Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(N(CC)CC)C.Cl.[Cl-].[Na+]>CO.C(Cl)Cl>[F:9][C:2]([F:1])([F:8])[C:3]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(=O)C(F)(F)F
Yield: 57.3 %

Procedure:
Ethyl trifluoroacetate (7.1 g, 50 mmole) is added with stirring to a suspension of 6-aminocaproic acid (I, 5.0 g, 40 mmole) in methanol (25 ml) and triethylamine (40 mmole) is added, with stirring. After stirring for 12 hours, by which time all the acid is in solution, the mixture is diluted with methylene chloride (100 ml) and made acidic (pH 1) with 1 N HCl. Saturated sodium chloride solution (90 ml) is then added and the lower layer is separated. The aqueous layer is extracted with methylene chloride (100 ml) and the two organic extracts are combined, dried over sodium sulfate and the solvents evaporated to afford 5.21 g of the desired acid II (Scheme I).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([NH2:24])[C:18](=[CH:22][CH:23]=1)[C:19](O)=[O:20]>>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]2[C:18]([C:19](=[O:20])[N:6]3[C:5]4[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=4[NH:3][C:2]3=[N:24]2)=[CH:22][CH:23]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Cc1cc2nc(Cl)[nH]c2cc1C
Product: Cc1cc2[nH]c3nc4cc(C(F)(F)F)ccc4c(=O)n3c2cc1C

Procedure:
3-Trifluoromethyl-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 4-trifluoromethylanthranilic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.[OH-].[Li+].S(OC)(O[CH3:21])(=O)=O>C1COCC1.C(OCC)C>[CH3:21][O:13][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1c(C)cccc1OC
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of ethyl 6-methylsalicylate (1.27 g, 6.97 mmol) in THF (35 mL) was added lithium hydroxide monohydrate (0.594 g, 14.2 mmol) followed by dimethyl sulfate (1.00 mL, 10.6 mmol). The resultant mixture was heated to reflux for 1 hour then cooled to room temperature. The mixture was diluted with diethyl ether (70 mL), washed with saturated aqueous NaHCO3 (4×10 mL), dried (MgSO4) and concentrated. Purification of the crude material by column chromatography on silica gel (9:1 hexanes-EtOAc) provided 1.23 g (91%) of ethyl 2-methoxy-6-methylbenzoate as a white solid. 1H NMR (CDCl3) δ1.38 (t, 3H, J=7.2 Hz), 2.30 (s, 3H), 3.82 (s, 3H), 4.40 (q, 2H, J=7.2 Hz), 6.76 (d, 1H, J=8.4 Hz), 6.79 (d, 1H, J=7.8 Hz), 7.23 (dd, 1H, J=7.8, 8.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[N:18][CH:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:32](B1OC(C)(C)C(C)(C)O1)([CH3:34])=[CH2:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:32]([C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)=[N:18][CH:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1)([CH3:34])=[CH2:33]
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(c4ncc(Br)cn4)CC3)cn2)cc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 5-bromo-2-[4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidin-1-yl]pyrimidine (Example 57) (31 mg, 0.062 mmol) and isopropenylboronic acid pinacol ester (23 μL, 0.124 mmol) in dry N,N-dimethylformamide (0.3 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (complex with dichloromethane) (1 mg, 0.012 mmol) and cesium carbonate (40 mg, 0.124 mmol). The mixture was stirred at 90° C. overnight under N2, allowed to cool to room temperature, diluted with water (1 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound as a white crystal (23 mg, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[O:12]([CH2:11][C@H:10]([OH:13])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COc1ccccc1C[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
Under ice-cooling, to a solution of (R)-3-(2-methoxyphenyl)propane-1,2-diol (1.62 g) and imidazole (0.92 g)in dimethylformamide was added t-butyldimethylsilyl chloride (1.36 g),and stirred for 15minutes successively. The reaction solutionwas poured into water, extracted with ethyl acetate, and dried oversodium sulfate. After the solvent was evaporated in vacuo, thegained crude product was purified by silica gel columnchromatography, and it was eluted with a mixed solvent of hexaneand ethyl acetate (7:1, v/v). The fractions containing the desiredproduct were combined and evaporated in vacuo to obtain (R)-1-t-butyldimethylsiloxy-3-(2-methoxyphenyl)-2-propanol(2.22 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1.CCOCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:24][CH2:25][CH3:26]
Reactant: C#Cc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#Cc1ccccn1)(CCCC)CCCC
Reaction time: 0.25 h

