ethyl acetate (1.48 mmol) in 2.5 mL DMF was cooled to 0° C. and NaOAc (1.62 mmol) followed by hydroxylamine HCl (1.62 mmol) were added. The ice bath was removed and the reaction mixture was stirred at RT for 1.5 h. The mixture was diluted with EtOAc and washed once with water and brine. The comb. org. layers were dried over MgSO4 and conc. in vacuo. Purification with CC using Hept and EtOAc gives the desired compound as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:36][CH2:35][CH2:34][C:10]2([CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH3:33])[C:19]4[N:23]=[C:22]([C:24]5[C:25](=[O:31])[NH:26][CH:27]=[CH:28][C:29]=5Cl)[NH:21][C:20]=4[CH:32]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][CH2:38][C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=1)[OH:40].CCN(CC)CC>CCO>[CH2:1]([N:8]1[CH2:36][CH2:35][CH2:34][C:10]2([CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH3:33])[C:19]4[N:23]=[C:22]([C:24]5[C:25](=[O:31])[NH:26][CH:27]=[CH:28][C:29]=5[NH:37][CH2:38][C@H:39]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=5)[OH:40])[NH:21][C:20]=4[CH:32]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Yield: 36.9 %

Procedure:
A solution of 3-[6-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-4-chloro-1H-pyridin-2-one (17 mg, 0.034 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (29 mg, 0.17 mmol) and Et3N (34 mg, 0.34 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h and then the reaction mixture was evaporated. The residue was purified by chromatography (25:1 CH2Cl2/MeOH) to afford the title compound (8 mg, 64%). 1H NMR (MeOH-d4) δ 1.28 (m, 2H), 1.50-1.83 (4H), 2.07-2.27 (2H), 2.48-2.61 (2H), 2.54 (s, 3H), 2.82-2.94 (2H), 3.041-3.23 (2H), 3.40-3.55 (2H), 3.59-3.73 (2H), 4.75 (m, 1H), 4.98 (m, 1H), 6.20 (d, J=6 Hz, 1H), 6.75 (s, 1H), 6.84 (s, 1H), 7.19-7.32 (8H), 7.35-7.42 (2H), 7.54 (s, 1H). ESI-MS m/z 637 (MH+).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9](Cl)=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]=1[Cl:15]>O>[NH2:3][C:4]1[CH:9]=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([OH:14])=[O:13])[C:5]=1[Cl:15]
Reactant: Nc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)nc(C(=O)O)c1Cl
Reaction time: 0.5 h

Procedure:
In a 3-liter (L) beaker was added 2000 grams (g) of hot water, 115.1 g of 50 percent by weight NaOH, and 200 g of wet 4-amino-3,5,6-trichloropyridine-2-carboxylic acid (79.4 percent). The solution was stirred for 30 minutes (min), filtered through a paper filter, and transferred to a 5-L feed/recirculation tank. This solution weighed 2315 g and contained 6.8 percent 4-amino-3,5,6-trichloropyridine-2-carboxylic acid. This feed was recirculated at a rate of about 9.46 L/min and a temperature of 30° C. through an undivided electrochemical cell having a Hastelloy C anode (15 cm×4 cm) and an expanded silver mesh cathode (15 cm ×4 cm). After normal anodization at +0.7 volts (v), the polarity of the cell was reversed and the electrolysis was started. The cathode working potential was controlled at −1.1 to −1.4 v relative to an Ag/AgCl (3.0 M Cl−) reference electrode. The reference electrode was physically located directly behind the silver cathode and connected electrically with an aqueous salt bridge. While recirculating the feed, a solution of 50 percent NaOH was slowly pumped into the recirculation tank to maintain the NaOH concentration at a 1.5 to 2.0 percent excess. The current ranged from 1.0 to 5.2 amps.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C@@H:5]([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:2].[CH3:12][Mg]Br.C1COCC1.C1(C)C=CC=CC=1>C1COCC1>[OH:2][CH:1]([CH3:12])[CH2:3][CH2:4][C@@H:5]([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: C[Mg]Br
Reactant: COC(=O)C[C@H](C)CCC=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C[C@H](C)CCC(C)O
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
To a solution of aldehyde from Step 1 (1.03 g, 6.5 mmol) in THF (20 mL) at -70° C. was added 1.4M methyl magnesium bromide in THF-toluene 1:3 (4.66 mL, 6.52 mmol). The mixture was stirred at -70° C. for 45 minutes, quenched with aqueous saturated NH4Cl and allowed to warm up to room temperature. It was diluted with ether, and the organic phase was washed twice with brine, dried over MgSO4 and evaporated down. The residue was chromatographed on silica gel, eluting with a 1:2 mixtue of ethyl acetate and hexane, to afford the desired compound (293 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:38]=[CH:39][CH:40]=3)[O:20][C:21]3[N:25](CC4C=CC(OC)=CC=4)[N:24]=[N:23][C:22]=3[C:35](O)=[O:36])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:40]=[CH:39][C:38]4[C:35](=[O:36])[C:22]5[NH:23][N:24]=[N:25][C:21]=5[O:20][C:19]=4[CH:18]=3)[CH2:11][CH2:12]2)=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2nnc(C(=O)O)c2Oc2cccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=c1c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2oc2nn[nH]c12
Reaction time: 4 h
Yield: 35 %

