Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])C(=O)NC=2[S:4][CH:3]=1.CI.[C:20]([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]([CH:29]=[O:30])[CH3:28]>CC(=O)OCC.O>[CH3:26][N:27]1[C:28]2[S:4][CH:3]=[C:2]([CH3:1])[C:10]=2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]([O:16][CH3:20])=[O:15])[C:29]1=[O:30]
Reactant: Cc1csc2[nH]c(=O)n(CCC(=O)O)c(=O)c12
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCn1c(=O)c2c(C)csc2n(C)c1=O
Temperature: 40 °C
Yield: 63.6 %

Procedure:
To a solution of 3-(5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoic acid (330 mg, 1.17 mmol) in DMF (6 mL) was added CH3I (332 mg, 2.33 mmol) followed by K2CO3 (322 mg, 2.33 mmol). The reaction was heated in a sealed tube at 40° C. for 4 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with DCM/MeOH (50:1) to give methyl 3-(1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (210 mg, 63.6% yield) as a yellow solid. LCMS: MH+ 283 and TR=1.253 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.C([Li])CCC.[CH:29](=[O:31])[CH3:30].O>O1CCCC1.CCCCCC>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:29]([OH:31])[CH3:30])[C:3]=1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CC=O
Reactant: CC(C)(C)C(=O)Nc1cc(OC2CCCCO2)c(F)c(F)c1F
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1c(NC(=O)C(C)(C)C)c(F)c(F)c(F)c1OC1CCCCO1
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3.60 g (10.9 mmol) of the above 2,3,4-trifluoro-5-pivaloylamino-O-tetrahydropyranylphenol was dissolved in 50 mL of tetrahydrofuran, 14 mL of a 1.6 M solution of n-butyl lithium in n-hexane was added dropwise to the solution at an internal temperature of -60° C. or below, the mixture was warmed to -35° C. and cooled again to -60° C. or below. About 2 mL of acetaldehyde was added thereto in a gaseous condition and the mixture was stirred for 20 minutes. Water was added to the reaction solution, the mixture was warmed to room temperature and extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1-3:1) to give 2.45 g of a mixture of diastereomers of 2,3,4-trifluoro-6-(1-hydroxyethyl)-5-pivaloylamino-O-tetrahydropyranylphenol (yield: 60%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CCOCC.CC(C)=O>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:3]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 72 h
Yield: 86 %

Procedure:
A mechanically stirred mixture of 1 kg. (7.35 mole) of 3-hydroxyacetophenone, 1.035 kg. (7.5 mole) anhydrous potassium carbonate and 0.945 kg. (7.5 mole) of benzylchloride in 4.1 of acetone was heated at reflux for 24 hours after which 0.1035 kg. (0.75 mole) portion of potassium carbonate and 0.0945 kg. (0.75 mole) portion of benzylchloride were added and refluxing continued. This addition was repeated after 72 hours of refluxing and refluxing continued for 96 hours. The reaction was cooled, filtered and the filtrate concentrated on a rotovapor. The filtrate was then treated with 0.202 kg. (2.0 mole) triethylamine and stirred overnight. The reaction was diluted with 1 liter ether and filtered. The filtrate was evaporated and the residue distilled to yield 1.429 kg. (86%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2].[Br:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>C(#N)C.CCOCC>[Br-:12].[O:15]=[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][N+:11]1[CH:10]=[CH:9][S:8][C:7]=1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)OC(C)c1nccs1
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)OC(C)c1scc[n+]1CC(=O)c1ccccc1
Product: [Br-]
Reaction time: 120 h
Yield: 56.1 %

Procedure:
