Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1>>[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=[C:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[O:28])[C:16]2=[O:17])=[CH:38]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 77.2 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (293 mg, 0.608 mmol) was condensed with 1H-indole-3-carbaldehyde (106 mg, 0.729 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (2% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) yielded 286 mg of 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.25 (s) and 7.90 (s, total 1H), 8.16 (s, 1H), 7.58-7.67 (m, 4H), 7.37-7.53 (m, 6H), 7.07-7.17 (m, 3H), 6.94 (m, 2H), 4.90 (m, 1H), 4.55 (m, 1H), 4.25 (m, 1H), 3.96 (m, 4H), 1.10 (m, 6H); MS 610.8 (M+1), 608.5 (M−1)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[NH:6][CH:7]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Na+]>O.C1COCC1>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[N:6]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(CO)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CO)nc2C)cc1
Yield: 30 %

Procedure:
4-Hydroxymethyl-2-methylimidazole (0.7 g, 6.25 mmol), prepared as in Example 180A, and p-toluenesulfonylchloride (1.2 g, 6.25 mmol) were suspended in 5 mL of distilled water and 3 mL of THF. Sodium hydroxide (1N) was added to maintain a pH of 9 over a period of 3 hours. The reaction mixture was extracted with ethyl acetate (3×50 mL). The extracts were combined, dried over magnesium sulfate, concentrated and crystallized from ethyl acetate, collected by vacuum filtration and dried to give 4-hydroxymethyl-2-methyl-1-p-toluenesulfonylimidazole (0.5 g, 35%) as a white solid; m.p. 140-143°; 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 8.25 2H), 7.36 (d, J=8.25 Hz, 2H), 7.33 (s, 1H), 4.49 (s, 2H), 2.50 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.38, 140.96, 134.85, 130.51, 127.57, 116.05, 57.37, 21.84, 15.02; MS m/e calc'd: 266.0725, found: 266.0714.
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][CH:5]([CH2:10][CH2:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:25]([OH:27])=[O:26].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>O1CCCC1>[S:29]=[C:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][CH:5]([CH2:10][CH2:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=2)[CH2:4][N:3]1[C:25]([OH:27])=[O:26]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC1CC(CCc2ccc(C(=O)OCC(C)C)cc2)CN(C(=O)O)C1=O
Solvent: C1CCOC1
Product: CCC1CC(CCc2ccc(C(=O)OCC(C)C)cc2)CN(C(=O)O)C1=S
Temperature: 60 °C

