Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.CC(O)=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1CBr
Temperature: 25 °C
Yield: 21.4 %

Procedure:
To a solution of 3-methylpicolinonitrile (700 mg, 5.93 mmol) in CCl4 (15 mL) was added recrystallized N-bromosuccinimide (1.21 g, 6.82 mmol), followed by glacial HOAc (0.34 mL, 1.0 eq), and AIBN (97 mg, 0.60 mmol). The resultant mixture was heated to 65° C. for 3 hours, 80° C. for 2 hours, and then cooled to room temperature. The mixture was filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by flash chromatography (Hexanes/EtOAc, 90:10 followed by 80:20) provided 3-bromomethyl-pyridine-2-carbonitrile (250 mg, 21%) as a white solid. 1H NMR (CDCl3) δ 4.63 (s, 2H), 7.55 (dd, 1H, J=8.0, 4.6 Hz), 7.93 (dd, 1H, J=7.9, 1.2 Hz), 8.64 (dd, 1H, J=4.8, 1.4 Hz).
Reaction SMILES: C(O[C:4]([S-])=[S:5])C.[K+].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[NH2:18])[C:14]([CH3:20])([CH3:19])[C:13](=[O:21])[C:12]2([CH3:23])[CH3:22].C(O)(=O)C>O>[SH:5][C:4]1[NH:18][C:17]2[CH:16]=[C:15]3[C:11](=[CH:10][C:9]=2[N:8]=1)[C:12]([CH3:23])([CH3:22])[C:13](=[O:21])[C:14]3([CH3:19])[CH3:20]
Reactant: CC1(C)C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Temperature: 20 °C
Yield: 78.8 %

Procedure:
20 ml of water and 17.0 g of purified potassium ethylxanthate were added to 20.0 g of 5,6-diamino-1,1,3,3-tetramethyl-2-indanone, dissolved in 200 ml of alcohol, in a 750 ml sulfonation flask equipped with stirrer, thermometer, reflux condenser. The mixture was left to boil at reflux overnight, then diluted with 200 ml of water, neutralized with 20 ml of glacial acetic acid and stirrer at 60°-70° C. for an additional 1 hour. After cooling to 20° C., were removed by filtration under suction. There were obtained 18.8 g (78.9% of theory) of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno(5,6-d)-imidazol-6(1H)-one with a melting point above 300° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ncc(Br)c(Nc2ccccc2)n1

