Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][CH2:7][CH2:8][C:9]([CH2:12]O)=[C:10]([CH3:11])[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.CS([Cl:29])(=O)=O.C(OCC)C>ClCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][CH2:7][CH2:8][C:9]([CH2:12][Cl:29])=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(CO)CCOc2ccc(Br)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=C(CCl)CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 125 %

Procedure:
To a solution of (7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepin-4-yl)methanol from step H6 (1.53 g, 5.68 mmol) in dichloromethane (10 mL) was added DIPEA (2.98 mL, 17.1 mmol) followed by methanesulfonyl chloride (0.886 mL, 11.4 mmol) at 0° C. The mixture was allowed to gradually warm up to rt. After 18 h at rt, diethyl ether (50 mL) was added, the mixture was washed with water, and the organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to give 7-bromo-4-(chloromethyl)-5-methyl-2,3-dihydrobenzo[b]oxepine (2.05 g, 7.13 mmol, 125% yield). The crude material was used in the next step without further purification. 1H NMR (500 MHz, chloroform-d) δ 7.40 (d, J=2.4 Hz, 1H), 7.36-7.32 (m, 1H), 6.96 (s, 1H), 4.56 (t, J=6.3 Hz, 2H), 4.37 (s, 2H), 2.34 (t, J=1.0 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5Br)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[CH3:45][N:46](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5[C:45]#[N:46])=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(Br)c5nn4cc3-c3ccccc3)cc2)CCC1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(C#N)c5nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
150 mg (0.26 mmol) {1-[4-(7-Bromo-3-phenylpyrimido[1,2-b]indazol-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester (intermediate example Int-2-1), 1.7 mg (0.026 mmol) zinc, 21.6 mg (0.026 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 61.8 mg (0.53 mmol) zinc cyanide in 2.2 mL N,N-dimethylacetamide, (degassed) were stirred in the microwave for four hours at 110° C. After addition of a further equivalent of zinc cyanide and a spatelspitze of zinc and bis(diphenylphosphino)ferrocenedichloropalladium(II) stirring was continued for three hours at 110° C. Despite an incomplete reaction the mixture was worked up. After addition of ethyl acetate the organic phase was washed twice with water and saturated ammonium chloride, dried over sodium sulfate, filtrated, and the solvent was removed. 274 mg {1-[4-(7-Cyano-3-phenylpyrimido[1,2-b]indazol-2-yl)-phenyl]cyclobutyl}carbamic acid tert-butylester were obtained which were used without purification in the next step (cleavage of the protecting group).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2([CH2:43][C:44]([OH:46])=O)[C:34]1[C:35]([O:40][CH2:41][CH3:42])=[N:36][CH:37]=[CH:38][CH:39]=1.[CH3:47][N:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:50][CH2:49]1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2([C:34]1[C:35]([O:40][CH2:41][CH3:42])=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:43][C:44]([N:57]1[CH2:56][CH2:55][N:54]([CH:51]2[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]2)[CH2:59][CH2:58]1)=[O:46]
Reactant: CCOc1ncccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(CC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
195 mg (1.44 mmol) of 1-hydroxybenzotriazole and 276 mg (1.44 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added to a solution of 1.00 g of [5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid in 10 ml of dimethylformamide and, after stirring for 15 minutes, 277 mg (1.51 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 1.00 ml (7.41 mmol) of triethylamine were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate several times. The combined organic phase was extracted with water and saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g Redisep cartridge, mobile phase gradient from 10 to 70% methanol in dichloromethane). 311 mg of the title compound were obtained as a white foam.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([NH:19][CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:28][CH3:29])[C:7]2[N:8]([C:10]([C:14](OCC)=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1)=[O:3].[BH4-].[Li+].O1CCCC1>CO.O>[CH2:28]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:21]=1[CH2:20][NH:19][C:6]1[C:7]2[N:8]([C:10]([CH2:14][OH:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=1)[CH3:29]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C(N)=O)cn12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(CO)c(C)nc12
Reaction time: 1.33 h
Yield: 46 %

