Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.BrC1C=C(F)C=CC=1.[N:20]1[C:29]2[C:24](=[C:25]3C=CC=C[C:26]3=[C:27]3C=CC=C[C:28]3=2)[N:23]=[CH:22][CH:21]=1>O1CCCC1>[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)c1ccccc1c1nccnc21
Agent: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc2nccnc2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
First, 27.5 mL of a hexane solution of n-butyllithium (1.58 mol/L) was dropped in a mixed solution of 6.87 g of 3-bromofluorobenzene and 40 mL of tetrahydrofuran at −78° C. under nitrogen atmosphere, and immediately after that, the obtained solution was stirred at −78° C. for 2 hours. To this solution was added 7.54 g of dibenzo[f,h]quinoxaline at −78° C. in five separate additions. The reaction temperature was increased to room temperature, and then the solution was stirred at room temperature for 12 hours. Water was added to this mixture, and an organic layer was extracted with dichloromethane used as an extraction solvent. The obtained organic layer was dried over anhydrous magnesium sulfate. The dried solution was filtered. After the solvent of this solution was distilled, the resultant substance was recrystallized with ethanol to obtain an objective quinoxaline derivative Hdbq-3FP (light orange power, yield 23%). Synthetic scheme of Step 1 is shown in the following (a-2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:9]2[S:18][CH:19]=[CH:20][C:8]=2[CH:7]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:39]N1C(=O)CCC1=O.C(OCC)(=O)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:9]2[S:18][C:19]([Br:39])=[CH:20][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccsc2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Br)sc2n1C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To 6-tert-butoxycarbonyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (0.09 g, 0.31 mmol) as a solution in dichloromethane (1 mL) was added TBAF (1M THF, 0.46 mL) followed by N-bromosuccinimide (NBS) (0.07 g, 0.4 mmol). The resulting mixture was allowed to stir at 23° C. for 16 h, after which time the entire reaction mixture was placed directly on a silica gel column. Flash column chromatography (20% ethyl acetate in hexanes) afforded 6-tert-butoxycarbonyl-2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (0.04 g, 36% yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[CH:41][CH:40]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([C:39]2[CH:40]=[CH:41][C:42]([O:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[CH:43][CH:44]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(Oc3ccccc3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(Oc3ccccc3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.86 g), sodium hydrogen carbonate (2.70 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-6-oxo-1-(4-phenoxyphenyl)-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.37 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.52 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.48 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.15 g, 75%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:20])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17]N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21]([BH3-])#[N:22].[Na+].[CH2:25](O)[CH3:26]>C1C2C(=CC=CC=2)CC1=O>[CH2:2]([O:9][C:10](=[O:20])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17][NH:22][CH:21]1[CH2:26][C:25]2[C:5](=[CH:4][CH:3]=[CH:8][CH:7]=2)[CH2:6]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: Cl
Agent: O=C1Cc2ccccc2C1
Agent: [Na+]
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CNC1Cc2ccccc2C1
Yield: 33 %

Procedure:
Glycyl-L-proline benzylester hydrochloride (20.0 g, 64.1 m mole) was dissolved in dried ethanol (150 ml) and indan-2-on (4.23 g, 32.1 m mole), and Molecular Sieves (3A) (5 g) were added thereto. Sodium cyanoborohydride (2.01 g, 32.1 m mole) was gradually added to the above solution while cooling with ice, and stirring. The mixture was stirred for 1 hour under cooling with ice and then stirred for 2 hours at room temperature. A little insoluble material was separated by filtration. The ethanol was removed by distillation under reduced pressure from the reaction solution. To the residue water (150 ml) and ethyl ether (200 ml) were added and the solution was adjusted to pH 1.5 with 6N hydrochloric acid while stirring to dissolve it. The ethylether layer was removed and the remaining water layer was washed with ethyl ether (200 ml). Next, to the water layer ethyl ether (400 ml) was added and the solution was adjusted to pH 8.0 with sodium bicarbonate aqueous solution. The desired product was extracted with ethyl ether and the ethyl ether layer was separated. Further, the desired product was extracted by the addition of ethyl ether (200 ml) to the water layer and the thus extracted ethyl ether solution was separated. Such extracted ethyl ether layers were combined together, and washed with the aqueous solution saturated with sodium chloride (100 ml). The ethyl ether layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crystal. The crystal was washed with n-hexane, obtained on the filter paper and dried to yield a white crystal of N-(2-indanyl)glycyl-L-proline benzylester (8.02 g, 21.2 m mole, yield: 33%). Melting point: 96°-98° C.
