Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1O[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:8][N:7]=1.[NH2:23][C:24]1[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[O:28].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(Cl)(Cl)Cl>CN1CCN(C)C1=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:23]([C:24]2[C:25]([CH3:33])=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:9]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:8][N:7]=1
Reactant: COCCCc1nnc(-c2ccc(-c3ccccc3)nc2)o1
Reactant: Cc1c(N)cccc1C(N)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClC(Cl)Cl
Solvent: CN1CCN(C)C1=O
Product: COCCCc1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc(C(N)=O)c1C
Temperature: 200 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
5-[5-(3-Methoxypropyl)-1,3,4-oxadiazol-2-yl]-2-phenylpyridine (1.0 g) prepared in the Reference Example 7 was dissolved in 1,3-dimethyl-2-imidazolidinone (10 ml), followed by addition of 3-amino-2-methylbenzamide (1.53 g) prepared in the Reference Example 6 and D-10-camphorsulfonic acid (290 mg), and stirred at 200° C. for 16 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1), to afford the entitled compound (812 mg, 56%). The physico-chemical values are as follows.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C(#N)C>[C:10]([C@@H:2]([NH:1][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:11])[NH2:12]
Reactant: O=S1(=O)CCCO1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CC#N
Product: NC(=O)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of L-Phenylalaninamide (3.93 g, 23.9 mmol) in acetonitrile (25 mL) was added 1,3-propane sultone (2.70 g, 21.8 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetonitrile (2×25 mL). The solid product was suspended in EtOH (100 mL). The suspension was stirred at reflux for 1 hour. The solid material was filtered and dried in vacuo, affording the title compound (5.18 g, 83%). 1H NMR (D2O, 500 MHz) δ ppm 7.24 (m, 3H), 7.16 (m, 2H), 4.02 (m, 1H), 3.15 (m, 1H), 3.01 (m, 3H), 2.83 (m, 2H), 2.02 (m, 2H), 1.98 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.48, 133.72, 129.58, 129.21, 128.11, 61.55, 47.95, 45.52, 36.21, 21.44. [α]D=+23.1° (c=0.0021 in water), ES-MS 285 (M−1).
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]([NH:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[C:17]([Br:22])[CH:16]=1)=[S:13])(=O)C1C=CC=CC=1>O.C1COCC1>[Br:21][C:19]1[CH:20]=[C:15]([NH:14][C:12]([NH2:11])=[S:13])[CH:16]=[C:17]([Br:22])[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(Br)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)cc(Br)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
A solution of NaOH (46.30 g, 1.16 mol) dissolved in 480 mL of H2O was added to a solution of 1-benzoyl-3-(3,5-dibromo-phenyl)-thiourea (96.0 g, 0.23 mol) in 1.20 L of THF. The resulting reaction mixture was stirred at 70° C. for 12 hours. THF was distilled off and extracted with ethyl acetate (×3). The combined organic layer was dried over Na2SO4, filtered and distilled off to get the crude residue that was washed with hexane to obtain the desired compound as a grey solid (68 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>COCCOC>[Br:8][C:7]1[C:2]2[N:3]([CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=2)[CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[CH:6]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(C(F)(F)F)cc(Br)c2n1
Yield: 78.9 %

Procedure:
To a solution of 2-amino-3-bromo-5-(trifluoromethyl)pyridine (10.0 g, 41.5 mmol) in 1,2 dimethoxyethane (300 mL) at room temperature was added ethyl bromopyruvate (9.889 g, 45.64 mmol) dropwise. The reaction mixture was heated to reflux for 18 h. The 1,2-dimethoxyethane was removed under reduced pressure and the residual solid was recrystallized from 1-chlorobutane. The solid was isolated by filtration and dried to afford an off-white solid, 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid, ethyl ester (11.044 g).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@@H:8]([CH2:15][OH:16])[O:7]3)[CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@@H:8]([CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[O:7]3)[CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@@H]1CCc2ccc3ncccc3c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCc3ccc4ncccc4c3O2)cc1
