Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC(C)N
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNC(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.6 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and isopropylamine (0.29 ml, 4.65 mmol) in DMF (5 ml) was stirred at 100° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (307 mg, 75%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[N:4][CH:3]=1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:22][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[N:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: C[C@H]1CNCCN1c1cncc(Cl)n1
Solvent: CN(C)C=O
Product: C[C@H]1CNCCN1c1cncc(OCc2ccccc2)n1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a solution of (2S)-1-(6-chloro-2-pyrazinyl)-2-methylpiperazine (prepared in step 2 above; 0.16 g, 0.72 mmol) and benzyl alcohol (0.12 g, 1.1 mmol) in DMF (4 mL) was Na-t-BuO (0.14 g, 1.4 mmol) added and the mixture was stirred at 150° C. overnight. The solvent was evaporated off under reduced pressure and the residue taken up between CHCl3/H2O. The organic phase was concentrated and the crude product was purified by preparative C18-HPLC using acetonitrile/H2O/HOAc with UV detection at 254 nm. Yield: 1 mg (0.4%). MS m/z 284 (M)+. HRMS m/z calcd for C16H20N4O (M)+ 284.1637, found 284.1640.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH3:12][N:13]1[C:22]2[C:17](=[CH:18][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[O:32].C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>CCO.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>[NH2:11][CH:8]1[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:19]3[CH:18]=[C:17]4[C:22](=[CH:21][CH:20]=3)[N:13]([CH3:12])[C:14](=[O:32])[CH2:15][CH2:16]4)[C:3]=2[CH2:10][CH2:9]1
Reactant: NC1CCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [Cl-]
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC4N)ccc21
Temperature: 85 °C
Yield: 14.3 %

Procedure:
In a 50 ml round-bottomed flask, (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (intermediate A-3[C]) (107 mg, 500 μmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-1) (172 mg, 600 μmol) were dissolved in EtOH (9 mL) to give a brown solution. Na2CO3 (58.3 mg, 550 μmol), dissolved in water (1.5 mL) was added followed by tetrakis(triphenylphosphine)palladium (0) (17.3 mg, 15.0 mmol) after evacuation and replacing 5 times with Argon. The suspension was then heated at 85° C. overnight. A aq. 10% NaCl solution was added at RT, and the mixture was extracted with AcOEt (3×). The organic fractions were washed again with aq. 10% NaCl solution, dried over Na2SO4, filtered, evaporated and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (2%)) to afford the title compound (21 mg, 14%) as a dark green powder. MS: 294.2 (M+H+)
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)=[O:7].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][C@H:43]1[CH2:48][O:49][CH3:50].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][C@H:43]2[CH2:48][O:49][CH3:50])[CH2:10][CH:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)=[O:7]
Reactant: COC[C@@H]1COCCN1CCCl
Reactant: COCCOCOc1cc(CC2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COCCOCOc1cc(CC2CN(CCN3CCOC[C@H]3COC)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 73 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (440 mg) in N,N-dimethylformamide (2.2 ml) were added (3R)-4-(2-chloroethyl)-3-(methoxymethyl)morpholine hydrochloride (289 mg), potassium carbonate (434 mg) and potassium iodide (149 mg) at room temperature. The whole was stirred at 73° C. for 2 hours. After being cooled to room temperature, the mixture was poured into ice-water and the aqueous mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)-methoxy]-4-methylbenzyl]-4-[2-[(3R)-3-methoxymethyl-morpholino]ethyl]piperazine (450 mg) as a light yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]2)=[CH:30][CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]4)=[CH:30][CH:29]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc2ccc(N)cc2[nH]1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(NC(=O)C(CCOC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
100 mg (265 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate), 54.2 mg (265 μmol, 1.0 eq.) of ethyl 6-amino-1H-indole-2-carboxylate, 37.7 mg (265 μmol) of Oxima and 41.4 μl (265 μmol) of DIC in 5.5 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/0.1% formic acid and acetonitrile/0.1% formic acid, gradient 10% acetonitrile to 90% acetonitrile). Yield: 85 mg (54% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([CH3:10])[CH3:9])[N:5]=[C:4]([NH:12][CH:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:28][N:29]([CH:31]=[N:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([CH3:9])[CH3:10])[N:5]=[C:4]([NH:12][CH:13]([CH:23]2[CH2:24][CH2:25]2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1)[CH3:30]
Reactant: CC(C)(F)c1nc(N)nc(NC(CCCc2ccccc2)C2CC2)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1nc(NC(CCCc2ccccc2)C2CC2)nc(C(C)(C)F)n1

