Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[N:37]=[C:38]=[O:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8])=[O:39]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)Nc2cc(C(F)(F)F)ccc2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.2 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-chloro-2-isocyanato-4-(trifluoromethyl)benzene (60 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (152 mg, 78%) as a colorless powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.CC1CCC=CC1>C(O)C.[Pd].C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1CC=CCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
2.0 g 5-tert-butyl-2-methoxy-1,3-dinitro-benzene are dissolved in 20 ml of ethanol, combined with 100 μl water and 100 mg of 10% palladium on activated charcoal and then refluxed. 1.9 ml of 4-methyl-cyclohexene are added and the mixture is refluxed for a further 2 hours. Then a further 950 μl of 4-methyl-cyclohexene are added dropwise and then refluxed for 16 hours. The solvents are then eliminated in vacuo, the residue is taken up in ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with sodium sulphate the solvents are eliminated in vacuo and the residue is dried in vacuo.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]([C:13](=[O:22])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:10](=[O:12])[CH3:11])[C:3](OCC)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)C>[O:4]=[C:3]1[CH:2]([CH3:1])[CH:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]([C:13](=[O:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]([CH3:11])[O:12]1
Reactant: CCOC(=O)C(C)C(NC(C)=O)C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC1C(C)C(=O)OC(C)C1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 64 %

Procedure:
Ethyl 2-methyl-3-acetylamino-4-(4'-chlorophenylcarbamoyl)-5-oxohexanoate (Example 25) (12 g) was dissolved in trifluoroacetic acid (50 ml), treated with triethylsilane (7.5 ml) and stirred at room temperature for 40 hours. The reaction mixture was diluted with diethyl ether and filtered. The solid was warmed with ethyl acetate then cooled and filtered to give 2-oxo-3,6-dimethyl-4-acetylamino-5-(4'-chlorophenylcarbamoyl)-3,4,5,6-tetrahydro-2H-pyran (ttt isomer) (6.8 g) m.p. 280° C. decomp.
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O>[N:14]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[N+:15]=[N-:16]
Reactant: O=C1Nc2ccccc2CCC1I
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of 36.7 g (128 mmol) of 3-Iodo-2,3,4,5-tetrahydro-1H-[1]-benzazapin-2-one in 200 mL of dimethylformamide was added 9.97 g (153 mmol) of sodium azide. After 3 h, the mixture was poured into 800 mL of ice water and the precipitate collected on a filter. After washing the solid successively with water, 3% aqueous sodium bisulfite, and water, the product was dried under vacuum to give 21.5 g (83%) of a tan powder. 1H NMR (300 MHz, CDCl3) d 8.91 (1H, bs), 7.4-7.0 (4H, m), 3.89 (1H, t, J=9 Hz), 2.97 (1H, m), 2.73 (1H, m), 2.52 (1H, m), 2.32 (1H, m).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:36][CH:37]=1
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(CO)C2
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227d) and 5-methyl-pyridin-2-ylamine. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=8.84 Hz, 1 H) 8.05 (s, 1 H) 7.92 (d, J=8.84 Hz, 3 H) 7.28 (s, 1 H) 7.24 (s, 1 H) 7.15 (d, J=8.84 Hz, 2 H) 3.76 (d, J=111.87 Hz, 1 H) 3.62 (d, J=111.87 Hz, 1 H) 3.22 (d, J=116.67 Hz, 1 H) 3.07 (s, 3 H) 2.83 (d, J=116.67 Hz, 1 H) 2.42 (s, 3 H) 1.47 (s, 3 H); LCMS for C24H24N2O6S m/z 469.00 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]O)[CH3:2].S(Cl)(Cl)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][N:3]([CH2:15][CH3:16])[CH2:1][CH3:2])=[N+:22]=[N-:23]
Reactant: CCN(CC)CCOc1ccccc1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCN(CC)CCOc1ccccc1CN=[N+]=[N-]

Procedure:
[2-(2-diethylamino-ethoxy)-phenyl]methanol (Cossey, H. D. et al.; J. Chem. Soc. 1965; 954-973), thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 249 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:20]=2[CH2:21][O:22]C)=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:20]=2[CH2:21][OH:22])=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1COC)c1cccc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CO)c1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 102.6 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-5-methoxymethyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (510 mg, 1.1 mmol) in CH2Cl2 (10 mL) is added BBr3 (1.0 M in CH2Cl2, 1.6 mL, 1.6 mmol) dropwise. After stiffing at room temperature for 1 hour, the reaction mixture is quenched with methanol (25 mL) and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 20 to 60% EtOAc/hexanes) to afford 1-(4-chloro-phenyl)-5-hydroxymethyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (510 mg, >99%).
Reaction SMILES: CO[C:3](=O)[CH2:4][CH2:5][NH:6][CH2:7][CH3:8].[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19]>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[C:11](=[O:19])[CH2:10][CH2:18][C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=3[CH2:4][C:5]1=2)[CH3:8]
Reactant: CCNCCC(=O)OC
Reactant: O=C1Cc2ccccc2C1
Solvent: Cc1ccccc1
Product: CCN1C(=O)CCC2=C1Cc1ccccc12
Temperature: 25 °C
Yield: 27.1 %

Procedure:
3-Ethylamino-propionic acid methyl ester (2.41 g, 18.4 mmol) is added to a solution of 2-indanone (2.3 g, 17.33 mmol) in toluene (27 mL), and the reaction is brought to reflux for 2 hours. Toluene is removed in vacuo and the residue is dissolved in ethylene glycol (23 mL) and the resulting solution is heated to reflux for 8 hours. The reaction is allowed to cool to ambient temperature and is poured over water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated in vacuo to afford the crude title compound. The crude product is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-100%) affording 1 g (27% yield) of the title compound. MS (m/z): 213.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6](I)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: O[C@H]1CC[C@H](Nc2ncc(I)cc2F)CC1
Reactant: C#Cc1ccccc1
Product: O[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cc2F)CC1

Procedure:
The title compound, yellow solid, MS: m/e=311.2 (M+H+), can be prepared in accordance with the general method of example 1, step 1 from trans-4-(3-fluoro-5-iodopyridin-2-ylamino)cyclohexanol (example 18, step 1) and phenylacetylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH-].[Na+:19]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O-:16])=[O:15])[CH:7]=[CH:6]2.[Na+:19]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1

Procedure:
To a solution of 300 mg of (S)-2-(6-methoxy-2-naphthyl)-propionic acid in 5 ml of methanol is added a 1 molar equivalent of sodium hydroxide, in the form of a 0.1N solution. The solvent is evaporated in vacuo and the residue is taken up in 2 ml of methanol, followed by precipitation with ether, to yield crude sodium (S)-2-(6-methoxy-2-naphthyl)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH2:15])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].I[CH2:22][C:23]([NH2:25])=[O:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:15][CH2:22][C:23]([NH2:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1-c1cccc(Cl)c1
Reactant: NC(=O)CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CNCc1ccccc1-c1cccc(Cl)c1

Procedure:
A reaction vessel was charged with 8.8 g (40 mmole) of [(3-chlorophenyl)phenyl]methylamine, 4.2 g (50 mmole) of sodium bicarbonate, 7.4 g (40 mmole) of iodoacetamide and 200 ml of absolute ethanol. The resulting suspension was brought to reflux and held at reflux for 18 hours. Solvent was evaporated and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried over potassium carbonate and evaporated. The oil was dissolved in a minimum of ethanol, to which was added a solution of chlorhydric acid in ether. An oil was decanted which crystallized upon stirring. The white solid was then precipitated from ethanol by addition of ether.
Reaction SMILES: [F:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[Cl:21][C:16]1[CH:15]=[C:14]([C:2]([F:1])([C:10]([F:11])([F:12])[F:13])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5])[CH:19]=[CH:18][C:17]=1[NH2:20]
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Cl

Procedure:
4-(1,2,2,3,3,3-Hexafluoro-1-trifluoromethylpropyl)phenylamine (prepared as described in EP 1,006,102) (175.8 g, 565 mmol) was dissolved in acetonitrile (1000 ml) and N-chloro-succinimide (“NCS”) (76.2 g, 570.7 mmol) was added. The reaction mixture was heated to reflux for 90 minutes. The reaction mixture was concentrated, the residue suspended in diethyl ether and the solids removed via filtration. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/dichloromethane 9:1) to give 2-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenylamine. The same procedure was repeated using N-bromosuccinimide (“NBS”) (100.5 g, 565 mmol) as reagent. This time the residue was purified by column chromatography on silica gel (eluent:cyclohexane/dichloromethane 2:1) to give 2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenylamine (143.3 g, 59.7% yield). 1H NMR (400 MHz, CDCl3): 7.70 (s, 1H), 7.42 (s, 1H), 4.82 (s, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14]1.O>ClCCl>[CH3:15][C:16]1([CH3:17])[C:21]([CH3:13])([CH3:20])[O:12][B:10]([C:7]2[CH:6]=[CH:5][C:4]([NH:1][C:2]([N:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:13]3)=[O:3])=[CH:9][CH:8]=2)[O:11]1
Reactant: O=C=Nc1ccc(B(O)O)cc1
Reactant: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: O
Product: CC1(C)OB(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)OC1(C)C

Procedure:
500 mg (4-Isocyanatophenyl)boronic acid pinacolester (1.979 mmol) and 365 mg isoindoline (2.97 mmol) were dissolved in 10 ml dichloromethane and the resultant mixture was stirred over night at room temperature. After adding water, the mixture was extracted several times with dichloromethane, the combined organic phases were washed with dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. Column chromatography of the residue with dichloromethane resulted in the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10].[Cl-].[K+].C([O-])([O-])=O.[K+].[K+].C([O:21][CH:22](OCC)[CH:23]=[CH2:24])C>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:24]=[CH:23][CH:22]=[O:21]
Reactant: C=CC(OCC)OCC
Reactant: COc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=CC=O)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a mixture of 4-bromo-3-chloro anisole (35 g, 0.159 mol), KCl (11.9 g, 0.160 mol, 1 eq.), K2CO3 (33 g, 0.238 mol, 1.5 eq) in 400 mL DMF in a sealed tube was added acrolein diethylacetal (73 mL, 0.479 mol, 3 eq.) and Bu4NOAc (96 g, 0.318 mol, 2 eq.). N2 was bubbled through the mixture and Pd(OAc)2 (1.1 g, 4. mmol, 3 mol %) was added. The reaction mixture was heated in an oil bath for 6 hr at 100° C. then cooled in an ice-bath. 300 mL of water was then added, followed by 500 mL of 1N HCl. The ice-bath was removed and the mixture was stirred for 30 min. The solution was extracted with ethyl acetate once then with diethyl ether 3 times. The combined organic layer washed with water, brine, dried over MgSO4, filtered and concentrated to provide the crude product which was recrystallized from hot ethyl acetate-hexanes to provide 15.5 g of crystalline 3-(2-chloro-4-methoxy-phenyl)-propenal. The mother liquor was concentrated and chromatographed with 10% ethyl acetate to provide another 5.6 g of 3-(2-chloro-4-methoxy-phenyl)-propenal.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:40]([NH:43][CH3:44])([CH3:42])[CH3:41]>ClCCl.CN(C=O)C>[CH:28]([N:26]([CH3:27])[C:24]1[C:23]([C:31]([F:33])([F:34])[F:32])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:43]([CH:40]([CH3:42])[CH3:41])[CH3:44])=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)([CH3:30])[CH3:29]
Reactant: CNC(C)C
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (220 mg, 0.47 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (110 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.[CH2:55]([OH:57])[CH3:56]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][O:57][CH2:55][CH3:56])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3cccc(F)c3)n2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2cccc(F)c2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 1.60 g 4-((S)-4-Carboxy-2-{[5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 30 ml dichloromethane were added 526 mg EDC, 335 mg DMAP and 676 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 295 mg MS (ES+): m/e=728.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.N[C@H]1C2CCN(CC2)C1>>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:19]2
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: NC1CN2CCC1CC2
Agent: N[C@@H]1CN2CCC1CC2
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccccc1Cc1ccccc1

Procedure:
Proceeding as in Example 1, Method A, but replacing 2,3-dimethyl benzoic acid with 2-benzylbenzoic acid and (RS)-3-amino-1-azabicyclo[2.2.2]octane with (S)-3-amino-1-azabicyclo[2.2.2]octane gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzylbenzamide.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Sm+3:4].[Li].C([Li])CCC.[CH:11]1[CH:16]=[C:15]2[CH:17]=[CH:18][C:19]([OH:32])=[C:20]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][C:22]=3[OH:31])[C:14]2=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+].O>C1COCC1.CCCCCC>[Sm:4].[CH:27]1[CH:26]=[C:25]2[CH:24]=[CH:23][C:22]([OH:31])=[C:21]([C:20]3[C:14]4[C:15](=[CH:16][CH:11]=[CH:12][CH:13]=4)[CH:17]=[CH:18][C:19]=3[OH:32])[C:30]2=[CH:29][CH:28]=1
Reactant: [Sm+3]
Agent: CC(C)(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: [Sm]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 128 mg (0.50 mmol) of anhydrous samarium trichloride (SmCl3) in 4.0 ml of THF were added, in an argon atmosphere at room temperature, a lithium binaphthoxide solution in THF [prepared by adding 1.25 ml (2.0 mmol) of a 1.6N n-butyllithium solution in hexane to a solution of 286.4 mg (1.0 mmol) of (R)-1,1'-bi-2-naphthol in 4.0 ml of THF], 48.1 mg (0.50 mmol) of sodium t-butoxide and 99 μl (5.5 mmol) of water, in that order, and the mixture was stirred at room temperature for 15 hours and then allowed to stand overnight to allow the insoluble matter to precipitate. The supernatant solution was submitted to the reaction proper as a samarium/(R)-1,1'-bi-2-naphthol complex solution (0.05 mmol/l).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:22]1C=C[CH:25]=[CH:24][CH:23]=1)[C:18]([F:21])([F:20])[F:19].ClC1C=C2C(=CC=1)NC(=O)N(CC(F)(F)F)C2(O)C(F)(F)F.C([Mg]Cl)CCC>>[CH2:22]([C:5]1([C:18]([F:20])([F:21])[F:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:15])([F:17])[F:16])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)(C(F)(F)F)N1CC(F)(F)F
Agent: CCCC[Mg]Cl
Agent: O=C1Nc2ccc(Cl)cc2C(O)(C(F)(F)F)N1CC(F)(F)F
Product: CCCCC1(C(F)(F)F)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F

Procedure:
Utilizing the general procedure outlined for 6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one, 6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (100 mg, 0.3 mmol) was reacted with 1.0M butyl magnesium chloride (1.0 ml, 1.0 mmol) to afford 4-butyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one as an oil. 1H NMR (CD3OD, 400 MHz) δ 7.41 (s, 1H), 7.35 (dd, J=2.4 and 8.4 Hz, 1H), 6.9 (d, J=8.4 Hz, 1H), 4.55 (m, 1H), 4.29 (m, 1H), 2.50 (m, 1H), 2.22 (m, 1H), 1.40 (m, 2H), 1.24 (m, 1H), 1.13 (m, 1H), 0.90 (m, 3H). Exact Mass (Electrospray, M+H) Cal'd, 389.0850; Found, 389.0850.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([O:10][N:11]=[C:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)[C:13]([OH:15])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12>>[C:1]([O:5][C:6]([CH:8]([O:10][N:11]=[C:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)[C:13]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:15])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(ON=C(C(=O)O)c1ccc(O)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1ccc(O)c(Cl)c1)C(=O)OC(C)(C)C
Yield: 94.6 %

Procedure:
2-(1-t-Butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2 g.) and 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) were reacted according to similar manners to those of Examples 1 and 2 to give powder of 7-[2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.6 g.).