Procedure:
Dissolve 2-ethynylpyridine (7.14 g, 69.23 mmol) in THF (350 mL) and cool the solution to −10° C. (ice/methanol) under nitrogen. Add n-butyllithium (1.6 M in hexanes, 47.6 mL, 76.16 mmol) dropwise and stir the mixture. After 15 minutes, add tributyltin chloride (20.7 mL, 76.2 mL) dropwise. Warn the mixture to room temperature overnight. Quench the reaction with water, dilute with ether, and wash with saturated ammonium chloride, then brine. Dry over sodium sulfate, filter and concentrate. No further purification necessary to give the title compound: 1H NMR (CDCl3) δ 8.50-8.54 (m, 1H), 7.51-7.59 (m, 1H), 7.35-7.43 (m, 1H), 7.11-7.18 (m, 1H), 1.59-1.64 (m, 6H), 1.32-1.42 (m, 6H), 1.05-1.10 (m, 6H), 0.88-0.94 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31]CC)=[O:30].[OH-].[K+]>C1COCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([OH:31])=[O:30]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (1.85 g, 3.09 mmol) was hydrolyzed with potassium hydroxide (0.523 g, 9.32 mmol) in THF (20 mL) and water (20 mL). Crystallization from methylene chloride/hexane and drying at 78° C for 12 hours yielded 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid a bright yellow solid (1.35 g), mp 115-117° C. Mass spectrum (+ESI, [M+H]+) m/z 573; 1HNMR (500 MHz, DMSO-d6): δ13.2-13.5 (br s, 1H), 8.45 (d, 1H, J=1.5 Hz), 8.2 (d, 1H, J=8.9 Hz), 8.1 (d, 1H, J=9.2 Hz), 8.05 (dd, 1H, J=7.7 Hz and 0.7 Hz), 8.0 (dd, 1H, J=8.9 Hz and 1.7 Hz), 7.75 (d, 1H, J=7.8 Hz), 7.4-7.45 (m, 6H), 7.3 (t, 2H, J=7.6 Hz), 7.25 (t, 1H, J=7.4 Hz), 5.35-5.4 (m, 1H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C32H27BrO5.0.10H2O: Calculated: C, 67.05; H, 4.78; N, 0.00. Found: C, 66.69; H, 4.38; N, 0.02.
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.[C:10]1([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]([O:28]CC)(=[O:27])C>O>[C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:10]2[CH:11]=[CH:12][C:13]([C:25]([OH:28])=[O:27])=[CH:14][CH:15]=2)[CH2:21][CH2:20]1)(=[O:24])[CH3:23]
Reactant: CCOC(C)=O
Reactant: CC(=O)N1CCC(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A mixture of aluminum chloride(III) (26 g, 195 mmol) and dichloromethane (200 mL) was stirred at 0° C., and oxalyl chloride (20 mL, 228 mmol) was dripped over 10 minutes. Then a mixture of 1-(4-phenylpiperidin-1-yl)ethanone described in Production Example 1-9 (12.3 g, 60.5 mmol) and dichloromethane (50 mL) was dripped over 30 minutes. The mixture was stirred under nitrogen atmosphere at 25° C. for 14 hours. The reaction liquid was poured onto ice and ethyl acetate (1 L) and water (1 L) were added for separation. The aqueous layer was extracted with ethyl acetate (1 L) twice, then the organic layer was washed with water (1 L) twice and then with a saturated saline solution (500 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. Ethyl acetate was added to the concentrated residue and the product was collected by filteration and washed with ethyl acetate to obtain the title compound (9.09 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[Cl:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.N1C=CC=CC=1>O1CCCC1.O>[Cl:14][C:15]1[C:20]([NH:21][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Nc1cccnc1Cl
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2cccnc2Cl)c1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of 5-methyl-2-nitrobenzoyl chloride (3.77 g, 18.9 mmol) in tetrahydrofuran (25 mL) was treated with a solution consisting of 2-chloropyridin-3-amine (2.6 g, 20.22 mmol), pyridine (6 mL) and tetrahydrofuran (15 mL). The reaction mixture was stirred for 2 hours then diluted with water (150 mL) and extracted with dichloromethane (3×70 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (100 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-(2-chloropyridin-3-yl)-5-methyl-2-nitrobenzamide (5.44 g) that was used without further purification. LCMS [M+H]: 292.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([F:50])[C:37]([F:38])=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48]O)=[CH:41][CH:40]=3)[CH:35]=[CH:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:19])[CH:17]=[CH2:18].N1C(C)=CC=CC=1C.O>ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([F:50])[C:37]([F:38])=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:41][CH:40]=3)[CH:35]=[CH:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCCO)cc3)=C2F)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOc1ccc(C2(F)CC=CC(c3ccc(CCCCOS(=O)(=O)C(F)(F)F)cc3)=C2F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
3.10 g of trifluoromethanesulphonic anhydride dissolved in 10 ml of dichloromethane was added dropwise at 0° C. to a solution of 4.40 g of 4-[2',3'-difluoro-4"-(4-hydroxy-butyl)-1,2':4',1"-terphenyl-4-yloxy]-butyl acrylate and 1.18 g of lutidine in 100 ml of dichloromethane. The reaction mixture was stirred at 0° C. for 90 minutes and subsequently poured into 100 ml of water and extracted twice with 50 ml of dichloromethane. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 4.20 g of 4-[2',3'-difluoro-4"-[4-(trifluoro-methanesulphonyloxy)-butyl]-1,2':4',1"-terphenyl-4-yloxy]-butyl acrylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([O-])[CH:3]=1.[Na+].P(Cl)(Cl)[Cl:14].O=P(Cl)(Cl)Cl>[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]([C:9]#[N:10])=[C:6]([CH3:8])[N:7]=1
Reactant: ClP(Cl)Cl
Reactant: Cc1nc(N)cc([O-])c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(N)cc(Cl)c1C#N
Temperature: 25 °C

