Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:50]N1C(=O)CCC1=O>O1CCCC1>[Cl:50][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
5-(4-Hydroxymethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (2.67 g) obtained in Example 93 was dissolved in tetrahydrofuran (300 ml) and triphenylphosphine (3.33 g) and N-chlorosuccinimide (1.70 g) were added. The mixture was stirred for 15 min and triphenylphosphine (3.33 g) and N-chlorosuccinimide (1.70 g) were added. The mixture was stirred for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and, after drying, concentrated. The obtained residue was recrystallized from ethyl acetate to give 5-(4-chloromethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (2.60 g), melting point 280° C. or above.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:24][C:25]([F:30])([F:29])[CH:26]([NH2:28])[CH3:27]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[O:21])=[CH:17][N:16]=1
Reactant: CC(N)C(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)C(F)(F)F)cn1
Yield: 47 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2,2,2-trifluoro-1-methyl-ethylamine (ABCR FO7820EFA) instead of methylamine, to the title compound (66 mg, 47%) which was obtained as a light yellow solid. MS: m/e=404.5 [M−H]−.
Reaction SMILES: C([O-])C.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](#[N:18])[CH:16]=[CH2:17].Cl>>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:7]2[CH2:17][CH2:16][C:15]([NH2:18])=[N:8]2)[CH:10]=1
Reactant: C=CC#N
Reactant: NNc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: NC1=NN(c2cccnc2)CC1
Temperature: 20 °C
Yield: 73.5 %

Procedure:
To a 4-neck, round bottomed flask (250 mL) was charged sodium ethanolate (21 wt % in ethanol, 32 mL). 3-Hydrazinopyridine-dihydrochloride (5.00 g, 27.5 mmol) was added, causing an exotherm from 20° C. to 58° C. The mixture was allowed to cool to 20° C. and acrylonitrile (2.91 g, 54.9 mmol) was added. The reaction was heated at 60° C. for 5 hours and cooled to 20° C. The excess sodium ethanolate was quenched with hydrochloric acid (4 M in 1,4-dioxane, 6.88 mL, 27.5 mmol) at <20° C. The mixture was adsorbed on silica gel (10 g) and the crude product was purified by flash column chromatography using 0-10% methanol/dichloromethane as eluent. The fractions containing pure product were concentrated to dryness to afford the title compound as a yellow solid (3.28 g, 74%): mp 156-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=2.8, 0.8 Hz, 1H), 8.01 (dd, J=4.6, 1.4 Hz, 1H), 7.22 (ddd, J=8.4, 2.8, 1.5 Hz, 1H), 7.12 (ddd, J=8.4, 4.6, 0.8 Hz, 1H), 4.20 (s, 2H), 3.70 (t, J=9.3 Hz, 2H), 2.92 (t, J=9.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 154.23, 144.78, 139.22, 135.08, 123.44, 119.44, 49.23, 32.74; ESIMS m/z 163 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=3)[NH:13][C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[C:36]1C=C(C2C3C(=CC=C(C(C4C=NC(Cl)=CC=4)(O)C4N(C)C=NC=4)C=3)NC(=O)C=2)C=CC=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Product: CCOc1cccc(-c2cc(=O)n(C)c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Yield: 13 %

Procedure:
The same procedure was used as that in example 2, except that 4-(3-ethoxy-phenyl)-6-(hydroxy-di-pyridin-3-yl-methyl)-1H-quinolin-2-one (91 mg, 0.202 mmol) was used in the place 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one to give the title compound of example 37C as a white solid (12 mg, 13% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1.C(=O)(O)[O-].[K+].Cl[CH2:20][C:21]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)=O>C1COCC1.O>[Cl:2][C:3]1[C:8]([C:9]2[NH:11][CH:20]=[C:21]([C:23]3[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=3)[N:10]=2)=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: CC(C)n1ncnc1C(=O)CCl
Reactant: COc1cc(Cl)c(C(=N)N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)c[nH]2)cn1
Yield: 53.9 %

