Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]=[O:8].C(N(CC)CC)C.[CH3:16][OH:17]>C(O)(C)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:16][OH:17])=[C:5]([CH2:7][OH:8])[N:6]=1
Reactant: CO
Reactant: C=O
Reactant: Cc1ncc[nH]1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1nc(CO)c(CO)[nH]1
Temperature: 78 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
82 g (1 mole) of 2-methylimidazole and 220 g (2.2 moles) of 30% strength by weight aqueous formaldehyde solution are stirred for 1 hour at 60° C., 50.4 g (0.49 mole) of triethylamine are added to the mixture, and stirring is continued for 48 hours under reflux at about 78° C. The solution is evaporated to dryness under reduced pressure at a bath temperature of 60° C., 160 g of crude product being obtained during this procedure. The crude product is stirred with 128 g of methanol and 32 g of isopropanol, for 30 minutes in each case, at 50° C. and at 10° C. with cooling. The colorless solid is then filtered off, washed with twice 200 ml of acetone and dried for 12 minutes at 45° C. to give 91.6 g of 2-methyl-4,5-dihydroxymethylimidazole of melting point 182°-182.5° C. This corresponds to a yield of 64.5%. The purity (HPLC) is 99.8%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:18]=1[OH:27])[CH3:16]>CN(C=O)C>[CH2:7]([O:27][C:18]1[CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=[CH:22][C:17]=1[CH2:15][CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CCCOc1ccc(CC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(CC)c(OCc2ccccc2)c1
Temperature: 45 °C
Reaction time: 15 h
Yield: 52.6 %

Procedure:
Potassium carbonate (17.8 g, 0.13 mol) followed by benzyl bromide (5.12 mL, 42.9 mmol) were added to a solution of 2-ethyl-5-propoxy-phenol (7.74 g, 42.9 mmol) in DMF (60 mL). The mixture was stirred at 45° C. for 15 hours and then partitioned between H2O and EtOAc. The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (6.1 g, 55%). 1H NMR (400 MHz, CDCl3): δ 1.02 (t, J=7.6 Hz, 3 H), 1.19 (t, J=7.6 Hz, 3 H), 1.78 (q, J=7.6 Hz, 2 H), 2.63 (q, J=7.6 Hz, 2 H), 3.88 (t, J=6.6 Hz, 2 H), 5.05 (s, 2 H), 6.44 (dd, J8.1, 2.3 Hz, 1 H), 6.51 (dd, J=2.3 Hz, 1 H), 7.05 (d, J=8.3 Hz, 1 H), 7.31 (m, 1 H), 7.38 (m, 2 H), 7.44 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O>>[F:17][C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc(F)c2)o1
Yield: 59 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.21 mmol) was converted using 3-fluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.75 mg, 59%) which was obtained as an off-white solid. MS: m/e 322.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:34])=[CH:18][C:16]=1[NH2:17].C(N(CC)C(C)C)(C)C.O>C(#N)C>[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:34])=[CH:18][C:16]=1[NH:17][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:12][CH3:13])[N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: COc1cc(Cl)c(N)cc1OCc1c(F)cccc1OC
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(Nc2nc(Cl)nc(OC)c2[N+](=O)[O-])cc1OCc1c(F)cccc1OC
Temperature: 40 °C
Reaction time: 72 h
Yield: 90.2 %

Procedure:
To a solution of 2,4-dichloro-6-methoxy-5-nitropyrimidine (1.79 g) in acetonitrile (21 mL) were added 2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyaniline (2.18 g) and N,N-diisopropylethylamine (1.28 mL), and the mixture was stirred at 40° C. for 3 days. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=3/1), and collected by filtration. The collected solids were dried under reduced pressure to give 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyaniline (3.15 g). The title compound was prepared in a similar manner to that described in Example 397 using this material instead of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1.S(=O)(=O)(O)O.[N+:17]([O-])([O-:19])=[O:18].[K+]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([N+:17]([O-:19])=[O:18])=[CH:6][N:5]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cc(N)ccn1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(N)c([N+](=O)[O-])cn1

Procedure:
Prepared analogously to example 83b from methyl-4-aminopicolinate, conc. sulphuric acid and potassium nitrate.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7](I)[C:5]([NH2:6])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(C(C)C)C(C)C)C.[O:23]1[CH2:27]CC[CH2:24]1.C[OH:29]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:6][C:5]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:3][C:2]([CH3:1])=[C:8]([CH3:9])[C:7]=1[C:24]([O:23][CH3:27])=[O:29]
Reactant: C1CCOC1
Reactant: Cc1cc([N+](=O)[O-])c(N)c(I)c1C
Reactant: CO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(C)c(C)cc([N+](=O)[O-])c1N
Temperature: 100 °C
Yield: 96 %