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A solution of (6S)-(7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.14 g, 0.65 mmole) and p-toluenesulfonyl chloride (0.25 g, 1.3 mmole) in anhydrous pyridine (50 mL) was allowed to stir for 24 hours and then the solvent was removed in vacuum. The residue was dissolved in ethyl acetate (50 mL) and washed with water (3×30 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (50% methylene chloride/hexane) afforded 0.23 g (96%) of the title compound as a solid, mp 123° C., [α]25D=+51.22° (4.92, CHCl3).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][C:20]=1[CH3:21].O>CN1CCCC1=O>[N+:22]([C:18]1[CH:19]=[C:20]([CH3:21])[C:15]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=2)=[CH:16][C:17]=1[CH3:25])([O-:24])=[O:23]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (0.4 g of 60% in oil) in dry N-methylpyrroli-dinone (10 ml) was slowly added 3-trifluoromethylphenol (1.62 g). When effervescence had ceased, 3-chloro-6-nitro-p-xylene (1.85 g) was added and the mixture stirred at 120-40° C. for 5 hours. On cooling, the mixture was poured into water and the mixture extracted with diethyl ether (x3). The combined ether extracts were dried (MgSO4), filtered and evaporated to give the title compound as a solid, m.p. 68-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].O[NH:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=3)[N:26]=2)[CH2:17][CH2:16]1)=[NH:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:14]=[C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=5)[N:26]=4)[CH2:19][CH2:20]3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N=C(NO)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4noc(-c5cccc(Cl)c5)n4)CC3)nn12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Chlorobenzoyl chloride (92 mg, 0.53 mmol) was added to a stirred partial solution of N-hydroxy-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboximidamide (165 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol) in THF (3 mL). The reaction mixture became a clear solution over 30 minutes and LCMS after 1 hour showed complete initial acylation. The reaction mixture was heated at 150° C. for 15 minutes by microwave after which LCMS showed complete cyclisation to the desired product. The reaction mixture was evaporated and the residue was boiled briefly with ethanol, cooled and filtered off to give 6-[4-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (104 mg, 46%) as a crystalline powder.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2nccc(C(F)(F)F)n2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane (1.0 mL) at room temperature was added 2-chloro-4-trifluoromethyl-pyrimidine (0.1 g, 0.55 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 150° C. in a microwave for 30 minutes, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate and hexane to provide (4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamic acid benzyl ester. MS (CI) n/z 395 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.48(d, 1H), 7.37-7.32 (m, 5H), 6.72 (d, 1H), 5.08 (s, 2H), 4.67 (bs, 1H), 4.22 (m, 2H), 3.49(m, 2H), 2.08 (m, 2H), 1.68-1.60 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.CC1C=CC2SC3C(=CC=C(F)C=3)C(=O)C=2C=1.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:38]=[CH:37][C:36]2[S:35][C:34]3[C:29](=[C:30]([CH3:39])[CH:31]=[CH:32][CH:33]=3)[C:28](=[O:40])[C:27]=2[CH:26]=1>CC(C)=O>[F:42][C:24]([F:41])([F:23])[C:25]1[CH:38]=[CH:37][C:36]2[S:35][C:34]3[C:33](=[CH:32][CH:31]=[C:30]([CH3:39])[CH:29]=3)[C:28](=[O:40])[C:27]=2[CH:26]=1
Reactant: Cc1cccc2sc3ccc(C(F)(F)F)cc3c(=O)c12
Agent: Cc1ccc2sc3cc(F)ccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1ccc2c(=O)c3cc(C(F)(F)F)ccc3sc2c1

Procedure:
This was then treated with sulphuric acid as described for 2-methyl-6-fluoro-9-thioxanthone. The resulting substance consisted mainly of 2-trifluoro-6-methyl-9-thioxanthone with some 2-trifluoromethyl-8-methyl-9-thioxanthone. When boiling this mixture with acetone the more soluble 8-methyl-compound will go into solution. The remaining 2-trifluoromethyl-6-methyl-9-thioxanthone was obtained as a yellow crystalline substance, which melts at 174-178 degrees Centigrade.--Yield: 80 grams.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[CH:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.O>ClCCl>[Br:2][C:1]([Br:5])=[CH:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Carbon tetrabromide (46.7 g, 141 mmol) was dissolved in 200 mL dichloromethane. The solution was cooled in an ice-water bath and triphenylphosphine (73.9 g, 282 mmol) in 200 mL dichloromethane was introduced via an addition funnel over 20 min. The reaction mixture was stirred at 0° C. for 10 min and a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (16 g, 70.4 mmol) in 100 mL dichloromethane was added via an addition funnel. The solution was stirred at 0° C. for 1 hour. Water (250 mL) was added and aqueous layer was extracted 3 times with 100 mL dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. 