Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14](I)[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])[N:15]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1oc(-c2cc(NC(C)=O)ncc2C)nc1I
Reactant: OB(O)c1ccccc1Cl
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-iodo-1,3-oxazole-5-carboxylate (0.14 g, 0.33 mmol), (2-chlorophenyl)boronic acid (0.076 g, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0.038 g, 0.032 mmol), and cesium carbonate (0.53 g, 1.62 mmol) in 1,4-dioxane (4.5 mL) and water (0.2 mL) was subjected to microwave irradiation at 150° C. for 20 min. The reaction mixture was filtered and the filtrate was concentrated. To the residue were added MeOH (10 mL) and aqueous NaOH (0.5 M, 1.5 mL). The mixture was allowed to stir at rt for 8 h and then concentrated to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-(2-chlorophenyl)-1,3-oxazole-5-carboxylic acid which was used in next step without further purification.
Reaction SMILES: [Cl:1]/[C:2](=[N:7]/[C:8]1[C:9]([CH3:26])=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])/[C:3]([F:6])([F:5])[F:4].[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:26][C:9]1[C:8](/[N:7]=[C:2](/[Cl:1])\[C:3]([F:5])([F:4])[F:6])=[CH:25][CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(/N=C(/Cl)C(F)(F)F)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(F)cc1Oc1cccc(/N=C(/Cl)C(F)(F)F)c1CBr

Procedure:
A mixture of EXAMPLE 215B (1.4 g), N-bromosuccinimide (0.671 g), and benzoyl peroxide (0.044 g) in CCl4 (20 mL) was heated under reflux for 4 hours. After cooling, the solid was filtered off. The filtrate was then concentrated. The residue was purified by flash chromatography on silica gel eluting 1:20 ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>CC(C)=O>[CH2:22]([O:21][C:19]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The title compound was prepared from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one (2.35 g, 0.0102 molel), ethyl chloroformate (1.1 ml, 0.0102 mole) and triethylamine (1 ml, 0.0102 mole) by reaction in 150 ml of acetone solvent according to the general method of Example 17. The yellowish, crude product was chromatographed on a Waters LC 500 instrument to give 1.62 g of a clear oil which crystallized to a solid, mp 84°-86° C. The confirmatory elemental analysis for the product is shown in Table III.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.Br[C:18]1[C:19]2[C:20]3[CH:33]=[CH:32][S:31][C:21]=3[C:22](=[O:30])[NH:23][C:24]=2[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][C:24]2[NH:23][C:22](=[O:30])[C:21]3[S:31][CH:32]=[CH:33][C:20]=3[C:19]=2[C:18]=1[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 60.5 %

Procedure:
Following General Procedure E, tert-butyl 4-bromobenzylcarbamate (0.78 g, 2.7 mmol) was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (0.76 g, 2.5 mmol) to afford the desired product (0.66 g, 62%) as a brown solid: ESI MS m/z 437 [C24H24N2O4S+H]+.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(C(C)C)C(C)C.CO[CH:16]=[N:17][C:18]1[C:19]([CH3:32])=[N:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:22]([Br:24])[CH:23]=1>ClCCl>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][CH:16]=[N:4][CH2:2][CH3:3])[C:19]([CH3:32])=[N:20][C:21]=1[O:25][CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: COC=Nc1cc(Br)c(OCCCC(C)C)nc1C
Reactant: CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN=CNc1cc(Br)c(OCCCC(C)C)nc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
In a 50 ml single-necked round-bottomed flask, 540 mg of N-[5-Bromo-2-methyl-6-(4-methyl-pentyloxy)-pyridin-3-yl]-formimidic acid methyl ester is dissolved in 6.60 ml of dry dichloromethane. Under stirring at an ambient temperature, 214 mg of ethylamine hydrochloride along with 0.45 ml of Hünig's base are added. Stirring is continued at room temperature for 20 hours. Then, the volatiles are removed in vacuo at 50° C. After purification on silica gel (eluent: heptane/ethyl acetate 8:1 (v:v) with 5% triethylamine) to give 530 mg of the title compound in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:38]1([CH2:44][C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51]4)=[O:46])[CH2:43][CH2:42]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H48N5O4Cl2 [(M+H)+] 720.3078, observed 720.3072.
Reaction SMILES: [C:1]([CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:17]O.C(=O)([O-])O.[Na+]>C(O)C>[CH2:2]([C:1]1[O:7][N:17]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCc1cc(C(=O)OCC)no1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of 38 g of ethyl hexanoylpyruvate in 190 ml of ethanol in the presence of 14.4 g of hydroxylamine hydrochloride and 16 g of sodium hydrogencarbonate was heated under reflux for 3 hours. After the reaction mixture was cooled to room temperature, the insoluble materials were separated by filtration, and the remaining filtrate was concentrated. The resulting residue was dissolved in chloroform (500 ml), which was washed with water, concentrated to give 5-pentyl-3-carboethoxyisoxazole as a liquid (36 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]1[C:14]2[CH:23]=[CH:22][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:15]=2[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)CC)C>CS(C)=O>[CH:34]1([NH:39][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[C:13]2[C:14]3[CH:23]=[CH:22][NH:21][C:15]=3[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1ccc(F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC2CCCC2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Yield: 25 %