Procedure:
A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (50.9 mmol) and potassium bicarbonate (20.4 g, 202.5 mmol) in THF (128 mL) and water (21 mL) was heated to reflux and treated with a solution of 2-chloro-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.55 g, 50.9 mmol) in THF (25 mL) added dropwise. The reaction mixture was heated at reflux for 24 h before removal of volatile solvent in vacuo. The resultant residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), treated with charcoal (15 g), filtered and concentrated in vacuo to give a solid. The solid was triturated with 10% diethyl ether in pentane then dried at 50° C. in vacuo to give 4-Chloro-5-[4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine as a pale brown solid (8.74 g, 54%). LCMS RT=2.86 min, [M+H]+=319/321. 1H NMR 400 MHz (CDCl3) δ: 9.03 (1 H, s), 7.89 (1 H, s), 7.83 (1 H, s), 7.26 (1 H, s) 6.88 (1 H, s), 4.01 (3 H, s), 1.58 (6 H, d, J=6.63 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20](=[O:21])[CH:22]=[CH:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=Cc1nc(-c2ccc(F)cc2)cs1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
2 g (10.57 mmol) of 4-(4-fluoro-phenyl)-thiazole-2-carbaldehyde and 4.177 g (11.09 mmol) of (tert-butoxycarbonylmethylene)triphenylphosphorane in 25 ml of THF were stirred at room temperature for 2 h. The reaction mixture was evaporated, and the residue was used in the subsequent step without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[O-:15][CH2:16][CH3:17].[Na+]>C(O)C>[CH2:16]([O:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])[CH3:17]
Reactant: CC[O-]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1c(C#N)cnc2ccc(I)cc12
Temperature: 100 °C
Reaction time: 10 h
Yield: 94.9 %

Procedure:
To the suspension of 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) (14 g, 0.039 mol) in anhydrous ethanol (180 mL) was added sodium ethoxide (4.16 g, 0.07 mol). The mixture was heated to 100° C. under a pressure tube and stirred for 10 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried to obtain 4-Ethoxy-6-iodo-quinoline-3-carbonitril (12 g, 92%) as a yellow solid. LC-MS m/e 325 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:16]([CH:18]1[CH2:20][O:19]1)=[CH2:17]>CN(C)C=O>[OH:19][CH:18]([CH:16]=[CH2:17])[CH2:20][S:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: C=CC1CO1
Reactant: CC1(CS)COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CC(O)CSCC1(C)COC(=O)N1
Temperature: 60 °C