Procedure:
A mixture of 3.75 g (10 mmol) of 4-(2-[2-oxo-3-ethylcarboxypiperidin-5-yl]ethyl)benzoic acid, 2,2-dimethylethyl ester and 2.44 g (5.5 mmol) of phosphorus pentasulfide in 70 mL of tetrahydrofuran is heated at 60° C. until complete conversion is obtained. The mixture is evaporated to a residue which is purified by chromatography on silica gel, providing 4-(2-[2-thioxo-3-ethylcarboxypiperidin-5-yl]ethyl)benzoic acid, 2,2-dimethylethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccccc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and benzoyl chloride (0.04 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting with 0% to 10% of MeOH/EtOAc to afford the title compound (0.110 g, 64%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.37-7.54 (m, 5H), 7.04 (d, J=8.9 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.61-4.03 (m, 8H), 3.23-3.62 (m, 6H); ESI MS m/z 471 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]2[CH:33]=[CH:34][N:35]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]=2[C:19]1=[O:46]>>[CH:14]1([CH2:13][O:12][C:3]2[C:2]([C:22]3[C:21]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:20]=4[C:19](=[O:46])[N:18]([CH3:17])[CH:23]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2[CH:5]=[N:6][N:7]3[CH3:11])[CH2:16][CH2:15]1
Reactant: Cn1ncc2c(OCC3CC3)c(Br)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(cnn5C)c4OCC4CC4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-(cyclopropylmethoxy)-1-methyl-1H-indazole and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C27H27N4O4S (M+H)+: m/z=503.2. found: 503.1.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:5]=1[CH2:6][N:7]([CH3:18])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2].[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:23][C:20]1[CH:21]=[CH:22][C:4]([CH2:3][C:1]#[N:2])=[C:5]([CH:19]=1)[CH2:6][N:7]([CH3:18])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1CC#N)C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(N)ccc1CC#N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of 36C (1.803 g, 5.31 mmol) in MeOH (30 mL) and THF (10 mL) was added zinc (dust) (3.47 g, 53.1 mmol) and ammonium chloride (5.68 g, 106 mmol). The resulting solution was stirred at rt for 2 h. MeOH was removed under reduced pressure. Na2CO3 (aq, 100 mL) and EtOAc (150 mL) was added, and the suspension was stirred vigorously for 10 min. The mixture was filtered through a glass frit, solid residue was washed with EtOAc (3×150 mL). Combined EtOAc fractions were washed with std. Na2CO3 (aq, 2×50 mL), water (2×50 mL), brine (1×50 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 36D (1.459 g, 4.72 mmol, 89% yield) as a yellowish oil. MS (ESI) m/z: 310.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.29-7.46 (5H, m), 7.15 (1H, br. s.), 6.60 (1H, d, J=7.28 Hz), 6.35-6.55 (1H, m), 5.18 (2H, s), 4.44 (2H, s), 3.71 (2H, br. s.), 3.41-3.66 (2H, m), 2.85 (3H, br. s.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[Br:17][CH:18](O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:17][CH2:18][CH2:19][O:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CC(O)Br
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
Bis(4-fluorophenyl)methanol was refluxed in toluene with an equimolar amount of bromoethanol in presence of a catalytic amount of p-toluenesulphonic acid. The mixture was refluxed for 12 hrs. in a Dean-Stark apparatus. The solvent was evaporated and the residue was dissolved in ether, washed with water (three times) and brine (three times). The organic layer was dried with sodium sulfate, filtered, concentrated and the residue was purified by distillation to obtain in 80% yield 1-bromo-2-[bis(4-fluorophenyl)methoxy]ethane, b.p. 170° C. at 0.1 mm Hg.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]([CH3:15])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:13]([O:12][C:10]1[C:9]([CH3:15])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=1)[CH3:14]
Reactant: CCOc1cc(COC(C)=O)ncc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(CO)ncc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.4 g of (4-ethoxy-5-methyl-2-pyridyl)methyl acetate were dissolved in 46 ml of ethanol. 23 ml of 3N sodium hydroxide solution were then added dropwise thereto and the mixture was stirred at room temperature for a further 3 hours. The ethanol was subsequently removed in vacuo, whereupon the residual aqueous solution was extracted three times with 100 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from petroleum ether and there was obtained 4-ethoxy-5-methyl-2-pyridylmethanol of melting point 99-101° .
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[CH3:15][S:16]([O:11][CH2:10][CH2:9][CH2:8][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57.8 %