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (6.84 g, 30.0 mmol), aniline (2.79 g, 30.0 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in n-butanol (75 ml) was heated under relux for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in DCM (100 ml). The solution was washed with water (3×100 ml) and saturated brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 15% ethyl acetate/isohexane, to give the product as an oil which solidifed on standing (5.12 g, 60%). NMR: 7.1 (t, 1H), 7.4 (t, 2H), 7.55 (d, 2H), 8.4 (s, 1H), 9.2 (br s, 1H); MS (MH+): 284, 286, 288.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:11][O-:12].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:12][CH3:11])[CH:7]=1
Reactant: C[O-]
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cnc(C#N)c(Cl)c1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
To a solution of 3,5-dichloropicolinonitrile (1.0 eq.) in dimethyl formamide (DMF) (0.5 M) was added sodium methoxide (1.5 eq.) and heated to 75° C. After stirring for 14 hours, the reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous NaHCO3 three times, water twice, dried over anhydrous MgSO4, and concentrated en vacuo. The crude residue was purified by a COMBIFLASH® system (ISCO) using 15% ethyl acetate in hexane to give a mixture of two methoxy regioisomers, one of which was the desired product. The mixture was carried onto the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(O)(C)C>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CI
Product: COc1ccc2c(c1)NC(=O)CC2
Yield: 89.5 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3) (16.317 g, 100 mmol) in anhydrous isopropanol (200 mL) was added potassium carbonate (16.585 g, 120.0 mmol) with stirring under an atmosphere of dry N2. The reaction mixture was stirred at room temperature for 30 minutes, then iodomethane (10.0 mL, 161.3 mmol) was added slowly. The reaction was heated to reflux with stirring for 60 hours, cooled, and the solvent evaporated under reduced pressure. To this residue water (200 mL) was added, and the mixture stirred and sonicated, filtered, and the pale yellow solid was washed with water (1000 mL), and dried under reduced pressure. To the crude dry solid was added 15% ethyl acetate in n-hexane (150 mL), and the mixture sonicated, filtered, washed with n-hexane (50 mL), and dried under reduced pressure, to afford 7-methoxy-3,4-dihydroquinolin-2(1H)-one (15.865 g, 89.5 mmol, 90%), the compound of formula (4). LCMS mz 178.0 (M+H), 200.0 (M+Na), anal HPLC >95% in purity, 1H NMR (400 MHz; dmso-D6) δ 7.09 (d, J=8.2 Hz, 1H); 6.57 (dd, J=8.2 and 2.7 Hz, 1H); 6.48 (d, J=2.7 Hz, 1H); 3.78 (s, 2H); 2.90 (t, J=7.0 Hz, 2H); 2.57 (t, J=7.0 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1.[Br:10]Br>ClCCl.[Fe]>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([S:8][CH3:9])=[CH:3][C:2]=1[CH3:1]
Reactant: CSc1cccc(C)c1
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: CSc1ccc(Br)c(C)c1
Temperature: 3 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Combine iron (25 mg, 0.45 mmol) and 1-methyl-3-methylsulfanyl-benzene (204 mg, 1.47 mmol) in dichloromethane (DCM, 2 mL). Cool the slurry to 3° C. and add Br2 (74 μL, 1.44 mmol) over 5 minutes. Stir at 3° C. for 10 minutes and remove the external cooling bath. Stir at room temperature for 4 hours, then quench with 10% aqueous Na2SO3 solution. Dilute the reaction with dichloromethane (10 mL) and separate. Wash the organic layer with brine, concentrate and chromatograph with dichloromethane in hexanes (0 to 5%) to give 125 mg of 1-bromo-2-methyl-4-methylsulfanyl-benzene (53%).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][N:7]([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH3:17][N:18]([CH3:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23].[CH3:29][N:30]([CH3:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>O>[CH3:6][N:7]([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]([C:34]2[CH:35]=[CH:36][C:31]([N:30]([CH3:37])[CH3:29])=[CH:32][CH:33]=2)[C:25]2[CH:26]=[CH:27][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][C:21]=2[C:22]([OH:24])=[O:23])=[CH:10][CH:9]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CN(C)c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1
Temperature: 60 °C
Yield: 51.3 %

Procedure:
A mixture of 46.0 ml of water, 49.4 g of 70 percent methanesulfonic acid, 14.9 g (0.1 mole) of 4-dimethylaminobenzaldehyde, 16.5 g (0.1 mole) of 3-dimethylaminobenzoic acid and 12.1 g (0.1 mole) of N,N-dimethylaniline was maintained at reflux temperature with stirring for approximately twenty-four hours. After cooling, the resulting solution was added slowly with stirring to a mixture of 700.0 ml of water and 27.0 ml of 50 percent aqueous sodium hydroxide. The resulting solution having a pH of 12.6 was maintained at 60° C. for approximately one hour. Two grams of diatomateous earth was added to the solution and the resulting mixture was clarified by filtration. The hot filtrate was added slowly with stirring to a solution of 100.0 ml of water and 10.0 ml of glacial acetic acid. Glacial acetic acid was added slowly to adjust the pH to 4.9 and stirring was continued for approximately fifteen minutes. The solid which formed was collected by filtration, washed with water and dried at approximately 50° C. in vacuo to obtain 21.4 g of 2-[bis(4-dimethylaminophenyl)methyl]-5-dimethylaminobenzoic acid (Formula II: Y=4-N(CH3)2 ; R=R1 =R2 =R3 =CH3), a pale green-colored solid which melted over the range of 179° to 184° C. After one recrystallization from toluene, the melting point was 210° to 212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(N)c1