Reaction SMILES: C[C@@H](N)[C@@H](O)C1C=CC=CC=1.B#B.O1CCCC1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[C:28](/[N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)\[C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].Cl>ClCCCl>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[C:28](/[N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)\[CH:29]([OH:34])[C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: B#B
Agent: C[C@@H](N)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Reaction time: 24 h
Yield: 99.4 %

Procedure:
In a nitrogen atmosphere, a solution of 0.272 g of (+)-norephedrine in 4 ml of 1,2-dichloroethane was added dropwise at -78° C. to a mixture comprising 1.8 ml of a 0.500M diborane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, and the temperature of the resulting mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, to this solution was added dropwise at room temperature a solution of 0.39 g of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane, and stirring was carried out for 24 hours. Thereafter, 6 ml of 2M hydrochloric acid was added to the reaction solution, followed by stirring for about 2 hours. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel using a chloroform solvent and then concentrated under reduced pressure to obtain 0.39 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crude crystal. The conversion was 98.6%, and the composition of the product obtained was: E-form alcohol, 98.6% and Z-form alcohol, 1.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>CN(C)C=O>[C:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:19][CH2:20]1)(=[O:39])[CH3:38]
Reactant: Nc1ccc2[nH]c(=O)cc(CCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2[nH]c(=O)cc(CCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of 6-amino-4-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2(1H)-quinolinone (III-20) (1 g, 2.59 mmol) in dimethylformamide (8 ml) was added triethylamine (0.7 ml, 5 mmol). To the mixture was added dropwise acetyl chloride (0.2 ml, 2.75 mmol) at 0 ° C. and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into water and the separated solid was filtered off. After washing with water and drying, the solid was recrystallized from a mixture of methanol, tetrahydrofuran and water to give the desired product (III-21) (900 mg) as pale yellow crystals (yield 81.1%, mp 180°-183° C. (methanol/tetrahydrofuran/water).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:7][CH:6]=1.S(OC)(O[CH3:25])(=O)=O.O>[OH-].[Na+]>[CH3:25][O:12][CH2:11][CH:10]([O:9][C:8]1[CH:14]=[CH:15][C:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
6 g of β-[4-(2,4-dichlorophenoxy)phenoxy]propanol was dissolved in 3.4 g of 30% aqueous sodium hydroxide. The solution was heated at a temperature of 60° C, then 3.1 g of dimethyl sulfate was added dropwise to the solution with stirring and the mixture was allowed to react for 1.5 hours. The reaction mixture was poured into an appropriate amount of water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate, and the ether was removed by distillation. The residue was distilled under reduced pressure to obtain 3.0 g of the desired product having a boiling point of 182° to 185° C/1.5 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:11])=[CH:6][C:5]=1[Cl:21].[OH-:23].[Na+].Cl>O>[Cl:21][C:5]1[CH:6]=[C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:22])=[O:2].[Cl:21][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:22])[C:10]([OH:11])=[O:23]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cc1Cl
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 2 L RB flask equipped with a magnetic stirrer, a slurry of crude 2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid methyl ester (Example 74; 32 g, 0.10 mol) in water (300 mL) was treated with 1N sodium hydroxide solution (300 mL, 0.3 mol). Most of the solids quickly dissolved and the solution was stirred at room temperature overnight. The mixture was filtered through Celite® to remove undissolved solids (residual N,N-dicyclohexylurea) and the filter cake was washed with water (2×30 mL). The combined filtrates were transferred to a separatory funnel and extracted with diethyl ether (2×300 mL). Each diethyl ether extract was back-washed in turn with brine (50 mL). The combined aqueous phases were stirred as they were acidified by the addition of 6N hydrochloric acid (55 mL, 0.33 mol). The resulting mixture was stirred overnight at room temperature, then the precipitated solids were collected by filtration and the filter cake was washed with water (2×60 mL). The slightly off-white solid was dried in vacuo over P2O5 then was dissolved in warm ethyl acetate (400 mL) and the solution was treated with charcoal (4 g) and filtered through a bed of Celite®. The filter cake was washed with ethyl acetate (2×40 mL). The combined filtrates were concentrated to about 250 mL then sufficient hexane was added to the hot stirred solution to produce a permanent cloud point. The mixture was cooled to room temperature, then was stored at −20° C. overnight. The solids were collected by filtration and were washed with hexane (2×50 mL) to give 2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid, mp 167-1690° C. (27.1 g, 88.6%) from 3-chloro-4-(methoxycarbonyl)benzoic acid].
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1>CCO>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccncc1
Reactant: C1CNCCNC1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)Cl
Product: c1cc(CN2CCCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved in anhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution of homopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and a solution of 4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) in EtOH (40 mL) was added. The reaction mixture was heated to reflux for 16 h, cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with CH2Cl2 (300 mL) and was washed with 2N KOH (1×300 mL). The aqueous layer was extracted with CH2Cl2 (1×300 mL) and the organic phase was washed with 2N KOH (150 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 5% H2O-5% NH4OH—1PrOH) afforded the desired product (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC Rf 0.45 (5% H2O-5% NH4OH—1PrOH): 1H NMR (CDCl3, 300 MHz) δ 8.77 (d, J=5.9 Hz, 2H), 7.53 (d, J=5.7 Hz, 2H), 3.91 (s, 2H), 3,19 (m, 4H), 2.92 (m, 4H), 2.04 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[F:10][C:11]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl.FC(F)(F)C1C=CC=C[C:32]=1[O:33]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:32]([N:17]2[CH2:18][CH2:19][CH:14]([O:13][C:12]3[CH:20]=[C:21]([C:24]([F:26])([F:25])[F:27])[CH:22]=[CH:23][C:11]=3[F:10])[CH2:15][CH2:16]2)=[O:33])=[CH:7][CH:6]=[N:5]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Cn1nccc(N)c1=O
Reactant: Fc1ccc(C(F)(F)F)cc1OC1CCNCC1
Agent: Cl
Product: Cn1nccc(NC(=O)N2CCC(Oc3cc(C(F)(F)F)ccc3F)CC2)c1=O
Yield: 41 %

Procedure:
Compound 54 is prepared from intermediate 4c and from 4-(2-fluoro-5-trifluoromethyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 41%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]([CH2:30][CH2:29][CH2:28][O:27][CH3:26])[CH3:32])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: CNCCCOC
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3OC)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.76-2.04 (m, 2 H) 3.09 (d, J=7.3 Hz, 3 H) 3.21 (s, 2 H) 3.36 (s, 2 H) 3.43-3.56 (m, 2 H) 3.65 (t, J=6.9 Hz, 1 H) 3.98 (s, 3 H) 7.31-7.36 (m, 2 H) 8.05 (br. s., 1 H) 8.28-8.64 (m, 3 H). MS m/z [M+H]+ 422.4.