Procedure:
A solution of 1.71 g (5 mmol) of 2-amino-4-(1-fluoro-1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine and 2 ml of N,N-dimethylformamide dimethyl acetal in 30 ml of toluene is refluxed for 2 hours. All volatile constituents are subsequently carefully distilled off. This gives 1.94 g (97.5% of theory) of 2-dimethylaminomethyleneamino-4-(1-fluoro-1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine as colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[CH:42][C:43]([C:46]#[N:47])=[N:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:41]=[CH:42][C:43]([C:46]#[N:47])=[N:44][CH:45]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)nc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 5-bromo-2-pyridinecarbonitrile (283 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (372 mg, 70%) as a light yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)C>[C:27]1([NH:33][C:34]([C:2]2[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CSc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.8 g (0.0022 mol) of 2-bromo-4-methylmercapto-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the obtained solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.6M-hexane solution of BuLl (0.0022×1.1 mol) was added to the solution, followed by stirring the resultant mixture for about 10 minutes. After 0.52 g (0.0022×2.0 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23].O>CN(C)C=O>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-N-(t-butoxycarbonyl)piperidine (0.133 mol, 30.5 g, prepared by the method of Mach, R. H. et al., J. Med. Chem. (1993) 36(23), 3707-20) and triethylamine (1.5 equivilents, 0.2 mol, 20.2 g, 27.8 ml) in dimethylformamide (230 ml) was cooled to 0° C. and m-cyanophenylisocyanate (1.1 equivilents, 0.146 mmol, 21.1 g) in dimethylformamide (70 ml) was added dropwise. The reaction was stirred at ambient temperature for 18 h. It was poured into water and extracted with ethyl acetate (3×). The ethyl acetate extracts were washed with 1N HCl and brine, then dried (Na2SO4) and evaporated to give 43.56 g of crude material. Pure N-(3-cyanophenyl)-N'-(1-(t-butoxycarbonyl)piperidin-4-yl)urea was isolated by flash chromatography on silica gel (1.2 kg) eluted with 2:1 hexane:ethyl acetate (6 L) then 1:1 heaxane ethyl acetate collected in 800 ml fractions. Fractions 9 thru 14 contained pure product, yield 21.69 g.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33]I)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)C.[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.C(OC(C)C)(C)C>CC(N(C)C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][N:39]2[CH:43]=[CH:42][N:41]=[CH:40]2)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(=O)N(C)C
Solvent: CC(C)OC(C)C
Solvent: CC(Cl)Cl
Product: O=C(O)C(=NOCCn1ccnc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-iodoethoxyimino)-acetic acid solvated with dichloroethane (=2.56 g of pure acid), 4.2 g of imidazole and 10 ml of dimethylacetamide was stirred for 3 hours at room temperature and after addition of another 10 ml of dimethylacetamide, the mixture was stirred for 40 hours at room temperature. The mixture was poured into 200 ml of isopropyl ether and the mixture was stirred for 30 minutes and was then decanted. The gummy residue was triturated in 200 ml of isopropyl ether and then treated with 300 ml of ether. The mixture was stirred for 30 minutes and was vacuum filtered. The product was rinsed with ether and was then taken up in 30 ml of acetone. The solution was stirred for one hour and was vacuum filtered and the recovered product was rinsed with acetone, with ether and dried to obtain 1.243 g of the syn isomer of 2-(2 -tritylamino-4-thiazolyl)-2-(2-imidazol-1-yl-ethoxyimino)-acetic acid (internal imidazolium salt) melting at 280° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[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]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:53][CH2:52]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) 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 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H49N4O5SCl2 [(M+H)+] 743.2795, observed 743.2795.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([O:18]C)[CH:6]=[CH:5][C:4]=1[C:20](=[O:22])[CH3:21].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([OH:18])[CH:6]=[CH:5][C:4]=1[C:20](=[O:22])[CH3:21]
Reactant: COc1ccc(C(C)=O)c(OC)c1CCCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1ccc(O)c(CCCc2ccccc2)c1O
Temperature: -50 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
A solution of 10.0 g (33.5 mmol) of 1-[2,4-dimethoxy-3-(3-phenylpropyl)phenyl]ethanone from the preceding example in 250 mL of dichloromethane was stirred at -50° C. while 67 mL (67 mmol) of 1m boron tribromide in dichloromethane was added over a 15 min period. The reaction mixture was stirred at -50° C. for 1 hr and at room temperature for 3 days before being poured onto ice. Work-up with 9:1 dichloromethanemethanol in the usual manner gave a product which was a chromatographed on silica gel. Elution with hexane-ether mixtures gave 6.69 g (74%) of the title compound as a solid. Recrystallization of a sample from ether-hexane gave colorless solid, mp 120°-122° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:10]([OH:13])[CH2:11][CH3:12]>>[CH2:10]([O:13][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: CCCO
Reactant: O=[N+]([O-])c1ccccc1
Product: CCCOc1ccc(N)cc1

