Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:32][C:31]=12
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cn1ccnc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. After-stirring for 3 minutes, 5 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, and brine. The solution is dried with Na2SO4 and the volatiles concentrated in vacuo to give the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1.O=P(Cl)(Cl)[Cl:22]>>[F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([Cl:22])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F

Procedure:
The Route A below schematically depicts a method whereby the substituted pyridine compounds of this invention may be prepared from compounds which are known in the art. In this route, acetone dicarboxylic acid 1 is cyclized into the corresponding anhydride 2 by reacting it with acetic anhydride. The anhydride 2 is dissolved in methanol and stirred to form the acetone dicarboxylic acid monomethyl ester 3. The monomethyl ester is then reacted with isobutylene in acid and a suitable organic solvent to form t-butyl, methyl acetone dicarboxylate 4. The dicarboxylate 4 is then sequentially reacted with magnesium chloride in a suitable organic solvent and with trifluoroacetic anhydride to form methyl, t-butyl diesterpyrone 5.The pyrone 5 is then reacted with trifluoroacetic acid to form the acid methyl ester pyrone 6. The pyrone 6 is then refluxed in a suitable organic solvent to remove the acid moiety and form the methyl ester pyrone 7. The pyrone 7 is then aminated by addition of methanol and ammonia to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl-4-hydroxy pyridine 8. Pyridine 8 is then chlorinated with a suitable chlorinating agent such as POCl3 to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl-4-chloropyridine 9. Pyridine 9 is then hydrogenated using standard laboratory techniques to form 2,6-bis(trifluoromethyl)-3-methoxycarbonyl pyridine 10. The pyridine 10 is then hydrolyzed with a strong base to form 2,6-bis(trifluoromethyl)-3-hydroxycarbonyl pyridine 11. ##STR4##
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>C1COCC1>[ClH:31].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:33]4[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=4[Cl:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)Nc1ccc(Cl)cc1Cl
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 40.2 mg (0.21 mmol) of 2,4-dichlorophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 25 mg (44.5% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([N+:47]([O-])=O)[CH:46]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:44]=[C:45]([NH2:47])[CH:46]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:43])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N)cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 90.7 %

Procedure:
18.80 g (0.027 Mol) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 350 ml of N,N-dimethylformamide and 25 ml water. 44.28 g (0.164 Mol) ferric chloride hexahydrate are added. 17.85 g (0.273 Mol) Zinc powder are added portionwise within 40 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 400 g silica gel using toluene:ethyl acetate (2:1) as eluant yielded 15.39 g (91%) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-diaminobenzoate as yellowish crystals.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)[C:5](Cl)=[O:6].Cl[C:13]1[CH:14]=[C:15]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=1)=[O:17].ClC1C=C(C=C(Cl)C=1)C(NC1C=CC(CC(O)=O)=CC=1)=O>>[Cl:34][C:32]1[CH:33]=[CH:13][C:14]([O:6][CH3:5])=[C:15]([CH:31]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1)=[O:17]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C(O)Cc1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1
Product: COc1ccc(Cl)cc1C(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
with 3,5-dichlorobenzoyl chloride, ethyl 4-(3,5-dichlorobenzamido)-phenylacetate; m.p. 152° C. (crude melting point); and from this, by saponification, 4-(3,5-dichlorobenzamido)-phenylacetic acid; m.p. 189° C., after recrystallization from ethanol-water.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[N:15]1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C.O.[Cl-].[Na+]>[CH2:22]([O:21][C:19]([C:17]1[C:16]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:33])([F:34])[F:35])[CH:26]=2)=[N:15][N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:12])([F:13])[F:11])=[CH:9][C:4]=2[NH2:1])[N:18]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])nc1Oc1cccc(OC(F)(F)F)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2N)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 2-[2-nitro-4-(trifluoromethyl)phenyl]-5-[3-(trifluoromethoxy)phenoxy]-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step F, 0.76 g, 1.5 mmol) in acetonitrile (30 mL) was added a solution of sodium hydrosulfite (1.31 g, 7.5 mmol) in water (20 mL). The mixture was stirred at 23° C. for 2.5 h. The reaction mixture was diluted with saturated aqueous sodium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the title compound (0.70 g) as a pale yellow solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]([C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)=[CH:10][CH:9]=2)[CH3:7])=[N:4][CH:3]=[N:2]1.CC[O:26]C(C)=O>C1C=C(Cl)C=C(C(OO)=O)C=1>[F:22][C:20]([F:23])([F:21])[C:18]1[N:19]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C@H:6]([C:5]3[N:1]([OH:26])[N:2]=[CH:3][N:4]=3)[CH3:7])=[CH:9][CH:10]=2)[S:16][CH:17]=1
Reactant: CCOC(C)=O
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ncn[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ncnn1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of intermediate 15b (0.21 g, 0.62 mmol) in EtOAc (5 ml), m-CPBA was added (0.17 g, 0.97 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water (2×10 ml) and anhydrous Na2SO4 and evaporated under vacuum to give a crude that, after purification by flash chromatography, afforded the pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-1,2,4-triazol-1-ol (15) as a white solid (67%). [α]D=−35 (c=0.82; CH3OH); 1H-NMR (CD3OD): δ 9.40 (bs, 1H, NH); 7.55 (d, 1H, J=2.5 Hz); 7.40 (d, 2H, J=7 Hz); 7.35 (d, 2H, J=7 Hz); 7.15 (s, 1H), 6.25 (d, 1H, J=2.4 Hz); 3.80 (q, 1H, J=7 Hz); 1.60 (d, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[C:20]([NH:4][CH2:1][C:2]#[CH:3])([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: C#CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of propargylamine (20 g) and triethylamine (60.7 mL) in ethyl acetate (500 mL) was added benzyloxycarbonyl chloride (71.7 g) slowly while maintaining the reaction temperature between −5° C. and +5° C. The mixture was then stirred at room temperature overnight. The mixture was washed sequentially with 1.5 M HCl (200 mL), 5% NaHCO3 in water (200 mL), and saturated aqueous sodium chloride (100 mL). The solvent was switched to hexane while the desired product precipitated as colorless crystals (60.1 g).
Reaction SMILES: C[N:2]1C(C)=CC(=O)N(C)C1=O.C[N:13]1[CH:20]=[C:19]([CH3:21])[C:17](=[O:18])[N:16](C)[C:14]1=O.CN1C=C(CC2C=CC=CC=2)C(=O)N(C)C1=O>>[CH3:21][C:19]1[C:17](=[O:18])[NH:16][C:14]([NH2:2])=[N:13][CH:20]=1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Reactant: Cc1cn(C)c(=O)n(C)c1=O
Agent: Cn1cc(Cc2ccccc2)c(=O)n(C)c1=O
Product: Cc1cnc(N)[nH]c1=O