Reaction SMILES: C(N1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)C([Cl:31])=O)C2C=CC=C(O[Si](C(C)(C)C)(C)C)C=2)[C@@H:6](C)C1)C=C.[CH2:36](NC)[C:37]1C=CC=[CH:39][CH:38]=1.C(N)(=[O:52])C1C=CC=CC=1.C.Cl>C(O)C>[ClH:31].[CH2:11]([N:7]([CH3:6])[C:8](=[O:52])[C:9]1[CH:10]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:26]1[CH:34]=[CH:33][CH:32]=[CH:28][CH:27]=1
Reactant: CNCc1ccccc1
Reactant: NC(=O)c1ccccc1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Agent: C
Agent: Cl
Solvent: CCO
Product: CN(Cc1ccccc1)C(=O)c1ccccc1

Procedure:
This compound was prepared from 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride and N-benzyl-N-methylamine by the Benzamide Formation Method described in Example 9. NMR (300 MHz, DMSO-d6, 121° C.): δ0.93 (d, J=6.2 Hz, 3H) 1.06 (d, J=6.2 Hz, 3H); 1.96 (dd, J1 =6.7 Hz, J2 =11.0 Hz, 1H); 2.12 (dd, J1 =7.0 Hz, J2 =11.0 Hz, 1H); 2.58 (dd, J1 =2.9 Hz, J2 =11.4 Hz, 1H); 2.67-2.84 (m, 3H); 2.86 (s, 3H); 2.89 (dd, J1 =6.6 Hz, J2 =13.5 Hz, 1H); 3.18 (dd, J1 =4.0 Hz, J2 =14.1 Hz, 1H); 4.58 (s, 2H); 4.98 (s, 1H); 5.08 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H); 5.74-5.89 (m, 1H); 6.62-6.74 (m, 3H); 7.10 (t, J=7.8 Hz, 1H); 7.21-7.50 (m, 9H); 8.76 (s, 1H). Mass spectrum (CI--CH4) m/e: 484 (M+1,88%), 330 (33%), 153 (100%). [α]D20 =+14.3° (ethanol. c=1.25). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.4 followed by precipitation with diethyl ether from dichloromethane to give (+)-3-((αR)-α-(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamide monohydrochloride as a hygroscopic light yellow powder. Calc. for C31H37N3O2HCl 0.75 H2O: C, 69.78; H, 7.46; N, 7.87; Cl, 6.64 Found: C, 69.76; H, 7.48; N, 7.69; Cl 6.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:12])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc(Cl)c1
Solvent: Cc1ccccc1
Product: Cl
Product: ClCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-4-hydroxymethylpyridine (180 mg, 1.25 mmol), thionyl chloride (0.2 ml) in toluene (10 ml) was stirred at ambient temperature for 1 hour. The volatiles were removed by evaporation to give 2-chloro-4-chloromethylpyridine hydrochloride (180 mg, 0.9 mmol). A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (268 mg, 1 mmol), (prepared as described for the starting material in Example 13), potassium carbonate (680 mg, 5 mmol) and DMF (10 ml) was added to this crude product and the mixture was heated at 90° C. for 1 hour. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate (3×70 ml). The extracts were combined, washed with water (x3) and brine, dried (MgSO4) and the solvent removed by evaporation to give 7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (260 mg, 66%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)c1
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of crude (4′-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester (8.2 g 27 mmol) and Et3N (4.2 g, 40 mmol) in dichloromethane (250 mL) was added dropwise MsCl (3.2 g, 27 mmol) at 0° C. The reaction mixture was stirred at this temperature for 30 min and was then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to dryness. The residue was recrystallized with DCM/pet ether (1:3) to give [4′-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acid tert-butyl ester (7.5 g, yield 73%). 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.23-7.41 (m, 5H), 6.57 (s, 1H), 4.65-4.77 (m, 1H), 4.35 (d, J=6 Hz, 2H), 2.90 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]12([C:32](O)=[O:33])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([OH:31])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:32]([C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][C:21]([C:29]([OH:31])=[O:30])([CH2:22]4)[CH2:20]2)[CH2:26]3)=[O:33])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C23CC4CC(CC(C(=O)O)(C4)C2)C3)CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), 1,3-adamantanedicarboxylic acid (628 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg), 1-hydroxy-1H-benzotriazole monohydrate (253 mg), triethylamine (0.697 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give the title compound (352 mg, 61%) as a white solid.