1-(2-Thiazolyl)ethyl acetate (0.8 g, 4.67 mmole) and 2-bromo-1-phenyl-1-ethanone (0.93 g, 4.67 mmole) were combined and stirred at room temp. for 5 days. The viscous mixture was dissolved in acetonitrile (5 mL), diluted with ether (3 mL), and stored overnight at 4 C. The resulting crystals (1.5 g) were recrystallized from acetonitrile/ether to afford 0.97 g of the title compound, mp 155–156 C.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][N:17]([CH3:24])[CH2:18][C:19]#[C:20][C:21](O)=[O:22].[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][C:30]([C:36]#[N:37])=[C:29]2[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Br:45])[CH:40]=1>O1CCCC1.N1C=CC=CC=1>[Br:45][C:41]1[CH:40]=[C:39]([NH:38][C:29]2[C:28]3[C:33](=[CH:34][CH:35]=[C:26]([NH:25][C:21](=[O:22])[C:20]#[C:19][CH2:18][N:17]([CH3:24])[CH3:16])[CH:27]=3)[N:32]=[CH:31][C:30]=2[C:36]#[N:37])[CH:44]=[CH:43][CH:42]=1
Reactant: CN(C)CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
Isobutyl chloroformate(0.260 g, 1.91 mmol) and N-methylmorpholine(0.594 g, 5.88 mmol) were added to an ice cold solution of 0.370 g (2.94 mmol) of 4-dimethylamino-2-butynoic acid in 50 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.500 g (01.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water, and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.144 g (21%) of yellow solid; ESMS m/z 448.0 (M+H+); mp 114-118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH:24]([NH2:26])[CH3:25])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][CH:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(C)C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1

Procedure:
3-[4-(6-Benzyloxypyridin-3-yloxy)phenyl]-1-methylprop-2-ynylamine (705 mg, 6.97 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 370 mg (41%), M+H+: 387.42:
Reaction SMILES: [C:1]12[N:15]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]2.Br[CH:17]([CH2:23][CH2:24][C:25]([O-:27])=[O:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19].O.[C:29](#N)[CH3:30]>>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([N:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]2[N:15]=[C:1]([CH:14]=[CH:13][CH:12]=2)[CH2:2]1)[CH2:23][CH2:24][C:25]([O:27][CH2:29][CH3:30])=[O:26])[CH3:22]
Reactant: CC#N
Reactant: c1cc2nc(c1)CNCCNCCNC2
Reactant: CCOC(=O)C(Br)CCC(=O)[O-]
Solvent: O
Product: CCOC(=O)CCC(C(=O)OCC)N1CCNCCNCc2cccc(n2)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
10 mg of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene (48.5 μmol) are dissolved in a water-acetonitrile mixture (170 μl of acetonitrile and 7 μl of water). After the addition of 10 μl of TEA (1.4 eq), the mixture is heated to 50° C. and then 13 mg of ethyl bromoglutarate (1 eq) are added. The medium is stirred at 50° C. for 18 h.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[NH:45][C:46](N)=[O:47].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:33]2[CH:34]=[CH:35][C:30]3[O:29][C:46](=[O:47])[NH:45][C:31]=3[CH:32]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(O)c(NC(N)=O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4oc(=O)[nH]c4c3)n(-c3ccccc3)c(=O)c12
Yield: 49.1 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (35 mg, 0.07 mmol) was treated with 1-(2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (38 mg, 0.11 mmol), sodium carbonate (2M, 34 μl, 0.07 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (9 mg, 0.01 mmol) according to the method described in Example 3 to give 17 mg (48% yield) of the title compound. Purity 97%.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:16])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:15])[C:12]([OH:14])=[O:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.Cl>CO.O>[OH:4][CH2:5][CH:6]=[C:7]([CH3:16])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:15])[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC=C(C)CCC=C(C)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=CCO)CCC=C(C)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of acid 232a (20.0 g, 88.4 mmol) in 400 mL of methanol was added a solution of potassium carbonate (24.4 g, 177 mmol) in 100 mL of water. The resulting mixture was vigorously stirred overnight at room temperature. The reaction was cooled to 0° C., methylene chloride (200 mL) was added, and the aqueous layer was acidified to pH 3 with 1 M HCl. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (2×200 mL). The combined organic extracts were washed with brine, dried over MgSO4, and reduced to dryness in vacuo. The crude product (9.65 g, 52.4 mmol, 59% yield) was used in the next step without further purification: 1H NMR (500 MHz, CDCl3) δ: 6.86 (t of q, J=7.25 Hz, J=1.50 Hz, 1H, ═CH), 5.43 (t of q, J=7.00 Hz, J=1.50 Hz, 1H, ═CH), 4.16 (d, J=7.00 Hz, 2H, —CH2O—), 2.33(q, J=7.50 Hz, 2H, —CH2—), 2.16 (t, J=7.50 Hz, 2H, —CH2—), 1.83 (s, 3H, —CH3), 1.68 (s, 3H, —CH3). LC/MS (ESI): m/z 207 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][S:12][CH3:13])=[C:5]([Cl:7])[N:6]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[Cl:1][C:2]1[S:3][C:4]([N:8]([CH3:15])[C:9](=[O:14])[CH2:10][CH2:11][S:12][CH3:13])=[C:5]([Cl:7])[N:6]=1
Reactant: CSCCC(=O)Nc1sc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSCCC(=O)N(C)c1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
To a solution of N-(2,4-dichloro-thiazol-5-yl)-3-methylsulfanyl-propionamide (596 mg, 2.2 mmol) in DMF (11 mL) stirring at 25° C. was added K2CO3 (365 mg, 2.64 mmol) and iodomethane (375 mg, 1.2 mmol), the solution was stirred at 25° C. for 20 h. The solution was diluted with 50 mL H2O and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with H2O (3×20 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a clear oil (273 mg, 44%): 1H NMR (300 MHz, CDCl3) δ 3.23 (s, 3H), 2.79 (t, J=7.2 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.09 (s, 3H); ESIMS m/z 285.1 (M+1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.CO[CH:14]1[CH:18]=[CH:17][CH:16]([O:19][CH3:20])[O:15]1.[CH3:21][OH:22].[CH:23]([O:28][CH3:29])([O:26][CH3:27])OC>>[CH3:29][O:28][CH:23]([O:26][CH3:27])[CH:18]([O:22][CH3:21])[CH2:17][CH:16]([O:15][CH3:14])[O:19][CH3:20]
Reactant: COC1C=CC(OC)O1
Reactant: COC(OC)OC
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(CC(OC)C(OC)OC)OC
Temperature: 65 °C

Procedure:
0.2 g of p-toluenesulfonic acid was added to a solution of 265.3 g (2 mol) of 2,5-dimethoxy-2,5-dihydrofuran (IIa), 384 g (12 mol) of methanol (IIIa) and 214.4 g (2 mol) of trimethyl orthoformate (IVa) in a 2 1 glass reactor, and the mixture was then heated to 65° C. over the course of 20 minutes (min) and finally refluxed for 2 hours (h). The reaction was followed by gas chromatography (percentage areas). The following table shows the course of the reaction to form E,Z-butenedial bis(dimethyl acetal) (Ia) and 1,1,2,4,4-pentamethoxybutane (Va).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[CH:11]1[C:12]2[C:13]3([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)C=CC12CC(c3ccccc31)c1ccccc12
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCC12CC(c3ccccc31)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of β-(9,10-dihydro-9,10-methano-9-anthryl)acrylic acid (612 mg) and 5% palladium-charcoal (120 mg) in ethanol was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, and the solution was evaporated to dryness to give β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid. M.P. 185°-189° C.