Procedure:
Ethyl 6-(aminocarbonyl)-8-(2-ethyl-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (280 mg, 0.71 mmol) and lithium borohydride (16 mg, 0.71 mmol) were added to tetrahydrofuran (10 ml) and the reaction mixture was refluxed for 70 min. Additional amounts of lithium borohydride (16 mg) and methanol (45 mg, 1.42 mmol) were added and the mixture was refluxed for 80 min. Additional amounts of lithium borohydride (16 mg) and methanol (22 mg, 71 mmol) were added and the mixture was refluxed for 4 h. The reaction mixture was allowed to reach R.T. and water (1 ml) and methanol (5 ml) and was stirred for 40 min. at R.T. The solvents were evaporated under reduced pressure and the residue was added to water and was stirred for 80 min. The crystals were filtered off and washed with water, ethyl acetate/ethanol and diethyl ether to give the desired product (115 mg, 46%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([C:31]3[CH:35]=[CH:34][O:33][CH:32]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:36]C1C=CC(C([O-])=O)=C(CS(C2C=CC=CC=2)(=O)=O)C=1C1C=COC=1>>[C:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][O:20][C:15]1[C:14]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][C:4]([F:36])=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:16]=1[C:17]([OH:19])=[O:18])=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Reactant: O=C([O-])c1ccc(F)c(-c2ccoc2)c1CS(=O)(=O)c1ccccc1
Product: CC(C)(C)OC(=O)NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccc(F)cc2)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 6, starting from methyl 2-[2-(t-butoxycarbonyl)aminoethoxy]-6-(4-fluorobenzenesulphonylmethyl-3-(furan-3-yl)benzoate (Intermediate 13).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[CH2:12]([NH:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH2:12]([N:19]1[C:6]([NH2:7])=[C:5]2[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=[CH:8]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNCc1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1c2ccc(Br)cc2nn1Cc1ccccc1
Temperature: 140 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a dried flask charged with 4-bromo-2-fluorobenzonitrile (5.0 g, 22.5 mmol) in n-butanol (60 mL) was added a solution of benzylhydrazine hydrochloride (17.56 g, 90 mmol, 4.0 eq) and diisopropylethylamine (32.1 mL, 184.48 mmol, 8.2 eq). The reaction mixture was stirred at 140° C. under N2 for 3 days. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 5 to 60% EtOH/DCM) and the product containing fractions were concentrated to give 3.4 g (50%) of the title compound as beige solid. 1H NMR (300 MHz, CD2Cl2) δ 7.63 (dd, 1H), 7.37 to 7.30 (m, 4H), 7.20 to 7.16 (m, 2H), 6.94 (dd, 1H), 5.44 (s, 2H), 4.02 (broad s, 2H); ES-MS m/z 302.3/304.3 [M+H]+, RT (min) 2.34.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].C([O-])(O)=O.[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[CH2:20]([O:19][C:17](=[O:18])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a stirred solution of 10 g of 4-aminoacetophenone (74 mmol, 1 eq) in a mixture of 60 ml of water and 100 ml of dioxane at 0° C., 12.43 g of NaHCO3 (148 mmol, 2 eq) and 15.3 g of benzyl chloroformate (85 mmol, 1.15 eq, purity 95%) are added. The mixture is stirred at room temperature for 4 h and then concentrated under reduced pressure to remove the dioxane. The suspension is diluted with 70 ml of water and 150 ml of ethyl acetate. The phases are separated and the organic layer is washed with 2×50 ml of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 19.5 g of the product as solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O>[Pt](=O)=O.CO>[O:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12.5 h
Yield: 58 %

Procedure:
A mixture of 4-[4-nitro-2-(trifluoromethyl)phenyl]morpholine (compound of Reference Example 2; 1.20 g, 4.344 mmol), platinum(IV) oxide (0.10 g) and methanol (12 ml) was stirred at room temperature for 12.5 hours under hydrogen atmosphere. The reaction mixture was filtered and the residue obtained by evaporation of the solvent of the filtrate under reduced pressure was washed with n-hexane to give the title compound (0.62 g, 58%) as a colorless crystal.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][NH:14][NH2:15]>C(O)(=O)C>[CH2:10]([C:9]1[N:14]([CH3:13])[N:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CNN
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2,4-dioxohexanoate (12 g) in glacial acetic acid (75 ml) was cooled in an ice-bath and treated with methylhydrazine (3.21 g) in a dropwise fashion over 5-10 m. On complete addition the ice cooling was removed and the yellow homogeneous solution stirred at room temperature for ca. 2 h. The acetic acid was then removed in vacuo and the residual oil re-dissolved in ethyl acetate (~ 100 mls). The ethyl acetate solution was washed with saturated sodium hydrogen carbonate (3×) and brine. After drying over anhydrous magnesium sulphate the solvent was evaporated. The crude material was purified by silica gel chromatography eluting with 20-70% ethyl acetate/hexane giving the title compound as a pale yellow oil, (6.656 g, 52%); dH (CDCl3) 1.28 (3H, t, J7.6 Hz), 1.38 (3H, t, J7.1 Hz), 2.61 (2H, q, J7.6 Hz), 3.84 (3H, s), 4.38 (2H, q, J7.1 Hz) and 6.58 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].S(Cl)([Cl:19])(=O)=O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:19])=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 85.8 %

Procedure:
A mixture of 5-bromoindole-2-carboxylic acid ethyl ester (4.00 g, 14.9 mmol), sulfurylchloride (1.8 mL, 22.4 mmol) and benzene (125 mL) was stirred at 90° C. for 2.5 h. The mixture was cooled to room temperature, NaHCO3 (aq., sat.) was added and the mixture extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4. Concentration and recrystallisation (from toluene) gave the sub-title compound (3.87 g 85%).
Reaction SMILES: [CH2:1]([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)[CH2:2][CH2:3]C.[O:31]1CCC(N)[CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:16]2[C:15]([NH:5][CH:1]3[CH2:33][CH2:32][O:31][CH2:3][CH2:2]3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:25][CH:26]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: NC1CCOCC1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2NC2CCOCC2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with tetrahydro-pyran-4-ylamine ([38041-19-9]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=328.4 [M+H+].
Reaction SMILES: CC1(C)O[O:3]1.[C:6]([O:19][CH:20]1[CH2:25][CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:23][CH:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21]1)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CC(C)=O>[C:6]([O:19][CH:20]1[CH2:21][CH:22]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:23]([OH:3])[CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25]1)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: CC1(C)OO1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)N(O)C(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
A solution of 590 mL (27.7 mmol) of dimethyldioxirane, 0.047M in acetone (prepared by the procedure of Eaton and Wicks, J. Org. Chem. 1988, 53, 5353) is added via a cannula to a 0° C. solution of 12.1 g (27.7 mmol) of 2,6-diphenyl-4-piperidyl laurate in 200 mL of acetone. After stirring for 10 minutes at 0° C.; the reaction mixture is concentrated under reduced pressure and the residue is recrystallized from methanol to yield 9.7 g (78% yield) of the title compound as a white solid: mp 89°-90° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH3:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:20]>C(O)CCC.CO>[CH3:20][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:15][CH3:16])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:18]
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: CCc1ccccc1Nc1ccnc(Cl)n1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CCc1ccccc1Nc1ccnc(Nc2ccc(OCC(O)CN(C)C)cc2)n1
Temperature: 100 °C
Yield: 60.9 %

Procedure:
2-Chloro-4-(2-ethylanilino)pyrimidine (Reference Example A-5; 210 mg, 0.90 mmol) was dissolved in n-butanol (20 ml). To this solution was added a hot solution of 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 229 mg, 0.81 mmol) in methanol (2 ml). The reaction mixture was heated at 100° C. for 18 hours, allowed to cool to ambient temperature and then evaporated onto silica (3 ml). The residue was purified by column chromatography eluting with 0–5% 2.0M methanolic ammonia solution in DCM to give the title product as a colourless solid (201 mg, 61%). NMR (300 MHz): 1.09 (t, 3H), 2.17 (s, 6H), 2.31 (m, 2H), 2.58 (q, 2H), 3.80 (m, 3H), 5.96 (d, 1H), 6.72 (d, 2H), 7.20 (m, 3H), 7.36 (d, 1H), 7.53 (d, 2H), 7.89 (d, 1H), 8.56 (s, 1H), 8.76 (s, 1H); m/z: (ES+) 408.3 (MH+)
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[H-].[Na+].[CH3:15][N:16]=[C:17]=[O:18]>O1CCCC1>[CH3:15][NH:16][C:17]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:18]
Reactant: CN(C)C=Nc1ccncc1O
Reactant: CN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cnccc1N=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a hot suspension of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (7.0 g) in dry tetrahydrofuran (THF) were added sodium hydride (168 mg) and methyl isocyanate (2.6 ml). The reaction mixture was stirred at room temperature overnight, cooled in an ice-methanol bath and filtered. The solid was washed with diethyl ether and distributed between methylene chloride (250 ml) and saturated ammonium chloride (30 ml) and, extracted twice more with methylene chloride (200 ml). The solution was dried (MgSO4) and concentrated and the solid was recrystallized from ethyl acetate and dried under high vacuum and refluxing ethanol to yield 6.18 g of crystals, m.p. 137°-139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][N:13]2[CH:14]=[N:15][N:16]=[CH:17]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(SCCn2cnnc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(SCCn2cnnc2)cc1
Yield: 89.8 %

Procedure:
A mixture of 4-[2-(4-nitrophenylthio)ethyl]-4H-1,2,4-triazole (1.0 g), reduced iron (1.12 g) and calcium chloride (0.22 g) in 15% hydrous ethanol (30 ml) was heated to reflux for 22 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate.: 1:19→1:9), to give 4-[2-(4-aminophenylthio)ethyl]-4H-1,2,4-triazole (0.79 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=2)[N:13]=[CH:12]1.[NH2:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1>>[O:32]1[CH:33]=[CH:34][C:30]([NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[CH:18]=4)[N:13]=[CH:12]3)[CH:4]=2)=[N:31]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(CN3CCOCC3)cc2c1=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(CN3CCOCC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzoic acid was reacted with 3-aminoisoxazole to give N-isoxazol-3-yl-4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzamide; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.41 (t, 4H), 3.60 (t, 4H), 3.65 (s, 2H), 7.06 (d, 1H), 7.62 (d, 1H), 7.77 (d, 1H), 7.87 (m, 1H), 8.10 (m, 2H), 8.15 (d, 1H), 8.32 (s, 1H), 8.86 (s, 1H), 11.47 (s, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](OB(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C.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.C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CCCc1ccc(OB(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(-c2cc(F)cc(Cl)c2)cc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
At first, 25.8 g of 4-propylphenylboric acid (S1-1), 30.0 g of 1-bromo-3-chloro-5-fluorobenzene (S1-2), 2.5 g of tetrakis(triphenylphosphine)palladium, 50.1 g of sodium carbonate and 700 ml of a mixed solvent of toluene/ethanol/water=3/3/1 (volume ratio) were added into a reactor under nitrogen atmosphere, and then the mixture was refluxed for 5 hours. Next, the reaction solution was cooled to room temperature, added with toluene and then washed with 1N hydrochloric acid and water. Then, the resulting solution was dried over magnesium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by silica-gel column chromatography with heptane as eluent and then dried under reduced pressure to obtain 34.8 g of 4-propyl-1-(3-chloro-5-fluorophenyl)benzene (S1-3). The yield of the compound (S1-3) from (S1-1) was 97.7%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:27][C:16]1[CH:17]=[CH:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:29]=[CH:30][CH:31]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=1)=[O:28])=[O:39]
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: O=C(O)c1cccc(O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(O)c2)c1
Reaction time: 18 h
Yield: 29.6 %

Procedure:
To a mixture of 4.1c (91 mg, 0.20 mmol), 3-hydroxybenzoic acid (28 mg, 0.20 mmol), and diisopropylethylamine (104 □L, 0.60 mmol) in DMF (2 mL) was added HATU (76 mg, 0.20 mmol) and the solution stirred for 18 h. The solvent was removed and the resulting residue purified by reverse-phase HPLC eluting with a water/acetonitrile gradient containing 0.1% TFA and lyophilized to give 34 mg (30%) of the product.