300 mL ether was added to the residue, and the resulting suspension was filtered. The solid was washed 3 times with 150 mL ether. The combined filtrate was concentrated and passed through a plug of silica gel, washed thoroughly with 10% acetone/hexanes to afford yellow oil which was used without further purification.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22].O>O1CCCC1>[N:23]1([C:21]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:22])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=NC(=O)n1ccnc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
2.0 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6carboximidate and 1.83 g of 1,1'-carbonyldiimidazole are stirred at room temperature for 5 hours in 20 ml of tetrahydrofuran. The reaction mixture is poured into water and extracted twice with ethyl acetate. The extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on silica gel with n-hexane/acetone (1:4) as the eluent, and there is obtained ethyl N-(1-imidazolylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6 carboximidate, m,p. 134°-137° C.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[C:3]([F:6])([F:5])[F:4].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:19][CH:18]=1)=[CH2:16].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:14][C:9]1[CH:8]=[C:7]([CH:2]([C:3]([F:6])([F:5])[F:4])/[CH:16]=[CH:15]/[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:21][CH:22]=2)[CH:12]=[C:11]([Cl:13])[CH:10]=1
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Reactant: C=Cc1ccc(-n2cncn2)cc1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: FC(F)(F)C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 180 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
To a stirred solution of 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2,2-bipyridyl (0.2 g, 1.3 mmol). The resultant reaction mixture was degassed with argon for 30 min, then stirred at 180° C. for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (t, J=1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O>CN(C)C=O>[Cl:15][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cnc(F)cc12
Solvent: CN(C)C=O
Product: Fc1cc2c(Cl)ncnc2cn1
Reaction time: 0.5 h

Procedure:
A suspension of 6-fluoropyrido[3,4-d]pyrimidine-4(3H)-one (U.S. patent application Ser. No. 08/358,352, 1994) (1.65 g) in 50 mL thionyl chloride and several drops of dimethyl formamide was heated under reflux until a clear solution was obtained (20 minutes), and then for a further 30 minutes. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with aqueous Na2CO3. The solvent was dried and removed to give crude 4-chloro-6-fluoropyrido[3,4-d]pyrimidine which was dissolved in 2-propanol (50 mL) containing 3-bromoaniline (2.1 g). The mixture was heated under reflux for 15 minutes to give a precipitate, which was redissolved by the addition of triethylamine. After the addition of water, the solution was concentrated and cooled to give 4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]-pyrimidine, (2.29 g), mp (MeOH) 219.5-221° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=3)[N:14]([CH2:26][CH3:27])[C:13]2=[O:28])[CH2:8][CH2:7]1)=O)C.Br.C(N1C2C(=CC([N+]([O-])=O)=CC=2)C(=O)N(C2CCNCC2)C1=O)C.[Cl:53][C:54]1[N:63]=[C:62](Cl)[C:61]2[C:56](=[CH:57][C:58]([O:67][CH3:68])=[C:59]([O:65][CH3:66])[CH:60]=2)[N:55]=1>>[Cl:53][C:54]1[N:63]=[C:62]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=4)[N:14]([CH2:26][CH3:27])[C:13]3=[O:28])[CH2:8][CH2:7]2)[C:61]2[C:56](=[CH:57][C:58]([O:67][CH3:68])=[C:59]([O:65][CH3:66])[CH:60]=2)[N:55]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CCOC(=O)N1CCC(n2c(=O)c3cc([N+](=O)[O-])ccc3n(CC)c2=O)CC1
Agent: Br
Agent: CCn1c(=O)n(C2CCNCC2)c(=O)c2cc([N+](=O)[O-])ccc21
Product: CCn1c(=O)n(C2CCN(c3nc(Cl)nc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 78 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 3.62 g (9.4 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound ii) was used in place of Compound a, whereby 3.20 g of crude 1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound jj) was obtained. The product (198.0 mg) was treated in the similar manner as in Example 40, except for the use of 2,4-dichloro-6,7-dimethoxyquinazoline in place of 4-chloro-6,7-dimethoxy-quinazoline, to give 220.7 mg (yield: 78%) of Compound 79 as pale yellow crystals.