Procedure:
A suspension of sodium 6-amino-3-cyano-2-methylpyridin-4-olate (690 mg, 4.03 mmol, prepared in analogy to WO2001062233A2 and isolated as sodium salt) in PCl3 (3.50 ml, 40.3 mmol) and POCl3 (0.94 ml, 10.1 mmol) was heated to reflux for 12 h. After cooling to room temperature, the reaction mixture was carefully given onto 2N NaOH (200 ml) and 50 g ice. The mixture was extracted with DCM (7×50 ml), and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was used without additional purification. LCMS RtM=1.45 min, [M+H]+=168.1.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([N:22]=[C:23]=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:24]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1cccc2ccccc12

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(1-naphthyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 1-naphthylisocyanate (3.24 mmol) according to the procedure in General Method B. The product precipitated from methylene chloride and filtered. The resulting solid was titruated with 1:3 triethyl amine:methylene chloride. The filterate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with 1N HCl in water. The desired product precipitated from solution and was collected by filtration(0.11 g, 10%). EI-MS m/z 324(M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[S:42][C:41]([CH2:43]Cl)=[N:40][C:39]=2[CH:45]=1>CN(C=O)C.O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[S:42][C:41]([CH2:43][O:8][C:7]3[C:2]([F:1])=[C:3]([C:10]#[N:11])[C:4]([F:9])=[CH:5][CH:6]=3)=[N:40][C:39]=2[CH:45]=1
Reactant: ClCc1nc2cc(Cl)ccc2s1
Reactant: N#Cc1c(F)ccc(O)c1F
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
A mixture of 2,6-difluoro-3-hydroxybenzenecarbonitrile (4.5 g, 29.0 mmol), K2CO3 (6.01 g, 43.5 mmol) and Nal (0.78 g 5.8 mmol) in DMF (75 ml) was stirred at room temperature for 5 minutes. 5-chloro-2-(chloromethyl)-1,3-benzothiazole was then added and the mixture heated at 40° C. for 18 hours, cooled to room temperature and poured into water (450 ml). Buff solid was filtered off and dried (9.46 g). This was the recrystallised from acetonitrile (30 ml) and dried in vacuo at 40° C. to give a beige solid. Yield 79%, mp 145-147° C., HPLC (Gemini C18, 50×4.6 mm): m/z 337 [M+H]+, Rt=4.93 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][CH:19]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][CH2:18][CH2:19][N:39]3[CH2:38][CH2:37][N:36]([S:33]([C:28]4[CH:27]=[CH:26][C:25]5[C:30](=[CH:31][CH:32]=[C:23]([Cl:22])[CH:24]=5)[CH:29]=4)(=[O:35])=[O:34])[CH2:41][CH2:40]3)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CCC=O)cc2C1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2sc(CCCN3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1

Procedure:
In the same manner as in Referential Example 321, a reaction was effected using 3-(5-tert-butoxycarbonyl -4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)propanal and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:9]2[CH2:10][CH2:11][CH:12]([N:15]=[CH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccccn1
Reactant: NC1CCN(C(c2ccc(Br)cc2)c2ccccc2Cl)CC1
Product: Clc1ccccc1C(c1ccc(Br)cc1)N1CCC(N=Cc2ccccn2)CC1

