Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH2:19][CH:20]1[CH2:25][C:24]([F:27])([F:26])[CH2:23][CH2:22][CH:21]1[CH:28]([OH:43])[CH:29]([C:35]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:11]([O:18][CH2:19][CH:20]1[CH2:25][C:24]([F:26])([F:27])[CH2:23][CH2:22][CH:21]1[C:28](=[O:43])[CH:29]([C:35]1[CH:36]=[CH:37][C:38]([S:41][CH3:42])=[CH:39][CH:40]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(c1ccc(SC)cc1)C(O)C1CCC(F)(F)CC1COCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)C1CCC(F)(F)CC1COCc1ccccc1)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (2.9 mL, 34 mmol) was added dropwise to a −78° C. solution of dimethyl sulfoxide (2.9 mL, 41 mmol) in CH2Cl2 (40 mL). Stirring was continued at −78° C. for an additional 10 min prior to the slow introduction down the flask wall of a solution of ethyl 3-{2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-3-hydroxy-2-[4-(methylthio)phenyl]propanoate (5.09 g, 10.6 mmol) and triethylamine (16 mL, 120 mmol) in CH2Cl2 (40 mL). The mixture was then held at −78° C. for 10 min followed by rapid warming to rt before being poured into 2 M HCl in a separatory funnel. The layers were shaken and separated, and the aqueous phase was extracted with an additional portion of CH2Cl2. The combined organics were washed with water, dried (Na2SO4) and concentrated. Flash chromatography of the residue on silica gel eluting with 1/4 ethyl acetate/hexanes afforded ethyl 3-{2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-2-[4-(methylthio)phenyl]-3-oxopropanoate as a thick, tan colored syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:36])[NH:33][C:32]3=[O:37])=[CH:38][CH:39]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)c(OC)c1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: COc1ccc(-c2ccc(C(C)=NOCCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c(OC)c1
Yield: 89.8 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 256 mg of 4'-(2,4-dimethoxyphenyl)acetophenone and 382 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 467 mg of the title compound, melting at 186-188° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.O.NN.[OH-].[K+]>C(O)COCCO>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([CH2:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[CH:10]2
Reactant: COc1ccc2nc(N)c(C(=O)c3ccccc3OC)cc2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc2nc(N)c(Cc3ccccc3OC)cc2c1
Temperature: 160 °C

Procedure:
(2-Amino-6-methoxyquinolin-3-yl)(2-methoxyphenyl)methanone (1.1 g, 3.6 mmol) was dissolved in diethylene glycol (15 mL), mixed with hydrazine hydrate (0.56 mL, 18 mmol) and pulverized potassium hydroxide (1.1 g, 19.8 mmol) and heated to 160° C. for 1.5 hours.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=[O:18].[OH-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2F)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(CC(=O)O)cccc1Oc1ccccc1F
Temperature: 25 °C
Yield: 136 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(2-fluorophenoxy)phenyl]acetate (5.7 g.), sodium hydroxide (1.6 g.), water (25 ml.) and dioxane (25 ml.) was refluxed under heating for 16 hours with stirring. The reaction mixture was left to cool at ambient temperature and dioxane was distilled off under reduced pressure. To the residue was added water and the mixture was washed with diethyl ether. Diethyl ether was added to the aqueous layer and the mixture was adjusted to pH 3 to 4 with 5% sulfuric acid. The diethyl ether layer was separated, washed with water and dried over magnesium sulfate and then the solvent was distilled off under reduced pressure to give 2-[2-amino-3-(2-fluorophenoxy)phenyl]acetic acid (7 g.). This crude substance was recrystallized from a mixture of ethyl acetate and n-hexane to give the pure compound (3.6 g.), mp 122° to 123° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: Nc1ccc(OCCO)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(OCCO)ccc1N
Reaction time: 1 h
Yield: 81.5 %