Procedure:
A mixture of 4,5-dimethyl-6-iodo-2-nitroaniline (17.52 g, 60 mmol), bis(triphenylphosphine)palladium (II) chloride (1.75 g) and ethyldiisopropylamine (11.5 mL, 66 mmol) in tetrahydofuran/methanol (1:1, 300 mL) was heated at 100° C. under a carbon monoxide atmosphere (100 psi, 6.7 atm) in an autoclave for 8 hours. After being cooled, the mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (150 mL) and water (150 mL). The aqueous layer was extracted with dichloromethane (2×150 mL), and the combined extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography, eluting with hexane:ethyl acetate (9:1), then (3:1) and finally hexane:dichloromethane (1:1) gave methyl 2-amino-5,6-dimethyl-3-nitrobenzoate (12.94 g, 96%) as an orange solid.
Reaction SMILES: [OH:1][C@:2]1([C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C:24](=[CH:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[C:20](=O)[CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CN(C=[O:35])C.[Cl:36][C:37]1[CH:38]=[C:39]([N:43]=[C:44]=[O:45])[CH:40]=[CH:41][CH:42]=1>O>[OH:1][C@:2]1([C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C:24](=[CH:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[CH2:20][CH2:21]2)[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)[C:3](=[O:35])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:44]([NH:43][C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([Cl:36])[CH:38]=2)=[O:45])[CH2:9][CH2:10]1
Reactant: C[C@]12CC(=O)C(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)CCN1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCN(C(=O)Nc2cccc(Cl)c2)CC1
Reaction time: 1 h

Procedure:
17α-Hydroxy-21-(1-piperazinyl)pregna-4,9(11)-diene-3,2-dione (EXAMPLE 6A, 5.00 g) is treated om DMF (20 ml) with m-chlorophenylisocyanate (1.84 g) for 3 days. The mixture is poured into water (200 ml). After 1 hr, the liquid is decanted. The solid is dissolved in methylene chloride and is extracted with aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (3% methanol in methylene chloride to 4%) to give the title compound which is crystallized from hot ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])[CH3:7].[I-].[CH3:20][N:21]1[C:29]2[C:24](=[C:25]([CH3:30])[CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:31][N+](C)(C)C)=[CH:22]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:31][CH:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[N:21]([CH3:20])[CH2:22]2)[C:9]1=[O:17])[CH3:7]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COC(=O)CCC(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCC(C)n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a mixture of 4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-pentanoic acid methyl ester (85 mg, 0.34 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (175 mg, 0.51 mmol) in DMF (2.5 mL) was added K2CO3 (95 mg, 0.69 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 25% EtOAc in Hexane as the eluent to afford the desired 4-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanoic acid methyl ester (120 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([NH:40][S:41]([C:44]1[S:48][C:47](Br)=[CH:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])[CH3:38].CCCCCC>C1(C)C=CC=CC=1.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>[C:37]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=3)[CH:22]=2)=[CH:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:36])[CH3:38]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
A stirred mixture of 4-(4-fluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.14) (0.34 g, 0.57 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19 g, 0.63 mmol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.033 mmol) in toluene (5 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) as a white solid.
Reaction SMILES: [C:1]([S:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH:16]OS([O-])=O.[K+]>CO>[C:1]([S:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Sc1ccc(C(=O)O)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)S(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 156.7 %

Procedure:
4-(tert-Butylthio)benzoic acid (3.18 g, 15.1 mmol) was dissolved in methanol (78.70 mL) followed by the addition of water (7.9 mL) and OXONE (4.65 g, 7.56 mmol). The reaction mixture was stirred at room temperature for 45 minutes before it was filtered using methanol. The solvent was evaporated under reduced pressure. Water (35 mL) was added to the residue and the mixture was basified using solid NaOH and was washed with ethyl acetate (3×50 mL). The aqueous layer was acidified with 1N HCl before it was extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-(tert-butylsulfinyl)benzoic acid (2.68 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 8.12-8.08 (m, 2H), 7.73-7.69 (m, 2H), 1.09 (s, 9H). ESI-MS m/z calc. 226.1, found 227.3 (M+1)+; Retention time: 1.05 minutes (3 min run).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=3)[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:24]4[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=4)[CH:15]=3)[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCN(CCN3CCCC3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCCC4)CC3)ncn2)s1