Procedure:
When an equivalent quantities of 1-[(4-bromophenyl)(2-chlorophenyl)methyl]-4-piperidinamine and 2-pyridinecarboxaldehyde are substituted in the procedure of Example 1, there is obtained 1-[(4-bromophenyl)(2-chlorophenyl)methyl]-N-[(2-pyridyl)methylene]-4-piperidinamine having the following structural formula ##STR30##
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32]C(C(O)=O)=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 4 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol) was added dropwise to a solution of 3-(tert-butyloxycarbonyl)-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.0 g, 3.7 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J.Org.Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.5 ml, 10 mmol) in 10 ml of anhydrous CH2Cl2. After 4 hrs, CH2Cl2 was removed by evaporation at reduced pressure. Flash chromatography (4×20 cm, hexane-ethyl acetate, 1:2) afforded 1b as a yellow crystalline solid (1.25 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.39 (d, 1H, J=1.4 Hz, NH), 8.02 (m, 1H, C6F4H), 7.9 (br s, 1H, C4-H), 7.45 (d, 1H, J=1.4 Hz, C8-H), 7.33 (d, 1H, J=9 Hz, C5-H), 4.02 (t, 2H, J=9 Hz, NCH2CH2), 3.26 (t, 2H, J=9 Hz, NCH2CH2), 1.51 (s, 9H, C(CH3)3). Anal. Calcd. for C22H18N2O4F4 : C, 58.67; H, 4.03; N, 6.22. Found: C, 58.45; H, 4.09; N, 6.13.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (319 mg, 1.0 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (246 mg, 1.0 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (297 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([O:23][CH2:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[CH:29][CH:30]=1)(=O)C1C=CC=CC=1.[I-].[K+].COCCOCCOCCOC>CO>[C:10]([OH:12])(=[O:11])[C:9]1[CH:13]=[CH:5][CH:6]=[CH:7][CH:8]=1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]2[N:27]([CH:26]=1)[C:10](=[O:12])[C:9]1[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:13]=1)[N:14]=2
Reactant: O=C(OCc1ccc(Cl)nc1)c1ccccc1
Reactant: CC(C)Oc1ccc(N)c(C(=O)O)c1
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOCCOC
Solvent: CO
Product: CC(C)Oc1ccc2nc3ccc(CO)cn3c(=O)c2c1
Product: O=C(O)c1ccccc1

Procedure:
A suspension of 1.0 g. of 5-isopropoxyanthranilic acid, 1.1 g. of 6-chloro-3-pyridinemethanol benzoate and 0.01 g. of potassium iodide in 10 ml. of triglyme was heated to 150° overnight under a stream of argon. On cooling, the reaction mixture was dissolved in hot methanol, filtered and evaporated to an orange oil. Chromatographic separation and recrystallization from hexane-dichloromethane yielded 8-hydroxymethyl-2-isopropoxy-11H-pyrido[2,1-b]quinazoline-11-one benzoate, mp 123°-126°.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][N:9]([CH3:18])[CH:10]=[N:11][C:12]1[S:13][CH:14]=[C:15]([CH3:17])[N:16]=1>>[Br-:1].[CH3:18][N:9]([CH:10]=[N:11][C:12]1[S:13][CH:14]=[C:15]([CH3:17])[N+:16]=1[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8]
Reactant: Cc1csc(N=CN(C)C)n1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)C[n+]1c(C)csc1N=CN(C)C
Product: [Br-]

Procedure:
prepared by reaction of ethyl bromoacetate with N,N-dimethyl-N′-(4-methyl-thiazol-2-yl)-formamidine. LC-MS: tR=0.61 min; [M+H]+=256.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([O:13][C:4]=2[CH:3]=1)=[C:11]([NH2:14])[N:10]([CH3:15])[N:9]=3.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:12]([O:13][C:4]=2[CH:3]=1)=[C:11]([NH:14][C:16](=[O:18])[CH3:17])[N:10]([CH3:15])[N:9]=3
Reactant: Cn1nc2c(oc3cc(Cl)ccc32)c1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c2oc3cc(Cl)ccc3c2nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-2-methyl-2H-benzofuro[3,2-c]pyrazol-3-amine (6.0 g, 27.1 mmol, described in Example 6) and acetic anhydride (60 mL) was stirred at room temperature for 2 hr. The precipitate was collected and washed with diethyl ether to give the title compound (7.0 g), mp 290°-300° C. Crystallization from ethanol gave title compound having mp 293°-298° C.: IR (mineral oil) 3220, 3170, 1665 and 1540 cm-1 ; UV max (MeOH) 297 nm (ε=7755), 274 (22760) and 229 (21360); NMR (DMSO-d6) δ2.13 (3H, s), 3.82 (3H, s), 7.33 (1H, 2d), 7.76 (1H, d) and 7.82 (1H, d); and Anal. Calcd for C12H10ClN3O2 : C, 54.66% H, 3.82% N, 15.94% and Found: C, 54.52% H, 3.86% N, 15.86%.