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[CH:5][C:6]#[N:7]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A stirred solution of sodium hydride (1.8 g, 75 mmol) in dimethylformamide (150 ml) was treated with a solution of diethylcyanomethyl phosphonate (13.3 g, 75 mmol) in dimethylformamide (50 ml). The reaction was stirred 30 min at rt. After this time the reaction was treated with 3-chlorobenzaldehyde (10.54 g, 75 mmol) and stirred 1 hr at rt and 30 min at 60° C. The reaction was then quenched by the addition of water (200 ml). The reaction mixture was transferred to a separatory funnel using diethyl ether (300 ml) and the resulting organic phase washed with water (5×300 ml) and brine. The organic layer was dried over anhydrous potassium carbonate and concentrated to yield 3-chlorocinnamonitrile (11.06 g) as a solid. The solid was dissolved in tetrahydrofuran (50 ml) and treated with excess diborane and stirred 30 min at rt. The reaction was poured over ice/10% HCl. The acidic aqueous phase was washed with diethyl ether (2×200 ml). The aqueous phase was made basic by the addition of 10 N NaOH and extracted with diethyl ether (200 ml). The ether extract was dried over anhydrous potassium carbonate and concentrated to afford 3-(3-chlorophenyl)propylamine as an oil (0.6 g, 3.54 mmol). The 3-(3-chlorophenyl)propylamine (0.60 g, 3.54 mmol), 3′-methoxyacetophenone (0.53 g, 3.54 mmol) and 1.25 molar equivalents titanium(IV) isopropoxide (1.26 g, 4.43 mmol) were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). The reaction was stirred 16 hr at rt, diluted with diethyl ether (50 ml) and treated with water (0.32 ml, 17.7 mmol). After mixing thoroughly the solution was centrifuged and the ether layer concentrated to a milky solid. This material was suspended in diethyl ether and filtered through a 0.45 μM CR PTFE Acrodisc. The ether wash was concentrated to an oil. Chromatography of this material (silica, preparative thin-layer chromatography) using 3% methanol-dichloromethane (containing 0.1% isopropylamine) afforded N-[3-(3-dichlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 6X; m/z (rel. int.) 303 (M+, 3), 288 (40), 196 (3), 164 (8), 135 (100), 125 (46), 103 (26), 91 (29), 77 (29).
Reaction SMILES: Cl.S1C=CC=C1C(N)=N.Cl[C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(OC)(=O)CC(C)=O.Cl.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([NH2:36])=[NH:35].C(=O)C1C=CC=CC=1.[C:45]([O:51][CH2:52][CH3:53])(=[O:50])[CH2:46][C:47]([CH3:49])=O>>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]1[NH:36][C:47]([CH3:49])=[C:46]([C:45]([O:51][CH2:52][CH3:53])=[O:50])[CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:11]=2)[N:35]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: N=C(N)c1ccco1
Agent: COC(=O)CC(C)=O
Agent: Cl
Agent: N=C(N)c1cccs1
Solvent: O=Cc1ccccc1
Product: CCOC(=O)C1=C(C)NC(c2ccco2)=NC1c1ccccc1
Yield: 32 %

Procedure:
According to the process of Example 1, except that the 2-thienylformamidine hydrochloride, 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate were replaced by 2-furylformamidine hydrochloride, benzaldehyde and ethyl acetoacetate, respectively, and 0.21 g of a pale yellow particulates were obtained (yield: 32%); 1H-NMR (400 MHz, CDCl3-d1) δ 7.45 (s, 1H, ArH); 7.39-7.37 (d, 2H, J=7.2 Hz, ArH); 7.30-7.21 (m, 3H, J=7.2 Hz, ArH); 7.09 (s, 1H, ArH); 6.50 (m, 1H, ArH), 5.71 (s, 1H, CH); 4.12-4.09 (q, 2H, J=7.2 Hz, CH2); 2.45 (s, 3H, CH3): 1.21-1.17 (t, 3H, J=7.2 Hz, CH3). MS (EI) 310.2 (M+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](CC2C=CC=CC=2)[CH2:18][CH2:17]1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOCCn1c(CN2CCN(Cc3ccccc3)CC2)nc2ncccc21
Agent: [Pd]
Solvent: CO
Product: CCOCCn1c(CN2CCNCC2)nc2ncccc21
Yield: 46.1 %

Procedure:
A mixture of 8.3 parts of 1-(2-ethoxyethyl)-2-[[4-(phenylmethyl)-1-piperazinyl]methyl]-1H-imidazo[4,5-b]pyridine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.2 parts (46.1%) of 1-(2-ethoxyethyl)-2-(1-piperazinylmethyl)-1H-imidazo[4,5-b]pyridine as a residue (compound 31).