Procedure:
A mixture of Example 9a (0.094 g, 0.2 mmol), cyclopentanamine (0.034 g, 0.4 mmol), and triethylamine (0.081 g, 0.8 mmol) in DMSO (2 mL) was heated at 120° C. overnight. The reaction mixture was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water to afford 0.019 g of the title product. 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.02 Hz, 3H), 1.32-1.36 (m, 2H), 1.47-1.55 (m, 3H), 1.88-1.93 (m, 2H), 3.55 (s, 3H), 3.83-3.88 (m, 1H), 4.22 (q, J=7.02 Hz, 2H), 5.94 (t, J=2.29 Hz, 1H), 6.77 (d, J=8.85 Hz, 1H), 7.22 (s, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.63 (d, J=1.83 Hz, 1H), 7.82 (dd, J=8.54, 2.14, 1H), 12.01 (s, 1H). MS (ESI+) m/z 380.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Yield: 90.7 %

Procedure:
7-Chloro-3-(4-methoxyphenoxy)isoquinoline (3.50 g) was refluxed in a mixture of acetic acid (25 ml) and a solution of hydrogen bromide (25 ml, 48%) for 3 hrs. The mixture was cooled, poured into water, neutralized with sodium carbonate and extracted with ethyl acetate. The extract was washed thoroughly with water, dried (MgSO4) and evaporated to give 4-[(7-chloroisoquinolin-3-yl)oxy]phenol (3.02 g) as brown solid, mp 190° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.O=S(Cl)[Cl:16].CN(C=O)C>C(Cl)Cl>[Cl:16][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)ccc1CCl
Reaction time: 16 h
Yield: 92.1 %

Procedure:
To a solution of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (14.5 g, 71 mmol) in 100 mL CH2Cl2 at room temperature under argon was added SOCl2 (16.8 g, 142 mmol), followed by about 1.5 mL DMF, which was added to re-dissolve the rapidly formed, precipitating hydrochloride salt of the starting material. The resulting reaction mixture was stirred for 16 h. HPLC/MS analysis indicated that the reaction was complete. Solvent was evaporated under vacuum. The resulting residue was dissolved in 200 mL Et2O, and the resulting solution was washed with 10% aqueous sodium carbonate solution (100 mL), then saturated aqueous NaCl (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 13.7 g of the title compound as a tan oil, which was greater than 98% pure. HPLC/MS: retention time=2.9 min, [M+H]30 =210.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([O:24][CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[N:16]=1>CN(C)C(=O)C.[Cu]I>[CH3:22][N:21]([CH3:23])[C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:24][CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[CH:18]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CN(C)c1cc(Cl)nc(OCc2ccsc2)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To a solution of meta-trifluoromethylphenol (1.27 g, 0.0020×4.0 mol) in 20 ml of dry N,N-dimethylacetamide, sodium hydride (0.313 g, (ca.60% in mineral oil), 0.0020×4.0 mol) was added. After the bubbling ceased, a solution of 2-chloro-4-dimethylamino-6-(3-thienylmethyloxy)pyridine (0.526 g, 0.0020 mol) in 20 ml of dry N,N-dimethylacetamide was added dropwise, then CuI (0.186 g, 0.0020×0.5 mol) was added thereto and the resultant solution was stirred for 24 hours at the temperature of 170° to 180° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]([CH3:13])[CH:3]1[CH3:14].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C1(C)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:13])=[C:3]1[CH3:14]
Reactant: CC1c2cc(C=O)ccc2N(C)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1c(C)n(C)c2ccc(C=O)cc12
Yield: 12.1 %

Procedure:
1,2,3-Trimethylindoline (21.5 g) was formylated in a similar manner to that described in Step 2 of Example 1 to obtain 20.1 g of 1,2,3-trimethylindoline-5-carbaldehyde. The obtained aldehyde (7.5 g) was dissolved in 200 ml of 1,4-dioxane, followed by the addition of 18 g of DDQ. The obtained mixture was heated under reflux for 2.5 hours, followed by the addition of 100 ml of toluene. Insolubles were filtered out and the organic phase was concentrated in a vacuum. The obtained residue was purified by flash column chromatography to give 900 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[CH2:16]([OH:29])[CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>CN(C=O)C>[OH:29][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: OCCCCC#CC#CCCCCO
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCCCCC#CC#CCCCCO
Reaction time: 15 h
Yield: 33.4 %

Procedure:
In a glass reaction vessel, a suspension of 120 milligrams of sodium hydride was prepared in 10 milliliters dry DMF and 972 milligrams of 5,7-dodecadiyn-1,12-diol (HO(CH2)4C≡C—C≡C(CH2)4OH), was added. After stirring for 5 minutes 1.31 grams of CH3(CH2)11Br was added and the resulting mixture was stirred for 15 hours. The mixture was then quenched by addition of saturated NH4Cl solution and diluted with 100 milliliters of diethyl ether. The organic layer was separated and washed 3 times with brine, dried over MgSO4, filtered and the solvent was removed to yield a yellow oil. The oil was purified over silica gel (25%-35% by volume of ethyl acetate in hexanes gradient) to yield 606 milligrams of HO(CH2)4C≡C—C≡C(CH2)4O(CH2)11CH3 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)=[O:4].[ClH:29]>CO.O1CCOCC1>[ClH:29].[O:20]1[C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:28][C:15]=2[CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 55 °C
Yield: 97 %

Procedure:
To a solution of 1,1-dimethylethyl 7-{4-[(methyloxy)carbonyl]phenyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.90 g, 4.96 mmol) in dry methanol (10 mL) was added drop wise 4 N hydrogen chloride in dioxane (10 mL) at room temperature. The reaction mixture was warmed to 55° C. for 60 min, at which time it was cooled to room temperature. The precipitated product was isolated by filtration, washed with diethyl ether, and dried to yield methyl 4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate hydrochloride (1.53 g, 97% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH3:14])[CH:6]=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:24](=[O:26])[CH3:25])[CH2:13][CH3:14])[CH:6]=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Product: CCN(C(C)=O)c1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1

Procedure:
600 mg of 6-chloro-2-ethylamino 4-(4-nitrophenyl)quinoline (compound 2a) were added to 0.19 g of acetic anhydride. The mixture was boiled at 70° C. for 4 hours and cooled, and the acetic anhydride was removed by distillation. The residue was mixed with water, extracted with ethyl acetate and washed with water, and the product was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].F[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([NH2:12])=[O:11]>C1COCC1>[CH2:1]([O:3][C:14]1[CH:13]=[C:9]([CH:8]=[CH:7][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([NH2:12])=[O:11])[CH3:2]
Reactant: CCO
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(N)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethanol (0.8 mL, 13.8 mmol) was added drop wise to a stirred suspension of sodium hydride (60% dispersion in oil, 0.550 g, 13.8 mmol) in anhydrous THF (15 mL) at 0° C. and the resulting solution stirred for 0.5 hours. To this solution was added 3-fluoro-4-nitrobenzamide (2.11 g, 11.5 mmol) drop wise in anhydrous THF (15 mL). After complete addition the solution was stirred at 0° C. for 0.5 hours, before being allowed to warm to ambient temperature. The reaction was stirred at ambient temperature for 18 hours, quenched with water (30 mL) and the aqueous layer extracted with DCM (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The title compound was obtained as a yellow solid (1.694 g, 70% yield) after recrystallisation from MeOH.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:14]=2)[CH:11]=1)CCC.[I:30]I.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:9]3[CH:8]=[N:7][C:6]([I:30])=[CH:11][N:10]3[CH:12]=2)=[CH:16][CH:17]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cc(-c3ccc(O)cc3)nc2cn1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-c2cn3cc(I)ncc3n2)cc1
Temperature: 0 °C
Reaction time: 30 h
Yield: 61.9 %

Procedure:
314 mg (corresponding to 0.628 mmol) of 6-tributylstannyl-2-[4′-hydroxyphenyl]imidazo[1,2-a]pyrazine obtained from Example II-2 was dissolved in 5.0 mL of dichloromethane, to which 114 mg (corresponding to 0.942 mmol) of iodine dissolved in 5.0 mL of dichloromethane was added. The reaction mixture was stirred at the temperature of 0° C. for 10 minutes and at room temperature for 30 hours. Then, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium thiosulfate solution were added thereto. Precipitates were filtered and recovered, washed with water and ethyl acetate in this order, and dried under reduced pressure, to obtain 131 mg (corresponding to 0.389 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyrazine (FIG. 12, Step 1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.[OH-].[Na+].CO>C(O)(=O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and L=(N-methylene)piperidin-4-yl are prepared from amidines (V) or (VI) and [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. For example, 4-(2-keto-1-benzimidazolinyl)piperidine is reacted with a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. This carboxylic acid is reacted directly with amidine (V) or (VI), in the presence of an amine base, under peptide coupling conditions described above, to afford amidino benzimidazolinones (XV) of formula A in which Y=carbonyl and L=(N-methylene)piperidin-4-yl (Scheme 5).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C@H:20](O)[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32]C4CCCCO4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43]([OH:45])=[O:44]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C@H:20]([S:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43]([OH:45])=[O:44])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:30])[CH3:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@@H](O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(C)(S)CC(=O)O
Product: CC(C)(CC(=O)O)S[C@H](CCc1ccccc1C(C)(C)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
The title compound was prepared using the enantiomer of the alcohol of Example 6, Step 8, and 3-mercapto-3-methylbutanoic acid, following Method J.