Procedure:
In accordance with the above procedure, but where in place of 1,3,6-trimethyluracil there is employed 1,3,5-trimethyluracil or 1,3-dimethyl-5-benzyluracil, there is obtained the corresponding 5-methylisocytosine or 5-benzylisocytosine.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[CH2:30]([O:29][C:27]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:28])[CH3:31]
Reactant: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(C(=O)OCC)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.48 g of ethyl 3-hydroxy-1,4-dihydro1,4-dioxo-2-naphthoate and 1.5 ml of triethylamine in 10 ml of dry tetrahydrofuran was added dropwise 1 ml of ethyl chloroformate at 5° C. or below, and the mixture was stirred at room temperature for 2 hours. The resulting solid was removed by filtration, and the filtrate was evaporated to dryness to give crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphthoate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH2:24]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a suspension of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.79 mmol) in CH2Cl2 (25 mL) at 0° C. under an N2 atmosphere, was added dropwise tert-butyl piperidin-4-ylcarbamate (2.08 g, 10.13 mmol) and triethylamine (2.20 mL, 15.8 mmol) in CH2Cl2 (10 mL). The reaction was stirred overnight, quenched with water and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to afford tert-butyl 1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g, 100%-solvent residue). LC/MS: m/z 421.3 (M+H)+ at 2.70 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1.Cl>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:12]2[C:13]([O:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[O:10][CH3:9])[CH2:4][CH2:3]1
Reactant: COc1cc(OC)cc(OC)c1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(OC)c(C2=CCN(C)CC2)c(OC)c1
Temperature: 87.5 °C
Reaction time: 3.5 h

Procedure:
1-methyl-4-piperidone (340 g, 3.0 mol) was added slowly, to a solution of 1,3,5-trimethoxybenzene (500 g, 2.97 mol) in glacial acetic acid (600 mL), maintaining the temperature of the reaction mixture below 40° C. Conc. HCl (450 mL) was added over 20 min. The temperature was raised to 85-90° C. and the reaction mixture was stirred for 3.5 h. It was allowed to cool to 40° C., poured over crushed ice (4 kg) and stirred for 20 min. The precipitate of unreacted 1,3,5-trimethoxybenzene was filtered off. The filtrate was basified, below 10° C., to pH 11-12 using a 50% aqueous NaOH solution. The off white solid obtained was filtered, washed with water and dried to obtain the compound, 1-methyl-4-(2,4,6-trimethoxy-phenyl)-1,2,3,6-tetrahydropyridine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([CH:5]3[CH2:6][CH2:7][CH:2]([O:1][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2nc(C(F)(F)F)nn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(=O)OCC)CC2)c2nc(C(F)(F)F)nn12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(4-hydroxycyclohexyl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.14 g), rhodium(II) acetate (dimer) (88 mg) and toluene (20 mL) was added dropwise ethyl diazoacetate (571 mg) under an argon atmosphere at 80° C., and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35 (volume ratio)] to give the title compound as a colorless amorphous compound (695 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14].B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:29])([F:30])[F:31])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14]
Reactant: COc1cccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(=O)onc(C)c3c2)C(F)(F)F)c1Br
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc(O)c3Br)C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
78 mg of (+)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one is mixed in 1.4 ml of dichloromethane at 0° C. with 0.71 ml of a 1 molar solution of boron tribromide in dichloromethane. After 2 hours of stirring at 0° C., the mixture is added to water, extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. After the residue is triturated with hexane, the title compound is obtained in crystalline form, flash point 226-231° C., [α]D=+91.1° (c=0.5 in chloroform)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[CH3:12][O:13][C:14]([C:16]1[C:17]([CH:26]([CH3:28])[CH3:27])=[C:18]2[N:23]([CH:24]=1)[N:22]=[CH:21][N:20]=[C:19]2Cl)=[O:15].Cl>>[CH3:12][O:13][C:14]([C:16]1[C:17]([CH:26]([CH3:28])[CH3:27])=[C:18]2[N:23]([CH:24]=1)[N:22]=[CH:21][N:20]=[C:19]2[N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)=[O:15]
Reactant: CNc1cnc2[nH]ccc2c1
Reactant: COC(=O)c1cn2ncnc(Cl)c2c1C(C)C
Agent: Cl
Product: COC(=O)c1cn2ncnc(N(C)c3cnc4[nH]ccc4c3)c2c1C(C)C
Yield: 25 %