Procedure:
A mixture of (3-aminophenyl)acetic acid (5.0 g, 33 mmol), methanol (150 ml), and c.H2SO4 (10 ml) was heated at reflux overnight. The solvent was evaporated in vacuo and the residue taken up in water (50 ml) and ethyl acetate (200 ml). Solid Na2CO3 was added until the solution was pH 10. The layers were separated and the aqueous layer was extracted again with ethyl acetate (250 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a brown oil. 5.0 g.
Reaction SMILES: O1CCN(CCOC2C=CC(C3C=CC(CC#N)=NC=3)=CC=2)CC1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]([CH2:46][C:47](OC)=[O:48])=[N:44][CH:45]=3)=[CH:36][CH:35]=2)[CH2:27][CH2:26]1.[CH2:51]([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[O:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:58][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:48])=[N:44][CH:45]=3)=[CH:38][CH:39]=2)[CH2:29][CH2:30]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
In another aspect, the invention relates to the process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]=O>Cl>[CH2:13]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]([C:10]([OH:12])=[O:11])[NH:1]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cl
Product: O=C(O)C1Cc2ccccc2CN1
Reaction time: 16 h

Procedure:
A mixture of phenylalanine (40 g), formaldehyde (37% w/v in water, 91 ml) and concentrated hydrochloric acid (310 ml) was stirred and heated to reflux for 4 hours and then stored at ambient temperature for 16 hours. The precipitate was filtered off, washed with cold water and with acetone to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (11 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[CH:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:23])=[CH:27][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 72.3 %

Procedure:
Aspartic acid (100 g, 0.75 mol) was suspended in 400 ml methylene chloride and stirred mechanically. Trimethylsilyl chloride (244 g, 2.25 mol) was added. The mixture was refluxed for 1.5 hours and then cooled in an ice bath. Triethylamine (303 g, 3.0 mol) was slowly added with stirring and cooling. Carbobenzoxy chloride (128 g, 0.75 mol) was slowly added with cooling. The mixture was stirred for 2 hours at 0° C. and then warmed to RT for 2 hours. The reaction mixture was poured into a stirred mixture of 500 ml 2.5% NaHCO3 and 500 ml Et2O. The layers were separated and the aqueous phase was extracted with 3×300 ml Et20. The aqueous layer was acidified to pH 2 with conc. HCl and extracted with 3×200 ml EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to a white solid. Recrystallization from 290 ml H2O yielded 145 g (72.3%) Z-aspartic acid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][N:13]1CCCC1=O>>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)#[N:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN1CCCC1=O
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
2,6-dichloro-3-nitropyridine (5 g, 26 mmol), Cuprous cyanide (4.64 g, 0.59 mml) and appropriate amount of N-methyl pyrrolidone were mixed to form a solution which was heated to 180° C. to react for 15 min, then cooled to 10° C. and poured into ice-water (200 mL) and stirred for 30 min. The solution was then filtered, washed with water and dried. A mixture of the filter cake and Toluene (50 mL) were stirred and heated under reflux for 10 min, then filtered while still hot. Repeated the above operation 3 times, and combined the filtrate. The filtrate was washed with water for 3 times, then with saturated sodium chloride solution for 1 time. The organic phase was dried with anhydrous magnesium sulfate and kept overnight. After filteration, the solution was evaporated under reduced pressure to dryness, and then filtered with a mixture of petroleum ether/aether (4:1) and air-dried to yield 1.78 g of orange yellow solid product with a recovery rate of 37.55%.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at room temperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 110 mmol; Aldrich) was added all at once and stirring continued overnight (18 h). After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated to give a white slurry which was triturated with hexanes and filtered to afford the title compound as a white solid (20.34 g, 81% yield). 1H NMR (500 MHz, CDCl3): 7.59–7.55 (1H, m), 7.45–7.34 (5H, m), 6.75–6.71 (2H, m), 5.19 (2H, s); 13C NMR (125.76 MHz, DMSO-d6) δ ppm: 71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C14H11FNO: 228.2. found: 228.0.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+]([O-])=O)=[C:6](Cl)[C:7](Cl)=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-])=O.[H][H].O.[NH3:26]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:17]=[C:8]([CH:7]=[CH:6][CH:5]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:26])[CH:12]=1)=[O:10]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])c([N+](=O)[O-])c(Cl)c1Cl
Reactant: N
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 30 °C