Reaction SMILES: CC([N:5]([CH:9]1[CH2:12][N:11](/[C:13](/[NH:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30](=[O:45])[N:31]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[CH:32]=[N:33]3)=[CH:28][CH:27]=2)=[N:14]\[C@H:15]2[CH2:20][C@H:19]3[CH2:21][C@H:17]([C:18]3([CH3:23])[CH3:22])[C@@H:16]2[CH3:24])[CH2:10]1)C(=O)[O-])(C)C.N1CC(NC(=O)OC(C)(C)C)C1.Cl.O1CCOCC1>>[NH2:5][CH:9]1[CH2:10][N:11]([C:13](=[N:14][C@H:15]2[CH2:20][C@H:19]3[CH2:21][C@H:17]([C:18]3([CH3:23])[CH3:22])[C@@H:16]2[CH3:24])[NH:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30](=[O:45])[N:31]([CH2:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)[CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH2:12]1
Reactant: C[C@@H]1[C@@H](/N=C(/Nc2ccc3c(=O)n(CCc4ccc(F)cc4)cnc3c2)N2CC(N(C(=O)[O-])C(C)(C)C)C2)C[C@H]2C[C@@H]1C2(C)C
Agent: CC(C)(C)OC(=O)NC1CNC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1[C@@H](N=C(Nc2ccc3c(=O)n(CCc4ccc(F)cc4)cnc3c2)N2CC(N)C2)C[C@H]2C[C@@H]1C2(C)C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl[1-((Z)-({3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}amino){[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)-3-azetidinyl]carbamate (synthesized using 1,1-dimethylethyl 3-azetidinylcarbamate by the methods described previously) was treated with 4.0 N HCl/dioxane (4 mL) and stirred overnight. The reaction was then purified by preparatory HPLC to provide 3-amino-N-{3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximidamide as a white solid. LC/MS: M+H 517.20 at 2.19 minutes, Method D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:9][CH2:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)c1ccc(O)c(Br)c1
Reactant: OCc1cc(Cl)ccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cc(Cl)ccn2)c(Br)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (4-chloro-2-pyridinyl)methanol (Commercial eg Aldrich) (0.2 g) in THF (5 ml) were added 1-(3-bromo-4-hydroxyphenyl)ethanone (0.3 g) and triphenylphosphine (0.547 g). This was stirred for 10 min before cooling and adding slowly DEAD (0.363 g). This was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous was reextracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. This was purified through silica eluting with 0-35% ethyl acetate in hexane to give the title compound, 0.30 g
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[O:17])[CH:14](Br)[CH3:15])[CH:10]=[CH:11][CH:12]=1.O>CC(C)=O>[CH3:15][CH:14]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)=[O:17].[ClH:6]
Reactant: CC(C)(C)N
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Product: Cl
Temperature: 25 °C

Procedure:
t-Butylamine was added to a solution of m-chloro-α-bromopropiophenone obtained above in acetone and water and the reaction mixture was refluxed for 2.5 hours. Acetone, water and excessive t-butylamine was evaproated at the temperature of 120° C. The concentrated solution was cooled down to room temperature and then extracted with 1500 ml of chloroform and 250 ml of water. The organic phase was dried with anhydrous sodium sulfate (30 g) and concentrated to dryness under reduced pressure. A solution of HCl in ethanol was added to the concentrated solution at room temperature and a crude product of bupropion hydrochloride was obtained after filtration. The crude product of bupropion hydrochloride was added to 2000 ml ethanol and heated to 70° C., decolorized by activated carbon (2 g) for 30 minutes and filtered. The filtrate was cooled and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (−0.04˜−0.09 MPa, 70° C.) for 4 hours to obtain pure product. Total yield was 72% based on m-chloropropiophenone; and the HPLC's purify was ≧99.9%.