Procedure:
To a solution of 10 parts of 3-(cyclohexyloxy)-1-propanol in 160 parts of dichloromethane there were added 11.2 parts of N,N-diethylethanamine and dropwise 8.14 parts of methanesulfonyl chloride. The whole was stirred for 9 hours at room temperature. The reaction mixture was washed with Na2CO3 (aq.) and water and was then dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene. The product was filtered off and dried, yielding 8.6 parts (57.8%) of 3-(cyclohexyloxy)-1-propanol methanesulfonate (ester) (interm. 21).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(O)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 2-(2,4-dichlorophenoxy)benzoic acid (AMR01067, 1.24 g, 4.39 mmol) in dry DCM (20 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 2.5, 13.18 mmol) and triethylamine (0.6 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (AMR01068, 0.88 g, 4.39 mmol) in dry DCM (410 mL) was added. After stirring at room temperature for 48 h, the mixture was diluted with DCM, washed with HCl (1M, 3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using DCM/MeOH 99:1 as eluenty gave 4-[2-(2,4-dichlorophenoxy)benzoylamino]piperidine-1-carboxylic acid tert-butyl ester (953 mg, 40%) as white solid. Rf: 0.64 (DCM/MeOH 9:1) 1H NMR (270 MHz, CDCl3) δ 1.48 (9H, s, 3CH3), 1.92 (2H, m, CH2), 2.92 (2H, br t, CH2), 3.95 (2H, br d, CH2), 4.11 (1H, m, CH), 6.78 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.87 (1H, d, J=8.9 Hz, ArH), 7.21 (1H, dd, J=8.6, 2.5 Hz, ArH), 7.25 (1H, m, ArH), 7.35 (1H, br s, NH), 7.40 (1H, m, ArH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 2.0 Hz, ArH). LC/MS (APCI) tr=5.36 min, m/z 467.36 (18), 465.41 (M++H, 30), 411.33 (67), 409.38 (M+-C4H8, 100). HPLC tr=2.93 min (97.22%)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[CH:22]2>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][N:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Brc1ccc2ncncc2c1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ncncc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromoquinazoline (188 mg, 0.9 mmol; Parkway Scientific) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.22 (m, 4H) 2.42 (s, 3H) 2.91-3.01 (m, 1H) 3.06-3.32 (m, 4H) 4.33 (s, 2H) 6.92-6.99 (m, 1H) 7.02-7.09 (m, 1H) 7.23 (s, 1H) 7.99 (dd, J=9, 2 Hz, 1H) 8.12 (d, J=2 Hz, 1H) 8.22 (d, J=9 Hz, 1H) 9.33 (s, 1H) 9.63 (s, 1H); MS (DCI/NH3) m/z 355 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccccc2C)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2C)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 10, Part C) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCC(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 21.5 parts of ethyl 4-hydroxy-1-piperidinecarboxylate, 35.2 parts of bis(4-fluorophenyl)bromomethane and 8.6 parts of potassium carbonate is stirred and heated in an oil-bath at 140° C. for 3 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed successively with water, a diluted hydrochloric acid solution and a sodium bicarbonate solution, dried, filtered and evaporated. The forerun is distilled off (bp. till 143° C. at 0.5-1 mm. pressure), yielding ethyl 4-[bis(4-fluorophenyl)methoxy]-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([Cl:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)[C:7]=2[CH:14]=1
Reactant: COc1ccc2occ(CCI)c2c1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Product: COc1ccc2occ(CCN3CCN(c4cc(Cl)cc5cccnc45)CC3)c2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yield a brown solid. MP: 72° C.; Yield: 130 mg (30%); (M+H): 422; 1HNMR (400 MHz, CDCl3): δ□8.86˜8.84 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H); 8.05˜8.02 (dd, J1=1.7 Hz,J2=1.7 Hz, 1H); 7.60˜6.88 (m, 7H); 3.86 (s, 3H); 3.69˜2.57 (m, 12H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36].C(OCC)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35](=[O:37])[CH3:36])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 1 ml of pyridine, 268 mg of acetic anhydride and 10 mg of 4-dimethylaminopyridine were added to the solution, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution in that order, dried over anhydrous sodium sulfate, and then evaporated. By recrystallizing the resulting residue from ethanol, 139 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]acetamide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:3]=1[C:4](OC)=[O:5].C(O)(=O)C.[CH:20](N)=[NH:21]>COCCO>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:21][CH:20]=[N:1]2
Reactant: COC(=O)c1c(N)cc(OC)cc1OC
Reactant: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1cc(OC)c2c(=O)[nH]cnc2c1
Yield: 92.8 %

Procedure:
A mixture of methyl 2-amino-4,6-dimethoxybenzoate (16 g), formamidine acetate (24 g) and 2-methoxyethanol (330 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (100 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dimethoxy-3,4-dihydroquinazolin-4-one (14.5 g); NMR Spectrum: (DMSOd6) 3.82 (s, 3H), 3.86 (s, 3H), 6.5 (s, 1H), 6.7 (s, 1H), 7.9 (s, 1H), 11.7 (br s, 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=[N+]=[N-])cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
(S)-tert-Butyl 2-(4-aminophenyl)morpholine-4-carboxylate (150 mg, 0.54 mol) was dissolved in 3 M acetic acid, then cooled to 0° C. Sodium nitrite (93 mg, 1.35 mmol) was added and the yellow solution was stirred at 0° C. for 5 min. Then sodium azide (70 mg, 1.08 mmol) was added to the mixture and stirring was continued for 15 min. Ethyl acetate was added to dissolve the precipitate and stirring was continued for 15 min. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were extracted with 0.1M citric acid solution and with 1M sodium bicarbonate solution subsequently. After drying with MgSO4 the organic layer was evaporated to yield crude (S)-tert-butyl 2-(4-azidophenyl)morpholine-4-carboxylate as an yellow oil (161 mg) which was used for the following cycloaddition reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:11])[S:9][CH:10]=1)=[O:5])C.[Li+].[OH-]>CO.O>[Br:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1csc(Br)n1
Reaction time: 4 h

Procedure:
To a solution of 2-bromo-thiazole-4-carboxylic acid ethyl ester (Combi-Blocks, Inc., San Diego, Calif.; 5 g, 21.2 mmol) in MeOH (25 mL) and water (25 mL) was added LiOH (0.56 g, 23.3 mmol). After stirring for 4 h at reflux temperature, MeOH was evaporated in vacuo. To the residue was added more water, the mixture was acidified to pH 2 with concentrated HCl (3 mL), and extracted with EtOAc. The combined extracts were evaporated to give 2-bromo-thiazole-4-carboxylic acid which was used without further purification. The compounds of the present invention were preferably prepared by methods A to F: