Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 80 °C
Yield: 77.4 %

Procedure:
To a solution of (3S)-(+) -3-(tert-butoxycarbonylamino)pyrrolidine (410 mg, 2.20 mmol), in 22 mL EtOH, was added, (288 μL, 2.31 mmol) of 4-fluorobenzyl bromide, and (788 mg, 2.42 mmol) of finely powdered cesium carbonate. The stirred reaction mixture was heated at 80° C., under nitrogen for 3 h, after which time, TLC indicated the reaction was complete. The reaction was then concentrated in vacuo to about 5 mL, and was then diluted with 30 mL of EtOAc, and washed with 20 mL of 5% NH4OH. The aqueous fraction was extracted with diethyl ether (3×20 mL). The combined organics were washed with 20 mL of brine, dried (MgSO4), filtered and concentrated. The crude white solid was triturated with 1:1 ether-hexane to give 501 mg (77%) of the desired product as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.2-7.3 (m, 2H), 6.9-7.1 (m, 2H), 4.85 (br. s, 1H, exchanges), 4.18 (br. s, 1H), 3.55 (s, 2H), 2.65 (br. m, 1H), 2.58 (n, 1H), 2.50 (m, 1H), 2.2-2.4 (m, 2H), 1.5-1.7, (m, 1H), 1.4 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(OCC)(=O)C.ClCCl.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]([O:19][CH3:18])=[O:21])[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Temperature: 70 °C
Yield: 71.7 %

Procedure:
Under a stream of nitrogen, 0.400 g (1.37 mmol) of 5-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine obtained in step 5.3, 0.300 g (1.67 mmol) of 3-methoxycarbonylphenylboronic acid and 1.330 g (4.08 mmol) of caesium carbonate are placed in 5 mL of a 9/1 mixture of tetrahydrofuran and water. 0.11 g (0.13 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) is added and the medium is heated at 70° C. for 4 hours. The medium is then cooled to room temperature and diluted with 40 mL of dichloromethane and 40 mL of water. The medium is then filtered on a hydrophobic cartridge (Radleys® 70 mL liquid/liquid extraction column) and the organic phase is recovered and concentrated under reduced pressure after addition of 2 g of silica. The residue is purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 0.340 g (71%) of expected product is obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]2[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=2)[N:12]=1.Cl>CN(C)C=O.O>[CH:26]([C:23]1([CH3:25])[C:22](=[O:29])[NH:21][C:20]([C:13]2[N:12]=[C:11]([O:7][CH2:1][CH:2]3[O:6][CH2:5][CH2:4][CH2:3]3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)C1(C)N=C(c2nc(Cl)ccc2C(=O)O)NC1=O
Reactant: OCC1CCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C1(C)N=C(c2nc(OCC3CCCO3)ccc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 ml (0.01 mol) tetrahydrofurfuryl alcohol are added to a mixture of 1.0 g (0.033 mol) sodium hydride (80%) in 10 ml dimethylformamide and after-stirred for 1 hour. Then, 2.95 g (0.01 mol) 6-chloro-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-nicotinic acid, dissolved in 10 ml dimethylformamide, are added dropwise. The mixture is then stirred for 1 hour at 50°-60° C., cooled to room temperature, then 10 ml water is added, followed by acidifying with concentrated hydrochloric acid. The product is extracted with methylene chloride, the extract is dried across magnesium sulfate, filtered and compressed. After a certain period the product crystallizes from the obtained oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].CCN(CC)CC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38].O>C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=3)=[CH:8][C:2]=2[CH3:1])=[O:36])=[CH:30][C:29]=1[C:37]([F:38])([F:39])[F:40]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(C)c2)ccn1
Reaction time: 144 h
Yield: 48.9 %

Procedure:
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH2Cl2 (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 1H NMR (DMSO-d6) δ 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5, 2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J=5.5 Hz, 1H), 8.78 (q, J=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of the 2-(4-((3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy)propionyl chloride (prepared in Step A) in 50 ml of acetonitrile was added to a mixture of 3.82 g (19.4 mmol) of 4-aminobenzotrifluoride, hydrochloride and 4.90 g (48.4 mmol) of triethylamine in 25 ml of acetonitrile. The reaction mixture was warmed at reflux for 4.0 hours and then poured over crushed ice. The resulting precipitate was collected by filtration and dried. The residual solid was recrystallized from methylcyclohexane to give 9.1 g (93 percent of theoretical) of the above-named product as a tan solid which melted at 140°-143° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 1)
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[NH2:13][CH2:14][CH:15]([CH3:18])[CH2:16]N>C(O)C>[CH3:16][CH:15]1[CH2:14][NH:13][C:9]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=2)=[N:10][CH2:18]1
Reactant: CC(CN)CN
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: [Na]
Solvent: CCO
Product: CC1CN=C(c2ccc([N+](=O)[O-])cc2)NC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Anhydrous ethanol (460 mL) and sodium (0.57 g, 25 mmol, 0.1 eq) were added to a round bottom flask and stirred under argon until all of the sodium disappeared. 4-nitrobenzonitrile (38.0 g, 257 mmol, 1.0 eq) was then added. The suspension was stirred for 15 h at room temperature under argon. 1,3-diamino-2-methylpropane (22.0 g, 249 mmol, 0.97 eq) was added. The mixture was heated to reflux for 4 days. After removal of the solvent under reduced pressure, the resulting red residue was mixed with ethyl acetate (800 mL) and extracted with 2N HCl (3×200 mL). The combined aqueous mixture was washed with ethyl acetate (250 mL) and the organic layer was removed. The acidic aqueous mixture was basified with solid Na2CO3 and then 5N NaOH until pH was 13. The emulsion was extracted with ethyl acetate (1×400 mL, 2×250 mL). The combined organic layers were washed with brine (400 mL) and then dried over Na2SO4. Upon concentrating, compound 3 was obtained as a yellow solid (12.8 g, 23% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17]Br)[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1CCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1)OCC
Temperature: 120 °C
Yield: 34.8 %