Procedure:
To a solution of 4-(mercaptomethyl)-4-methyloxazolidin-2-one (1.79 g, 12.2 mmol) in N,N-dimethylformamide (20 ml) was added cesium carbonate (520 mg, 1.60 mmol) and 2-vinyloxirane (2.34 g, 33.4 mmol). The solution was heated to 60° C. for 14 hours, cooled to room temperature, concentrated in vacuo, and purified by flash chromatography (30% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (quantitative). LRMS (ESI/APCI) m/z 218 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(O)(C)C>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
Celite (66 g) was added to a solution of 4-hydroxy-N-CBZ-piperidine (18 g, 76.5 mmol) in methylene chloride (500 ml), followed by pyridinium chlorochromate (33 g, 153 mmol). The mixture was stirred overnight, and then isopropyl alcohol (12 ml) was added over a period of 3 hours. The reaction mixture was filtered through silica gel and the filter cake was repeatedly rinsed with methylene chloride and ethyl acetate. The combined filtrates were evaporated under reduced pressure. Silica gel chromatography using 50% ethyl acetate/hexane, gave 4-oxo-N-CBZ-piperidine as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17].O>CS(C)=O>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][O:9][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCO)cc1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(CCOCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
6.27 g of 4-methylthiophenethyl alcohol in 100 ml of dimethyl sulfoxide were treated with 3.58 g of a 50% sodium hydride dispersion in mineral oil and the mixture was stirred at 60° C. for 10 minutes. 3.53 g of chloroacetic acid were added and the heating was continued at 80° C. for 3 hours while stirring. The mixture was cooled, poured into water and washed with ethyl acetate. The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was separated, washed well with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was recrystallized from toluene/hexane to give 3.89 g (46%) of 2-(4-methylthiophenyl)ethoxyacetic acid of melting 58°-60° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([Si:21]([CH3:24])([CH3:23])[O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH3:1])=[N:3][NH:4]2)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1n[nH]c2cccc(O)c12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cccc(O[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To a solution of 3-methyl-1H-indazol-4-ol (0.13 g, 0.90 mmol) in N,N-dimethylformamide (10 ml) was added imidazole (0.31 g, 4.52 mmol) and tert-butyldimethylchlorosilane (0.16 g, 1.04 mmol) at 0° C. Following stirring at room temperature for 12 hours and the addition of distilled water (10 ml), the reaction mixture was extracted three times with ethyl acetate, washed with distilled water and brine, dried over magnesium sulfate, filtered, and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give 0.21 g of 4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indazole (Yield 89%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:18])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a suspension of 3-biphenyl-4-yl-acrylic acid methyl ester (9.384 g, 39.38 mmol) in THF (120 ml) and MeOH (80 ml) was added 1N KOH (79 ml) and the mixture refluxed. After 3 h, heating was stopped. The reaction mixture was concentrated to about 50 ml, diluted with water (200 ml) and acidified with 2N HCl (80 ml). EtOAc (1000 ml) was added and the whole mixture heated to boiling to dissolve all solids. After cooling, the layers were separated and the organic layer washed with 1N HCl (2×70 ml), water (3×70 ml), brine (2×50 ml), dried over Na2SO4, filtered, concentrated and dried to give 3-biphenyl-4-yl-acrylic acid (7.393 g, 32.966 mmol, 84%) as a white solid, dec. 223-226° C. 1H NMR (DMSO-d6) δ 6.58 (d, 1H), 7.37-7.53 (m, 3H), 7.62 (d, 1H), 7.70-7.84 (m, 6H), 12.40 (s, 1H); mass spectrum [ES(−)], m/z 223 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32]CC)=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:39]>CO.O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:22][C@@H:21]([OH:23])[CH2:20][N:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O-:32])=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:39]
Reactant: CCOC(=O)COc1cccc(CN2C[C@H](O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C([O-])COc1cccc(CN2C[C@H](O)C[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 3-{[(2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidin-1-yl]methyl}phenoxyacetate (353 mg) in MeOH:1,4-dioxane (1:1, 10 mL) was added 1N NaOH solution (0.744 mL) at 5° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated and Et2O was added thereto. The resulting solid was collected by filtration to give sodium 3-[(2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidin-1-ylmethyl]phenoxyacetate (327.7 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9](=[O:19])[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=O.C([O-])(=O)C.[NH4+:25]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:25][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][C:9](=[O:19])[CH:8]=1
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1ccccn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=c1cc(-c2ccccn2)[nH]c(-c2ccccn2)c1

Procedure:
A mixture of 10 g (37 mmol) of 1,5-di-pyridin-2-yl-pentane-1,3,5-trione and 20 g (260 mmol) of ammonium acetate is boiled under reflux in 250 ml of ethanol for 8 hours. The mixture so obtained is concentrated to about half its volume. After filtration, 1′H-[2,2′;6′,2″]terpyridine-4′-one is obtained in the form of a white solid. 1H-NMR (360 MHz, DMSO-d6): 7.40-7.50 (qm, 2H); 7.87 (s, 2H); 7.92-8.0 (tm, 2H); 8.57 (d, 2H, 7.7 Hz); 8.68 (d, 2H, J=4.5 Hz), 10.9 (s, 1H). MS (EI pos., 70 eV), m/z=249 (100, [M+]); 221 (40).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH:31]12[O:36][CH:35]1[CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=[C:14]([O:16][CH:35]2[CH:31]([OH:36])[CH2:32][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]2)[CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)CC2O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 135 °C