Procedure:
Then, in a closed glass vessel equipped with a thermometer and a stirrer, there are charged 34 g (0.1 moles) of said crude dinitro-dichloro benzophenone, 1 g of 5% Pd/C (from Nihon-Engelhardt Co.) and 100 ml of dioxane. While the mixture being stirred at 70°-80° C., hydrogen is introduced into the vessel so that 14.2 l (0.63 moles) of hydrogen is absorbed during 15 hours. After being cooled to 30° C., the mixture is added with 18.2 g (0.3 moles) of ammonia water and then again introduced, while being stirred at 30°-35° C., with hydrogen so as to absorb 4.3 l (0.19 moles) of hydrogen during 8 hours. After completion of reaction, the mixture is heated up to 70° C. for filtering in order to remove the catalyst. On cooling the mixture, there is obtained 3,3'-diamino benzophenone in yellow crystals. The crystals is filtered, washed with 10 ml of 50% aqueous solution of dioxane and dried. Yield 17.6 g (83.0%). M.P. 148.5°-150° C. Recrystallization from ethanol yields slightly yellow needle-like crystals of said diamino benzophenone. M.P. 150°-151° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (287 g, 1103 mmol) in DMF (150 mL), sodium carbonate (468 g, 4415 mmol) and methyl iodide (626.63 g, 4415 mmol) were added. Resulting reaction mass was heated at 60° C. for 8 h. On completion, solid precipitated was filtered, residue washed with diethyl ether (5 times). (Combined organic layers were dried, concentrated under reduced pressure giving the desired crude compound (302 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (11.5 g), prepared as described in Example 1, in dichloromethane (250 ml) was treated with triphenylphosphine (21.5 g), 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (13.2 g) and di-tert-butyl azodicarboxylate (19 g) and the mixture stirred at ambient temperature overnight. The crude reaction mixture was concentrated to a third and loaded onto a silica column and eluted using ethyl acetate/petroleum ether (35/65) as solvent. The relevant fractions were combined and evaporated under vacuum to give 7-{[1-(tert-butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyquinazoline as a white solid (20 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@H:6]([NH2:10])[C:7]([OH:9])=O)=[O:4].Cl.[CH3:12]CN(CC)CC.[Si](Cl)(C)(C)C.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:33][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:10][CH:6]([C:7](=[O:9])[CH3:12])[CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:31])=[CH:26][CH:25]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)C[C@H](N)C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)c1ccc(C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of L-aspartic acid β-methyl ester hydrochloride (250 g, 1.36 mol) in chilled (<5° C.) CH2Cl2 (4 L) was added Et3N (440 g, 4.35 mol) in a steady flow followed by a slow addition of Me3SiCl (324 g, 2.99 mol). The mixture was warmed to 25° C. and stirred for one hour, cooled again (<10° C.), and p-toluoyl chloride (205 g, 1.36 mol) was added dropwise. The mixture was allowed to warm to ambient slowly with stirring for 16 hours. The reaction mixture was then diluted with CH2Cl2 (500 mL) and washed with 1N HCl (500 mL), brine (500 ml), and dried over Na2SO4. The resultant amide product (310 g, 91%), a white solid, was obtained after solvent removal and drying under vacuum. It was then dissolved in pyridine (1.25 L) and DMAP (5 g) was added. Acetic anhydride (840 mL) was added slowly and then the reaction was heated at 90° C. for 2 hours. The cooled solution was poured into 7 L ice water and extracted with 6 L EOM. The organic layer was washed with 2N HCl (3×1 L) and 1N NaOH (1 L), dried over MgSO4 and concentrated to afford the title compound as a white solid (301 g, 93%).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl-].[Li+].CN(C)C=O.Cl>O>[OH:2][C:3]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)cc1O
Temperature: 155 °C
Yield: 85.2 %

Procedure:
A mixture of 10.0 g (0.042 mol) 2-methoxy-4-(trifluoromethyl)benzaldehyde, 5.3 g (0.126 mol) lithium chloride, and 50 mL of dimethylformamide was heated at 155° C. for 3 hours. The reaction mass was cooled, diluted with 100 mL of water, acidified with hydrochloric acid, and then extracted three times with 100 mL of ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated to provide 6.8 g of the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CS(C)=O.[OH-].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>O>[ClH:1].[ClH:25].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 146.8 %

Procedure:
First, 1-(4-chlorobenzyl)piperazine (20.0 g) is mixed with dimethyl sulfoxide (100 ml), potassium hydroxide (15.0 g) and 1-bromo-3-chloropropane (15.0 g) at room temperature for 3 hours. Water is added to the resulting solution, the reaction product is extracted with ether, dried (magnesium sulfate), and the salt is precipitated with ethereal hydrochloric acid to yield 25.1 g of 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid.