Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O-:25])([O-])=O.[K+].[K+].CN([CH:31]=[O:32])C>O>[CH3:22][O:25][C:31](=[O:32])[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:8](=[O:21])[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:19]1
Reactant: O=C(Nc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(C(=O)Nc3ccccc3)cc2)CC1
Reaction time: 16 h
Yield: 44 %

Procedure:
A mixture of N-phenyl-4-piperazin-1-yl-benzamide (4 mg, 0.02 mmol), methyl α-bromophenyl acetate (3 μL, 0.02 mmol), and K2CO3 (3 mg, 0.02 mmol) in DMF (1 mL) was stirred for 16 h. The mixture was diluted with H2O and extracted with methanolic DCM (2×). The combined organic layers were dried (MgSO4) and concentrated to give an oil, which was purified by PTLC to give a white solid (3 mg, 44%). MS (ESI): mass calcd. for C26H27N3O3, 429.51. m/z found, 430.4 [M+H]+. 1H NMR (CDCl3): 7.71 (d, J=8.9, 2H), 7.69 (br s, 1H), 7.61 (d, J=7.6, 2H), 7.47-7.45 (m, 2H), 7.39-7.33 (m, 5H), 7.12 (t, J=7.4, 1H), 6.89 (d, J=8.9, 2H), 4.07 (s, 1H), 3.71 (s, 3H), 3.36-3.33 (m, 4H), 2.64-2.61 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[CH2:13][CH3:14].[OH-:16].[Na+].Cl>>[CH2:13]([C:12]1[C:11]([OH:16])=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1)[CH3:14]
Reactant: [OH-]
Reactant: Nc1ncccc1C=O
Reactant: CCC(=O)CBr
Agent: Cl
Agent: [Na+]
Product: CCc1nc2ncccc2cc1O
Reaction time: 72 h
Yield: 74 %

Procedure:
2-Amino-pyridine-3-carbaldehyde (100 mg) and 1-bromo-butan-2-one (124 mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6 ml), and the suspension was hermetically sealed and, in this state, was allowed to stand for 3 days. The reaction solution was neutralized with 10% hydrochloric acid, and the precipitate was then filtered. The residue was washed with water and chloroform. The powder as the residue was dried under the reduced pressure to give 2-ethyl-[1,8]naphthyridin-3-ol (106 mg, yield 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>COCCO.O>[CH3:11][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:7][CH:6]=1)=[O:12]
Reactant: COC(=O)c1cccnc1Cl
Reactant: CC(C)C(=O)c1ccc(N)cc1
Solvent: COCCO
Solvent: O
Product: COC(=O)c1cccnc1Nc1ccc(C(=O)C(C)C)cc1
Yield: 118.9 %

Procedure:
A mixture of 1-(4-aminophenyl)-2-methyl-1-propanone (0.0637 mol) and methyl 2chloro-3-pyridinecarboxylate (0.0637 mol) in 2-methoxyethanol (200 ml) was stirred and refluxed for 90 hours. The mixture was taken up in water and EtOAc and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 22.6 g of methyl 2-[[4-(2-methyl-1-oxopropyl)phenyl]amino]-3-pyridinecarboxylate (interm. 20).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:12][CH2:13][CH:14]([NH:17][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]2
Reactant: CCOC(=O)Cl
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC1CCC2(CCc3ccccc3C2)CC1
Temperature: 0 °C

Procedure:
To an ice cooled solution of the free base prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C) in 12 ml. of pyridine, 1 ml. of ethyl chloroformate is added. The mixture is allowed to stand in the cold for about 5 hours and then poured into ice water. The solid that precipitates is collected on a filter and recrystallized from methylene chloride: benzene to give ethyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene] -4-carbamate [I(c)].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][O:32]S(C4C=CC(C)=CC=4)(=O)=O)[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.CN(C=[O:54])C>CO>[CH:31]([OH:32])=[O:54].[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[N:9]=[C:8]([CH:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:27][CH2:26]3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn34)CC2)cc1
Reactant: Nc1ccccc1
Reactant: CN(C)C=O
Solvent: CO
Product: Nc1nccn2c(C3CCC(CNc4ccccc4)CC3)nc(-c3cccc(OCc4ccccc4)c3)c12
Product: O=CO
Yield: 31 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl ester (29 mg, 0.05 mmol) in DMF (0.5 ml) was added aniline (23 μl, 0.25 mmol). The reaction was irradiated in the microwave (200 W, 150° C., 10 m), then evaporated to dryness. The crude reaction product was dissolved in MeOH (2 ml) and added to a pre-wetted MCX cartridge (6 ml/500 mg). The cartridge was washed with MeOH (10 ml) and the product was then eluted using 1% NH3 in MeOH (15 ml). The product was further purified using mass-directed HPLC, to give 1-(3-benzyloxy-phenyl)-3-(4-phenylaminomethyl-cyclohexyl)-imidazo[1,5-a]pyrazin-8-ylamine formic acid salt (7.8 mg, 31%) as an off-white solid: 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.60 (d, 1H, J=5.5 Hz), 7.48-7.41 (m, 3H), 7.36 (t, 2H, J=7.3 Hz), 7.33-7.27 (m, 1H), 7.25-7.22 (m, 1H), 7.18 (d, 1H, J=7.4 Hz), 7.13 (dd, 1H, J=5.5 Hz, 2.3 Hz), 7.08 (t, 2H, J=7.8 Hz), 6.97 (d, 1H, J=5.5 Hz), 6.63 (d, 2H, J=7.4 Hz), 6.58 (t, 1H, J=7.4 Hz), 5.16 (s, 2H), 3.12 (m, 1H), 3.00 (d, 2H, J=6.7 Hz), 2.06 (br. d, 4H, J=11.7 Hz), 1.88-1.70 (m, 3H), 1.30-1.22 (m, 2H), 3H not observed (NH2 and NH); MS (ES+) m/z 504.24 [MH+] at Rt 3.47 min.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[N:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9].Cl.CNC.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[N:30]=[C:29]([C:31]([N:3]([CH3:4])[CH3:1])=[O:32])[CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C(=O)O)n3)cs2)cc1OCC
Reactant: CCN(CC)CC
Agent: CCOP(=O)(C#N)OCC
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2nc(-c3cccc(C(=O)N(C)C)n3)cs2)cc1OCC
Reaction time: 3 h

Procedure:
1.13 ml of triethylamine was dropwise added, at room temperature, to a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(2-carboxy-6-pyridyl)thiazole, 245 mg of dimethylamine hydrochloride and 515 mg of diethyl cyanophosphate in 15 ml of dimethylformamide. The mixture was stirred at the same temperature for 3 hours. The reaction mixture was mixed with 20 ml of water. The resulting mixture was extracted with 50 ml of dichloromethane three times. The dichloromethane layer was dried over sodium sulfate and concentrated. The residue was recrystallized from n-hexane-ethyl acetate-dichloromethane to obtain 800 mg of 2-(3,4-diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyridyl)thiazole.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23](=[O:53])[CH2:24][N:25]2[C:30](=[O:31])[C:29]3[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=3[N:27]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)[C:26]2=[O:52])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([C:23](=[O:53])[CH2:24][N:25]2[C:30](=[O:31])[C:29]3[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=3[N:27]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:40][CH:39]=3)[C:26]2=[O:52])[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=1
Reactant: CCc1cc2c(=O)n(CC(=O)c3cc(OC)cc(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3cc(OC)cc(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A mixture of hydroxylammonium chloride (2.26 g), sodium hydrogencarbonate (3.4 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(3,5-dimethoxyphenyl)-2-oxoethyl]-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.14 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (30 mL). N,N′-Carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.6 g, 48%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].[C:9]([Cl:26])(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[ClH:26].[C:9]([N:6]([CH3:7])[CH2:5][CH2:4][CH2:3][N:2]([CH3:8])[CH3:1])(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CNCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N(C)CCCN(C)C
Product: Cl

Procedure:
To a solution of N,N,N'-trimethyl-1,3-propanediamine (25 g, 0.22 mmole) in methylene chloride (500 mL) was added palmitoyl chloride (57 g, 0.20 mmole) dropwise over 4 hours. After the addition was complete the solvent was removed under reduced pressure. The residue was refluxed in diethyl ether (600 mL) overnight. The precipitate was collected and a portion crystallized from ethyl acetate to give the title compound as a white solid. mp. 105.3°-107.9° C. 1H NMR (300 MHz, CD3OD): δ0.894 (3H, t, J=6.5 Hz), 1.282 (2H, bs), 1.56 to 1.64 (2H, m), 1.89 to 1.99 (2H, m), 2.411 (2H, t, J=7.1 Hz), 2.873 (6H, s), 3.071 (3H, s) and 3.460 ppm (2H, t, J=6.4 Hz). Analysis calculated for C22H48ClN2O: C, 67.56; H, 12.12; N, 7.16; Cl, 9.07. Found: C, 67.37; H, 12.03; N, 7.10; Cl, 9.20.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([NH:19][NH2:20])=[O:18]>C(O)C>[CH3:15][O:16][C:17]([NH:19][N:20]=[C:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: O=C1CCCCC1Cc1ccccc1
Reactant: COC(=O)NN
Solvent: CCO
Product: COC(=O)NN=C1CCCCC1Cc1ccccc1
Reaction time: 2 h
Yield: 69.9 %

Procedure:
18.83 g (0.1 mole) of 2-benzylcyclohexan-1-one and 9.0 g (0.1 mole) of N-methoxycarbonyl hydrazine are dissolved in 100 cm3 of anhydrous ethanol, and the solution is boiled for 2 hours. Then it is cooled, and the separated crystals are filtered off. 18.2 g (96.9%) of the named compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23](=O)[CH2:24][C:25]([O:27]CC)=O)=[C:10]1[C:31]([O:33][CH2:34][CH3:35])=[O:32].N12CCCC1=NCCC2.Cl.[NH2:46][C:47]([NH2:49])=[NH:48]>C(O)C>[NH2:48][C:47]1[NH:49][C:25](=[O:27])[CH:24]=[C:23]([CH2:22][O:21][CH2:20][C:11]2[NH:12][C:13]([CH3:19])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:10]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:46]=1
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Reactant: N=C(N)N
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2cc(=O)[nH]c(N)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 27.3 %

Procedure:
A solution of ethyl 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.74 g), 1,5-diazabicyclo[4.3.0]non-5-ene (0.25 g) and guanidine hydrochloride (0.14 g) in ethanol (30 ml) was heated under reflux for 5.5 hours and then evaporated. The residue was dissolved in chloroform and the solution washed successively with water, 10% aqueous sodium carbonate solution and water, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with ethyl acetate and the resulting precipitate collected, washed thoroughly with diethyl ether, recrystallized from ethyl acetate/ethanol and dried to give the title compound (0.20 g), m.p. 222°-225° C. Found: C,52.10; H,4.56; N,10.54. C23H24Cl2N4O6 requires C,52.78; H,4.62; N,10.70%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][OH:22].C(N(CC)CC)C>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:21]([CH3:20])[OH:22])=[O:9])=[CH:4][CH:3]=1
Reactant: CNO
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(O)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of 4-fluorocinnamic acid (2.0 g, 12 mmol), oxalyl chloride (1.65 g, 13 mmol) and N,N-dimethylformamide (four drops) in 40 ml dichloromethane was stirred overnight under nitrogen. The resulting solution was evaporated in vacuo, and the resulting solid redissolved in 10 ml dichloromethane. The resulting solution of 4-fluorocinnamoyl chloride was added dropwise to a cold (5°-10° C.), stirred mixture prepared from N-methylhydroxylamine hydrochloride (1.09 g, 13 mmol) and triethylamine (5 ml, 35 mmol), which had been stirred for 20 minutes. The reaction mixture was allowed to warm to room temperature, then washed successively with aqueous 1N HCl and 1N NaHCO3. The organic solution was then chromatographed on silica gel with 2% isopropanol in dichloromethane. The product was recrystallized from methanol-water, to provide 1.65 g of the titled compound as a white powder, mp 141°-141.5° C.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:9]([CH3:8])[O:10][CH3:11])=[O:18])=[CH:15][CH:14]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Pyridine (4.40 mL, 54.2 mmol) was added dropwise to N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) dissolved in CH2Cl2 (100 mL) at RT. The reaction mixture was stirred for 30 min, and 4-bromobenzoyl chloride (5.95 g, 27.1 mmol) dissolved in CH2Cl2 (50 mL) was added dropwise. The mixture was stirred for 24 h and the volatiles were removed under reduced pressure. Water (200 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined extracts were washed successively with 5% aqueous HCl (200 mL), 5% aqueous NaHCO3 (200 mL), water (200 mL), and brine (200 mL). The mixture was dried over MgSO4 and concentrated to afford 6.35 g (74%) of 80 as a colorless oil which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 3.35 (s, 3H), 3.53 (s, 3H), 7.54 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[O:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5].[CH3:14][CH:15]([Mg]Cl)[CH3:16]>>[CH3:14][CH:15]([C:4]([C:6]1[O:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:16]
Reactant: CC(C)[Mg]Cl
Reactant: CON(C)C(=O)c1oc(C)nc1C
Product: Cc1nc(C)c(C(=O)C(C)C)o1

Procedure:
Starting with N-methoxy-N-methyl-2,4-dimethyl-5-oxazolecarboxamide and 2-propyl magnesium chloride and following the general method of Preparation 3, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:43][C:44]2[CH:48]=[C:47]([CH3:49])[O:46][N:45]=2)=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1cc(N)no1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (800 mg) was dissolved in chloroform (20 ml) and triethylamine (1.0 ml) to prepare a solution. A solution of triphosgene (378 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 3-amino-5-methylisoxazole (270 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and was then concentrated. Ether was added to the residue for crystallization, and the crystal was collected by filtration. The collected crystal was purified by chromatography (chloroform:acetone=2:1) to give 636 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>O.C1COCC1>[O:19]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CCC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl ester 47 (195 mg, 0.73 mmol) in water/THF (1:1, 0.07M) was added LiOH (46 mg, 1.1 mmol). The resulting solution was stirred overnight at room temperature or until no starting material was detected by TLC. HCl 1N was added and the solution was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4. Filtration and evaporation of the solvent under vacuum followed by purification by column chromatography using 10% MeOH/CH2Cl2, gave the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[S:7].[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([S:14]([O:17]C)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(O)C>[C:8]1([CH3:19])[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:12][CH:13]=1.[NH2:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[S:7][CH3:8]
Reactant: NN1CCNC1=S
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: CSC1=NCCN1N
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 16 h
Yield: 138.1 %

Procedure:
1-Aminoimidazolidine-2-thione (2.34 g) and methyl p-toluenesulfonate (4.1 g) in ethanol (15 ml) are heated to reflux for 10 minutes, then kept at room temperature for 16 hours. The crystalline precipitate is filtered out and washed with isopropanol to give 4.613 g of 1-amino-2-methylthio-2-imidazoline p-toluenesulfonate as colorless needles, of which 3.79 g is placed in methanol (15 ml) and treated with concentrated aqueous ammonia. After stirring for 6 hours, the mixture is diluted with 20 ml isopropanol. After another 12 hours, 5 ml of liquid is distilled off at atmospheric pressure, and 10 ml isopropanol is added to the remainder. The crystals which separate on cooling are filtered out and washed with isopropanol to give 2.323 g of 1,2-diamino-2-imidazoline p-toluenesulfonate, melting point 190°-190.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[CH:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][C:19]=1[CH:28]([NH:35][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:15])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Agent: Cl
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
Prepared in analogy to example 1.1 from (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and rac-C-(2-Chloro-5-trifluoromethyl-phenyl)-C-phenyl-methylamine hydrochloride (CA [13954-13-7]).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:24]([NH2:25])=[C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1>O1CCOCC1.C(OCC)(=O)C.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][C:23]=3[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:16][CH:17]=1
Reactant: Nc1c(Nc2ccc(Cl)cc2)ncnc1N1CCCC1
Reactant: O=C(O)c1ccccc1F
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1nc2c(N3CCCC3)ncnc2n1-c1ccc(Cl)cc1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
2-Fluorobenzoic acid (22 mg, 0.15 mmol) and N4-(4-chlorophenyl)-6-pyrrolidin-1-yl-pyrimidine-4,5-diamine I-(17A-1)a (30 mg, 0.10 mmol) were dissolved in dioxane (0.7 ml) and 50% propanephosphoric acid cyclic anhydride in ethyl acetate (0.3 ml). The resulting mixture was shaken at 95° C. for 48 h. The reaction was cooled and diluted up to a volume of 1.8 ml with water for purification. The purification of the crude mixture was accomplished by reverse phase preparative Gilson 215 HPLC with the Hewlett Packard Series 1100MSD, and G1315A DAD using a Luna 5 micron C8(2) 250*21.2 mm Phenomenex column. The gradient eluant used was 0.1% formic acid in water (A) and acetonitrile (B) with trifluoroacetic acid as a buffer: 0.04 min.—80% A, 20% B; 20 min.—20% A, 80% B; 25 min.—100% B. The fractions with the desired compound were combined and evaporated to dryness to give title compound 18A-1. The residue was dissolved in methanol (1.5 ml) and treated with 4M HCl/dioxane (0.2 ml). The resulting mixture was shaken at 40° C. for 1 h then dried in a flow of nitrogen at 30° C. over 18 hours to obtain the hydrochloride salt of compound as a solid 18A-1 (4.2 mg, 10%): +ESI MS (M+1) 394.3; 1H NMR (500 MHz, CD3OD) δ 8.36 (s, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.59 (m, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.40–7.33 (m, 3H), 7.14 (t, J=9.3 Hz, 1H), 4.49 (br s, 2H), 3.84 (br s, 2H), 2.24 (br s, 4H).