Procedure:
The carboxylic acid from example 3 (10.0 g, 16.89 mmol) was dissolved in dry dichloromethane (450 ml) and thionyl chloride (2.742, 20.27 mmole) was added together with 10 drops of N,N-dimethylformamide. The mixture was refluxed with stirring for 4 hours under nitrogen and the solvent and excess thionyl chloride were removed in vacuo. Fresh dichloromethane (500 ml) was added and the freshly ground anhydrous aluminium chloride (7.88 g, 59.1 mmole, 3.5 equiv.) was added in three portions (over 20 minutes) at room temperature whilst under nitrogen. After a further 30 minutes the supernatant was separated from the brown oil which separated and 2M hydrochloric acid was added (250 ml). Trituration afforded a white solid which was partitioned between water and dichloromethane. Evaporation of the dried organic phase afforded crude title compound which after silica gel chromatography gave 2.68 g (35%) of material identical with that previously described in European Pat. No. 34,004.
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].CO[C:23](=[O:40])[CH:24]([OH:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23](=[O:40])[CH:24]([OH:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCCCCCCCCCC(O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCC(O)C(=O)N(CCCCCCCCCCCC)CC(O)CO

Procedure:
N-(2,3-dihydroxypropyl)-N-dodecylamine (1.00 g, 0.0039 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl-2-hydroxyhexadecanoate (1.12 g, 0.0039 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.9 g). The waxy solid was recrystalized from hot hexane (yield=1.26 g).
Reaction SMILES: [2H]C(C(O)(C([2H])([2H])[2H])[C@H](/C=C/[C@H]([C@@H]1[C@@]2(C)CCC/C(=C\[CH:22]=[C:23]3\[CH2:24][C@@H:25](O)[CH2:26][C@H:27]([OH:30])[C:28]\3=[CH2:29])/[C@@H]2CC1)C)C)([2H])[2H].C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[CH2:26]([CH:27]1[CH:28]([CH2:23][CH3:22])[CH2:29][O:30]1)[CH2:25][CH3:24]
Reactant: [2H]C([2H])([2H])C(O)([C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2/C(=C/C=C3/C[C@@H](O)C[C@H](O)C3=C)CCC[C@]12C)C([2H])([2H])[2H]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1OCC1CC
Reaction time: 0.75 h

Procedure:
This compound was prepared after the method of Moulines et al, Synthesis, (1981), 550. 18 g 2-ethylhexa e-1, 3-diol (Aldrich Chemical Co.) was dissolved in dry THF (350 ml) and the solution was chilled to -3° C. (ice-salt bath). n-Butyllithium solution (1.6M in hexane, 94 ml, 0.15 mol) was added dropwise with stirring over 45 minutes (temperature 5°±5° C.). Stirring was continued for a further 1 hour at room temperature, then p-toluenesulphonyl chloride (28.6 g, 0.15 mol) in dry THF (75 ml) was added dropwise over 45 minutes with cooling in an ice-bath. After a further period of stirring of 1 hour a second portion of n-butyl lithium (94 ml) was added over 30 minutes at 5°-10° C. (ice-bath cooling), and the mixture was stirred overnight at room temperature. Finally, the mixture was heated at 60°-65° C. for 2.5 hours (thick white suspension forms), prior to concentration in vacuo, addition of water (750 ml) and continuous extraction with ether for 4 hours. After removal of the ether the resulting pale yellow oil was distilled to give 5.25 g (33%) of (CXXIII), bp 70.4°-71.8° C./100 mbar.