Reaction SMILES: F[C:2](F)(F)[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.Cl[C:14]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][C:15]=1[NH:21][NH2:22].[OH-].[Na+]>C(O)(=O)C.O>[C:15]1([N:21]2[C:5](=[O:7])[CH2:4][C:3]([C:2]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[N:22]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 171.5 %

Procedure:
To a mixture of ethyl trifluoroacetoacetate (5.0 g, 27.2 mmol) in acetic acid (50 mL) was added 2,4-dichlorophenylhydrazine (4.82 g, 27.2 mmol). The reaction mixture was refluxed for 22 hours and then was diluted with water (50 mL), neutralized with 2N NaOH and extracted with EtOAc (3×50 mL). The EtOAc extracts were combined, dried over Na2 SO4, filtered and concentrated to afford 5.51 g (70%) of 2,4-dihydro-2-(2,4-dichlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =2,4-Cl2 --Ph; R2 =CF3 ; R3 =H).
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16](=[O:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.CN1CCOCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:37]([O:44][C:45](=[O:50])[CH:46]([OH:49])[CH2:47][NH2:48])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:48][CH2:47][CH:46]([C:45]([O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:50])[OH:49])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:18])[CH3:17]
Reactant: CC(=O)SCC1(C(=O)O)CCc2ccccc2C1
Reactant: NCC(O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)SCC1(C(=O)NCC(O)C(=O)OCc2ccccc2)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 2-carboxy-2-[(acetylthio)methyl]-1,2,3,4-tetrahydronaphthalene (2.88 g, 10.0 mmol) in dry dimethylformamide (20 mL). To this solution add N-methyl morpholine (1.01 g, 10.0 mmol), isoserine benzyl ester tosylate salt (3.67 g, 10.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10.0 mmol). Stir the reaction mixture for 18 hours under an atmosphere of argon at ambient temperature then partition between ethyl acetate and dilute HCl. Wash the organic solution with water, saturated sodium hydrogen carbonate then brine. Dry the solution (MgSO4) and concentrate in vacuo. Purify the residue by column chromatography (ethyl acetate:hexane) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][CH:48]([N:53]([CH3:70])[C:54](=[O:69])[CH:55]([NH:67][CH3:68])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[C:49](=[O:52])[NH:50][CH3:51].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][CH:11]=[CH:12][C:13](=[O:15])[N:67]([CH:55]([C:54](=[O:69])[N:53]([CH:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[F:40])[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccccc1F)N(C)C(=O)C(Cc1ccc2ccccc2c1)N(C)C(=O)C=CCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.19 g; 0.783 mmol) was dissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotriazole (0.12 g; 0.861 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g; 0.900 mmol) was added and the reaction mixture was stirred 15 min at room temperature. N-[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.33 g; 0.783 mmol) and diisopropyl ethylamine (0.15 ml; 0.861 mmol) was added and the reaction mixture was stirred 12 hours at room temperature. Methylene chloride (50 ml) was added and the reaction mixture was washed with water (50 ml), sodium hydrogen sulfate (10%; 50 ml), sodium hydrogen carbonate (sat; 50 ml), water (50 ml) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.366 g of {4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester. {4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butyl ester (0.36 g; 0.557 mmol) was dissolved in methylene chloride (3 ml). Trifluoro acetic acid (3 ml) was added and the reaction mixture was stirred 5 min at room temperature. Methylene chloride (25 ml), sodium hydrogen carbonate/sodium carbonate (3 ml) and sodium hydrogen carbonate (s) was added until pH=8. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was lyophylised to afford 0.237 9 of the title compound.