Procedure:
A stirred mixture of methyl 2′-cyano-5-hydroxy-4′-methylbiphenyl-3-carboxylate (300 mg, 1.1 mol), potassium carbonate (320 mg, 2.4 mmol), DMSO (8 mL), and tert-butyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (2.4 mmol) (J. Am. Chem. Soc. 2008, 130, 3900) was heated at 135° C. overnight. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-50% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S([O-])([O-])(=O)=[O:21].[Na+:25].[Na+]>O>[Na+:25].[Na+:25].[CH:1]([CH:13]([CH2:18][C:17]([O-:16])=[O:19])[C:14]([O-:21])=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCC=CC(CC(=O)[O-])C(=O)[O-]

Procedure:
500 g of distilled water were mixed with 3500 g of n-Dodecenylsuccinic Anhydride (98% concentration, Milliken Chemical Company, Inman, S.C.) at 70 degrees Centigrade for approximately 16 hours. Following the 16 hour reaction period, 3070 g of a 1% sodium sulfate solution was added and mixed for one more hour and removed from heat. 1000 g of a 50% sodium hydroxide solution was then slowly added to the emulsion with constant mixing to form a 49% concentration of the n-Dodecenylsuccinic acid monosodium salt. From this, a representative sample was obtained and diluted to 6% concentration with distilled water and the pH was adjusted to 9 with sodium hydroxide solution to form the n-Dodecenylsuccinate Disodium Salt.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[N:9]=[C:8]([NH:18][CH:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>CO>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([S:12]([CH:15]([CH3:16])[CH3:17])(=[O:14])=[O:13])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(S(=O)(=O)C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Add 2 N NaOH (7.0 mL, 14.0 mmol) to a solution of 2-sec-butylamino-6-isopropanesulfonyl-isonicotinic acid methyl ester (1.46 g, 4.65 mmol) in methanol (10 mL) at 0° C. Stir the mixture at room temperature for 3 h and acidify the solution to about pH =2 and concentrate the solvent to one half volume. Partition the residue between ethyl acetate and water, and extract the aqueous layer with ethyl acetate (2×50 mL). Wash the combined organic extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound in 90% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([CH3:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-(isobutyl-methyl-amino)-4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M109) (0.33 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale brown solid (136 mg, 53%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([C:22]3[C:23](=[O:32])[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[C:27]=3[CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:33]>C(O)(=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([C:22]3[C:23](=[O:32])[C:24]([CH3:31])=[C:25]([CH3:30])[C:26](=[O:29])[C:27]=3[CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:33]
Reactant: COC(=O)CCCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccc(-n3ccnc3)cc2)=C(C)C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In acetic acid (17 ml) was dissolved 1.70 g (3.92 mmole) of methyl 7-[4-(1-imidazolyl)phenyl]-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoate, and concentrated hydrochloric acid (7.8 ml) was added to the solution, followed by stirring at 100° C. for 1 hour. The solvent was distilled off, and acetone was added to the residue, followed by concentration under reduced pressure. The crystals, which separated out, were collected by filtration and recrystallized from ethanol/ethyl ether to give 1.30 g (73%) of 7-[4-(1-imidazolyl)phenyl]-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoic acid·hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C(C)CNC1CCOCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCOCC1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a mixture of 2.05 g (0.0095 mole) of (rac)-2-methyl-3-(tetrahydro-pyran-4-ylamino)-propanoic acid ethyl ester, 1.85 g (0.0095 mole) of 2,4-dichloro-5-nitro-pyrimidine 50 mL of ethyl acetate and 25 mL of water was added 2.85 g (0.0286 mole) of potassium bicarbonate. The mixture was stirred for 3 hours and then diluted with 50 mL of ethyl acetate and 50 mL of water. The layers were separated, and the aqueous layer extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (75:25) to give 3.48 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(tetrahydro-pyran-4-yl)-amino]-2-methyl-propanoic acid ethyl ester (IV-45) as pale yellow oil.