Procedure:
The method of claim 1 wherein nitrobenzene is reacted with propanol to form p-propoxyaniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example J18) (719 mg, 2.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (803 mg, 2.0 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (985 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[N:11]=3)[S:7][C:6]=2[CH:28]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Cl:16][C:15]1[C:10]([C:8]2[S:7][C:6]3[CH:28]=[C:2]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])[CH:3]=[CH:4][C:5]=3[CH:9]=2)=[N:11][C:12]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[N:13][CH:14]=1
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(Br)cc4s3)n2)CC1
Reactant: O=C1CCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(N5CCCC5=O)cc4s3)n2)CC1
Temperature: 150 °C
Yield: 26.3 %

Procedure:
A microwave tube is charged with [4-(6-bromobenzo[b]thiophen-2-yl)-5-chloropyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine (0.045 g, 0.094 mmol), 1.5 equivalent of 2-pyrrolidinone (0.012 g, 0.14 mmol), 4 mol % of palladium acetate (0.010 g, 0.0040 mmol), 8 mol % of Xantphos (0.050 g, 0.0080 mmol), 1.5 equivalent of cesium carbonate (0.049 g, 0.15 mmol) and acetonitrile (2 mL). The reaction is sealed and heated under microwave condition at 150° C. for 15 minutes, cooled down, filtered and then evaporated to furnish a red oil. The crude material is subjected to reverse phase purification, eluting with 20-95% CH3CN/0.01 N NH4HCO3 in water, using a C18 Xterra column, to provide the title compound as a pale yellow solid (0.012 g, 23% yield). ES+(m/z) 485 (35Cl) and 487 (37Cl) [M+H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH:9]1[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1)[OH:8].B1([O-])OO1.[OH2:19].[OH2:20].O.O.[Na+]>C(O)(=O)C>[O:19]=[S:12]1(=[O:20])[CH2:11][CH2:10][CH:9]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[OH:8])[CH2:14][CH2:13]1
Reactant: O
Reactant: OC(c1ccccn1)C1CCSCC1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=S1(=O)CCC(C(O)c2ccccn2)CC1
Reaction time: 18 h
Yield: 68.6 %

Procedure:
Placed pyridin-2-yl(tetrahydro-2H-thiopyran-4-yl)methanol (1.560 g, 7.453 mmol) in glacial acetic acid (2 mL). Sodium perborate tetrahydrate (2.293 g, 14.91 mmol) was added and stirred for 18 hours. The reaction was partitioned between saturated sodium bisulfite and CH2Cl2. The solids were filtered off, washed with water and dried to afford the title compound (1.233 g, 68.56% yield)