Procedure:
The title compound was prepared in a manner similar to the preparation of Example 24 by using methyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine and 4-chloro-5-isopropylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester. (25% yield). LCMS; m/z 365 (M+H+). Monohydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, s), 8.22 (1H, s.), 8.00 (1H, s), 7.75 (1H, s), 7.50 (1H, s), 6.40 (1H, s.), 3.70 (3H, s), 3.26 (1H, m), 2.51 (3H, s), 0.54 (6H, d, J=7.3 Hz).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[N:11](C(OC(C)(C)C)=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.9 %

Procedure:
To a solution of compound 15c (900 mg, 2.14 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to give compound 15d (840 mg) as a white solid. MS m/z (M+H+) 320.0.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][P:9]([O-:12])[O:10][CH3:11].C[O-].[Na+]>CO>[CH3:7][O:8][P:9]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])(=[O:12])[O:10][CH3:11]
Reactant: C=CC(=O)OC
Reactant: COP([O-])OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCP(=O)(OC)OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
This procedure was reported by; Kreutzkamp, N.; Mengel, W. Chem. Ber., 1967, 100, 709-714. ##STR8## A mixture of methyl acrylate (30 mL, 28.7 g, 0.33 mol) and dimethylphosphite (36.7 g, 0.33 mol) was cooled to 0° C. and treated with a solution of sodium methoxide (1M) in methanol (5 mL). After a few min a vigorous exothermic reaction took place. When the reaction subsided, an additional portion of sodium methoxide was added. This procedure was repeated for a total of four times. The reaction was then allowed to stir at room temperature for 16 h and then the methanol removed by distillation. The residue was then vacuum distilled, bp 95° C. @ 0.15 mm, to provide 45.6 g, 70% of pure product. 1H NMR (CDCI3 /TMS/300 MHz) δ 3.71(d, J=11.1 Hz, 6H), 3.67(s, 3H), 2.57(td, J=8.4, 12.5 Hz), 2.06(td, J=8.4 12.5 HZ, 2H); 31P NMR (CDCI3) 33.3 (s); 13C NMR (CDCI3) 172.3, 52.3(d, J=6.5 Hz), 51.8, 27.0(d, J=4.1Hz), 20.8, 18.9.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O.O>[N:16]1([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)=[O:4])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(C(=O)Cn3ccnc3)ccc2N1

Procedure:
A solution of 9.0 g of 6-(chloroacetyl)-3,4-dihydrocarbostyril and 13.4 g of imidazole in 40 ml of N,N-dimethylformamide was heated at 80° C. for 18 hours. The reaction mixture was diluted with 1000 ml of water and the precipitate filtered off, washed with water followed by a little acetone and dried under vacuum to afford 6-[(imidazol-1-yl)acetyl]-3,4-dihydrocarbostyril, having a melting point of 269°-273° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])OC.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])/[CH:10]=[C:11](\[O:13][CH3:18])/[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(=O)Nc1cccc(OC(C)=O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC([O-])[O-]
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CO/C(C)=C\C(=O)Nc1cccc(OC(C)=O)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 2038 %

Procedure:
A mixture of 50 g of m-acetoxy-acetylacetanilide, 1 g of p-toluene sulfonic acid and 50 ml of methyl orthoformate was stirred for 16 hours at 20°C. and after the addition of 2 ml of quinoline and 200 ml of toluene, the reaction mixture was heated at 140°C. for 4 hours while distilling off a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with an 8-2 methylene chloride-acetone mixture and was crystallized from isopropyl ether to obtain 29.5 g of m-acetoxy-3-methoxy-crotonanilide melting at 111°C.