Procedure:
3.28 g (10 mmol) of (4S)-3-benzyloxycarbonyl-4-(2-bromomethyl)-1,3-oxazolidin-5-one (from Example 5) are mixed with 3.39 g (20 mmol) of triethyl phosphite and the mixture is heated under argon for 18 hours at 120° C. The excess triethyl phosphite is distilled off under high vacuum and the residue is purified by chromatography on silica gel (mobile phase: dichloromethane/acetonitrile). 1.34 g (34.8% of theory) of (4S)-3-benzyloxycarbonyl-4-[2-(diethoxyphosphinyl)ethyl]-1,3-oxazolidin-5-one are obtained as a colorless oil. Analytical data:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)C.[CH:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH:17]([CH3:18])[CH2:16][CH:15]=[O:19])[CH:11]=2)[CH:2]=1
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: C/C=C/C=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CC=O)n1cnc(-c2cccnc2)c1

Procedure:
To a solution 4pyridin-3-yl-imidazole (10 g, 68.88 mmol) in THF (300 ml) were added ethanol (4.04 ml, 68.88 mmol) and crotonaldehyde (22.83 ml, 275.52 mmol). The resulting mixture was heated under reflux for 18 hours. At this point of time, an additional 2 equiv of crotonaldehyde was added and contiuned to reflux for another 20 hours. TLC analysis indicated the reaction was complete. Solvent was removed in vacuo and the crude aldehyde of formula 18, wherein R7 is methyl and R3 is pyridin-3-yl, which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10](=[O:12])[CH3:11])=[O:4].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH:10]([OH:12])[CH3:11])=[O:4]
Reactant: COC(=O)c1sccc1C(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sccc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
3-Acetyl-2-thiophenecarboxylic acid methyl ester (3.87 g) synthesized in this manner was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-(1-hydroxyethyl)-2-thiophenecarboxylic acid methyl ester (3.77 g). This product was dissolved in ethyl acetate (100 ml), and methanesulfonyl chloride (2.86 g), triethylamine (3.5 g) and dimethylaminopyridine (0.2 g) were added. The mixture was stirred at room temperature for 2 hours, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (100 ml), and sodium iodide (10 g) was added. The mixture was stirred at room temperature for 2 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The desired fractions were concentrated under reduced pressure to give 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester (3.0 g). 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester was dissolved in dimethylsulfoxide (10 ml), and sodium borohydride (0.4 g) was added at room temperature. The mixture was stirred for 1 hour, and 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g). A mixture of 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g), 1N aqueous sodium hydroxide (15 ml), tetrahydrofuran (30 ml) and methanol (10 ml) was stirred at room temperature for 1 hour. The mixture was washed with diethyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-ethyl-2-thiophenecarboxylic acid (0.9 g) as crystals.
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][C:22]([OH:24])=O)[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH:33]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([CH3:35])[CH3:34].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:33]([C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:22](=[O:24])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]2[CH:5]=[C:6]([C:14]([F:16])([F:15])[F:17])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)CCC(Cc2ccc(Cl)cc2)N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reaction time: 18 h

Procedure:
A mixture consisting of 41.6 mg of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pentanoic acid, 12.8 mg of 4-isopropylaniline, 36.65 mg of propanephosphonic acid anhydride, 37 mg of triethylamine and 1.5 ml of methylene chloride is left to stand at room temperature for 18 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. In this way the title compound is obtained in the form of a white foam. Rf value=0.26 (ethyl acetate)
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([NH:40][S:41]([N:44]([CH2:46][CH:47](OC)[O:48]C)[CH3:45])(=[O:43])=[O:42])=[O:39])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@H:16]([N:26]([CH3:37])[CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:29][CH2:28][CH2:27][N:26]([CH3:37])[C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:38]([NH:40][S:41]([N:44]([CH3:45])[CH2:46][CH:47]=[O:48])(=[O:42])=[O:43])=[O:39])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1
Reactant: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC=O)cc3n2C1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl {2-[{(7R)-14-cyclohexyl-11-[({[(2,2-dimethoxyethyl)-(methyl)amino]sulfonyl}amino)carbonyl]-7,8-dihydro-6H-indolo[1,2-e][1,5]-benzoxazocin-7-yl}(methyl)amino]ethyl}carbamate (0.03 M) in DCM was treated with TFA (100 eq) and water (180 eq) at RT and the resulting mixture stirred vigorously for 3 h at 40° C. The volatiles were removed in vacuo and the residue diluted with Et2O and re-evaporated to drive off excess TFA. The product was used in the subsequent step without further purification. MS (ES+) m/z 582 (M+H)+; 600 (M+H2O+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.O.[Li+].[OH-]>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:3]=1
Reactant: COC(=O)Cc1ccc(O)cc1OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(O)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of methyl 4-hydroxy-2-(2,2,2-trifluoroethoxy)phenylacetate (1.3 g, 4.8 mmol) from Step 4 above in THF (15 mL) was added water (3 mL) and LiOH (0.62 g, 15 mmol). The mixture was stirred at ambient temperature for 6 h and the solvents were removed under reduced pressure. The residue was partitioned between CH2Cl2 and aqueous citric acid. The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-hydroxy-2-(2,2,2-trifluoroethoxy)phenylacetic acid as an amorphous solid (HPLC retention time=13.2 min (method D)).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[C:20]1(/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(Cl)=O)C(C)C>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:28](=[O:29])/[CH:27]=[CH:26]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH2:3][CH2:2]1
Reactant: NC1CCN(CCC2CCOc3ccccc32)CC1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CC(C)COC(=O)Cl
Product: O=C(/C=C/c1ccccc1)NC1CCN(CCC2CCOc3ccccc32)CC1
Yield: 61 %

Procedure:
N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-aminopiperidine was coupled to 3-phenyl-2E-propenoic acid utilizing the isobutylchloroformate protocol described in Example 6. This afforded the title compound; (61% yield) m.p. 168°-70°, Anal: C25H30N2O2 0.3 H2O, Calc. C, 75.84; H, 7.79; N, 7.08; Found, C, 75.90; H, 7.94; N, 7.32.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:31]1[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:16]3[C:15](=[O:18])[N:4]4[N:5]=[CH:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=5)=[C:2]([Cl:1])[C:3]4=[N:17]3)=[CH:22][CH:23]=2)=[CH:28][CH:29]=[N:30]1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 50 °C
Yield: 79 %

Procedure:
To a stirring suspension of 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one prepared as described in example 354G, and 5-(4-(bromomethyl)phenyl)isoxazole (122 mg, 0.51 mmol), prepared as described as in Example 250A in DMF (5 mL) at RT under argon was added K2CO3 (119 mg, 0.86 mmol). The resulting mixture was heated at 50° C. for 3 h. HPLC/MS analysis indicated complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (10 mL×2) to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc to obtain pure title compound, 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (149 mg, 79%) as a yellow solid. MS [M+H]+ 438; HPLC retention time=3.55 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40](O)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2].ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([CH2:40][OH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) is dissolved in tetrahydrofuran (2 ml), then thereto are added ethyl chloroformate (0.02 ml) and triethylamine (0.04 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is filtered, sodium borohydride (18 mg) is added to the filtrate, and the mixture is stirred for 1 hour and 40 minutes. To the reaction solution is added 1N-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→3:2) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (80 mg). MS (m/z): 614 [M+H]+
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].[CH:28](=[C:35]1[C:43]2[C:42](Cl)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:28](=[C:35]1[C:43]2[C:42]([N:25]3[CH2:24][CH2:23][CH:22]([C:14]4[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=[C:12]([C:7]5[CH:8]=[CH:9][C:10]([F:11])=[C:5]([Cl:4])[CH:6]=5)[N:13]=4)[CH2:27][CH2:26]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccccc1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(c2ncnc3c2C(=Cc2ccccc2)C(=O)N3)CC1

Procedure:
Combine {2-[4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-dimethyl-amine tris hydrochloride (0.5 g; 0.0013 mol; 1.0 equiv); 5-benzylidene-4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.33 g; 0.0013 mol; 1.0 equiv); DIPEA (1.7 mL 0.0098 mol; 7.6 equiv); 2-propanol (10 mL) and microwave at 100° C. for 30 min. Cool and concentrate in vacuo. Dilute with saturated sodium bicarbonate solution and extract with DCM. Wash organic layer with water and brine and dry over anhydrous sodium sulfate. Concentrate the crude compound and purify by reverse phase HPLC to give the title compound as a mixture of E and Z isomers (0.09 g; 12.2%). MS (ES+): m/z=572 (M+H)