Procedure:
6-[4-(2-Pyrrolidin-1-ylethyl)piperazin-1-yl]pyrimidin-4-amine 11-2 (0.35 g, 1.27 mmol), sodium hydride (0.101 g, 2.53 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.183 g, 1.27 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and isolated via lyophilization. Hi-Res MS: calc: 385.1921 found: 385.1918. 1NMR (DMSO): 12.1 ppm (s, 1H); 8.46 ppm (s, 1H); 8.27 ppm (s, 1H); 6.27 ppm (s, 1H); 3.63 ppm (m, 6H); 3.35 ppm (m, 4H); 2.76 ppm (m, 6H); 1.96 ppm (s, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5].C(N(CC)CC)C.[CH:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=[O:28]>CN(C)C=O.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[C:33]([C:32]1[CH:37]=[CH:38][C:29]([C:27](=[O:28])[CH2:2][CH2:3][C:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=3[CH:7]=2)=[O:5])=[CH:30][CH:31]=1)([O:35][CH3:36])=[O:34]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 1 h
Yield: 45.5 %

Procedure:
5.6 g (0.02 mole) of 6-(3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnapthalene and 3.3 ml (0.024 mole) of triethylamine in 30 ml of dimethylformamide were stirred for 1 hour at room temperature. Thereafter, a solution of 3.6 g (0.025 mole) of methyl 4-formylbenzoate and 1 g of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride in 10 ml of dimethylformamide was added dropwise. Stirring was continued for 1 hour, after which the mixture was poured onto ice/water and extracted twice with ethyl acetate, and the combined organic extracts were washed several times with water, dried over magnesium sulfate and evaporated down. 3.7 g of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione of melting point 139°-141° C. were obtained from the residue (6.4 g) after recrystallization from ethanol.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[N:6]1([C:12]2[CH:33]=[CH:32][C:15]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH2:34]([N:36](CC)[CH2:37]C)C.CNC.C1COCC1>C(Cl)Cl>[CH3:34][N:36]([CH3:37])[CH2:2][C:3]([N:9]1[CH2:10][CH2:11][N:6]([C:12]2[CH:33]=[CH:32][C:15]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:7][CH2:8]1)=[O:4]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCl
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(C(=O)CN(C)C)CC4)cc3)n2)n1C(C)C
Reaction time: 0.83 h
Yield: 60 %

Procedure:
Chloroacetyl chloride (50 μl, 0.65 mmol) was added dropwise to a stirred solution of 2-[4-(piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 200 mg, 0.53 mmol) and triethylamine (90 μl, 0.65 mmol) in DCM (5 ml) at room temperature. After 50 minutes, 2M dimethylamine in THF solution (2 ml, 4 mmol) was added and the reaction was stirred for 5 hours before evaporating under reduced pressure. Chromatography on neutral alumina (activity II) with MeOH:DCM (1:99 to 3:97) gave material which required further purification on silica gel with MeOH:DCM:7N NH3MeOH (3:97:0.0025 to 10:90:0.0025) to give the title compound as a yellow foam. (150 mg 60% yield). NMR: 1.39 (d, 6H), 2.19 (s, 6H), 2.46 (s, 3H), 3.02 (b t, 2H), 3.06 (b t, 2H), 3.59 (b t, 2H), 3.68 (b t, 2H), 5.69 (septuplet, 1H), 6.92 (d, 2H), 6.94 (d, 1H), 7.39 (s, 1H), 7.47 (d, 2H), 8.31 (d, 1H), 9.17 (s, 1H); m/z 463.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][NH2:15].CO>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[N:15]([CH3:14])[CH2:12]2
Reactant: CN
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CO
Product: CN1Cc2cc(Br)ccc2C1=O
Reaction time: 18 h

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)benzoate (410 mmol) in MeNH2/MeOH (1500 mL) was heated to reflux and stirred for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica eluting with petroleum ether/ethyl acetate (6:1 to 3:1) to afford the sub-titled compound (48.5 g).
Reaction SMILES: [N+]([C:4]1C=C(N)C=C[C:5]=1C(O)=O)([O-])=O.[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([OH:19])=[O:18].C(O)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[C:23]([F:24])=[C:22]([NH2:25])[C:21]([F:26])=[C:20]([F:27])[C:16]=1[C:17]([O:19][CH2:4][CH3:5])=[O:18]
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(F)c(F)c(N)c(F)c1F

Procedure:
Thus, in accordance with Reaction Scheme 6, 3-nitro-6-methyl-fluorobenzene (Aldrich) is subjected to oxidation, conversion of the resulting carboxylic acid to an acid chloride and thereafter to an ethyl ester, followed by reduction of the nitro group, to yield ethyl 2-fluoro-4-amino-benzoate (Compound C1). 3-Nitro-6-methyl-bromobenzene (Aldrich) and 3-nitro-6-methyl-chlorobenzene (Aldrich) are subjected to essentially to the same series of reactions to yield ethyl 2-bromo-4-amino-benzoate (Compound D1) and ethyl 2-chloro-4-amino-benzoate (Compound E1), respectively. 2-Nitro-4-aminobenzoic acid (Research Plus) is converted to its methyl ester (Compound F1) through the corresponding acid chloride. 2,3,5,6-Tetrafluoro-4-amino-benzoic acid (Aldrich) is esterified by treatment with ethanol in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine in CH2Cl2 to give ethyl 2,3,5,6-tetrafluoro-4-amino-benzoate (Compound G1). 2,4,6-Trifluorobenzoic acid (Aldrich) is converted to the methyl ester through the acid chloride, and the 4-fluoro atom is displaced by reaction with sodium azide, followed by hydrogenation, to yield methyl 2,6-difluoro-4-amino benzoate (Compound H1). Compounds C1, D1, E1, F1, G1 and H1 serve as amine reagents in accordance with Formula 3. Further examples of reagents in accordance with Formula 3 are nitro, fluoro, chloro, bromo and trifluoromethyl derivatives of amino substituted heteroaryl carboxylic acids, or their lower alkyl esters, such as ethyl 2-amino-4-chloropyridine 2-carboxylate, ethyl 5-amino-3-chloropyridine 5-carboxylate, and 3,4-dibromo-5-aminothiophene-2-carboxylic acid. The latter examples can be prepared by respective chlorination or bromination of 2-aminopyridine-5-carboxylic acid or of its ester, 3-aminopyridine-6-carboxylic acid or of its ester (described in WO 93/06086) and of 2-aminothiophene-5-carboxylic acid (described in PCT/US92/06485).
Reaction SMILES: ClC1C=CC(OC2C=CC(CN3CCC([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)CC3)=CC=2)=CC=1.[C:34]1([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([CH2:49][CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][CH:55](C4C=C(NC(=O)C(C)C)C=CC=4)[CH2:54][CH2:53]3)=[C:41]2[C:70]2C=CC=C[CH:71]=2)[CH:39]=CC=CC=1.C(N1C2C=CC(C=O)=CC=2C2C1=CC=CC=2)C.CC(C)C(NC1C=CC(C2CCNCC2)=CC=1)=O>>[CH2:34]([N:40]1[C:41]2[CH:70]=[CH:71][C:50]([CH2:51][N:52]3[CH2:53][CH2:54][CH:55]([C:23]4[CH:22]=[CH:21][C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])=[CH:19][CH:18]=4)[CH2:56][CH2:57]3)=[CH:49][C:42]=2[C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Agent: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Agent: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(CN3CCC(c4ccc(NC(=O)C(C)C)cc4)CC3)ccc21

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[4-(4CHLOROPHENOXY)BENZYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE (Example 108) N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde (22.3 mg, 0.100 mmol) and 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide (24.6 mg, 0.100 mmol) provided N-(4-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide. The product was obtained as a white crystalline solid (20 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 8.21–7.09 (m, 12H), 4.38 (q, 2H, J=7.2 Hz), 3.81 (s, 2H), 3.25–3.03 (m, 2H), 2.60–2.38 (m, 2H), 2.31–2.09 (m, 2H), 1.98–1.69 (m, 4H), 1.44 (t, 3H, J=7.2 Hz), 1.23 (d, 6H, J=6.8 Hz); ESMS m/e: 454.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1ccsc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccsc1
Yield: 91.7 %

Procedure:
3-Thiophene carboxylic acid (10.04 g, 78.3 mmol) was dissolved in dichloromethane (250 ml) and 4-dimethylaminopyridine (9.57 g, 78.3 mmol), N,O-dimethylhydroxylamine hydrochloride (7.64 g, 78.3 mmol), N-methylmorpholine (8.6 ml, 78.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.01 g, 78.3 mmol) added and the resultant solution stirred for 24 h at room temperature. The reaction was diluted with dichloromethane (100 ml) and washed with aqueous 2M hydrochloric acid (3×30 ml), aqueous saturated sodium bicarbonate solution (2×30 ml) and water (3×30 ml). The organic phase was dried (magnesium sulphate), filtered and evaporated to give the title compound as a colourless oil (12.3 g, 92%).