Procedure:
2-Amino-5-(2-hydroxyethoxy)benzoic acid hydrochloride (0.209 g, 895 μmol; CAS 78299-60-2) was suspended in dichloromethane (10 ml) at r.t under an argon atmosphere. The reaction mixture was diluted with MeOH (3 ml). Then trimethylsilyldiazomethane solution (1.45 ml, 2.9 mmol; 2M in hexane) was added dropwise. The reaction mixture was stirred at r.t for 1 hr. The solvents were evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient to give the title compound (154 mg, 82%) as light yellow, waxy solid.
Reaction SMILES: Cl[B:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][Si:11]([C:14]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15]1)([CH3:13])[CH3:12]>C(OCC)C>[CH3:10][Si:11]([C:14]1([B:2]([C:14]2([Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:18]=[CH:17][CH:16]=[CH:15]2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1)([CH3:13])[CH3:12]
Reactant: [Li]C1([Si](C)(C)C)C=CC=C1
Reactant: ClB(Cl)c1ccccc1
Solvent: CCOCC
Product: C[Si](C)(C)C1(B(c2ccccc2)C2([Si](C)(C)C)C=CC=C2)C=CC=C1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To 4.80 g (30.2 mmol) of dichloro(phenyl)borane, dissolved in 70 ml of diethyl ether, a suspension of 8.36 g (60.4 mmol) of trimethylsilylcyclopentadienyllithium in 100 ml of diethyl ether is slowly added at -78° C. The mixture is allowed to warm to room temperature in the cooling bath, and insolubles are filtered off. After concentrating the yellow filtrate to dryness in an oil-pump vacuum, 10.8 g of bis(trimethylsilylcyclopentadienyl) (phenyl)borane is obtained as a yellow viscous oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.C([N:30]([CH2:33][CH3:34])[CH2:31]C)C.[CH2:35]([CH2:42]N)[C:36]1C=CC=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:33]([N:30]([CH3:31])[C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:3])[C:34]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:42]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: CCN(CC)CC
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)N(C)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (32.7 mg) was dissolved in CH2Cl2 (2 mL), triethylamine (63 μL) added followed by N-benzylmethylamine (35 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg) and 4-dimethylaminopyridine (˜1 mg). Mixture was stirred at room temperature for 17 h then the solvent removed under reduced pressure. The residue was eluted on silica gel chromatography (1-2% MeOH in CH2Cl2) to yield 28.3 mg of the title compound. Mass Spectrum (ESI): m/e 463.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:7]2=[O:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:7]3=[O:12])=[O:29])=[CH:23][C:22]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cccc2c(=O)n(Cc3ccccn3)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2c(=O)n(Cc3ccccn3)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a solution of 5-amino-2-(pyridin-2-ylmethyl)isoquinolin-1(2H)-one (100.00 mg, 0.4 mmol) in N,N-dimethylformamide (0.7 mL, 0.009 mol) was added 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (190 mg, 0.000796 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (303 mg, 0.000796 mol) and N,N-diisopropylethylamine (277 uL, 0.00159 mol). The reaction mixture was stirred for 16 hours at 50° C. Checked LC/MS, the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC to obtain the pure product (134.2 mg). MS m/z=472.3 (M+1). 1H NMR (DMSO) δ 10.13 (s, 1 H), 8.48 (d, J=4.8 Hz, 1 H), 8.06 (d, J=7/9 Hz, 1 H), 7.90 (s, 1 H), 7.84 (d, J=7.1 Hz, 1 H), 7.76 (td, J=7.7, 1.8 Hz, 1 H), 7.75-7.68 (m, 2 H), 7.63 (d, J=7.7 Hz, 1 H), 7.47 (t, J=7.9 Hz, 1 H), 7.32-7.22 (m, 2 H), 6.73 (d, J=7.6 Hz, 1 H), 5.28 (s, 2 H), 3.93 (s, 2 H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(=O)=O.ClC1N=C2C(N=CN2CC2CCOCC2)=C(Cl)N=1>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C

Procedure:
To a solution of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (4.60 g) in dry N,N-dimethylformamide (55 ml) at room temperature and under was added potassium carbonate (7.25 g) in one go. The reaction was heated to 60° C. for 1.5 hours. A solution of tetrahydro-3-furanylmethyl methanesulfonate, Isomer 2 (2.6 g) in dry N,N-dimethylformamide (3 ml) was added via a Pasteur pipette and the reaction heated at 70° C. for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with brine (20 ml). The organic layer was concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluant (10-60%) to afford the title compound as a clear viscous oil (3 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]2=3)=[O:10])=[CH:4][CH2:3]1.[H][H]>C(O)C.[Pt]=O>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]2=3)=[O:10])[CH2:6][CH2:7]1
Reactant: CN1CC=C(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CN1CCC(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1
Yield: 91.6 %

Procedure:
3.5 g (0.01 mol) of 5,10-dihydro-5-[(1-methyl-1,2,5,6-tetrahydro-4-pyridinyl)acetyl]-11H-dibenzo[b,e][1,4]diazepin-11-one were dissolved in 100 ml of ethanol and hydrogenated in the presence of 0.5 g of platinum oxide at ambient temperature and under a pressure of 3 bar. After the uptake of hydrogen had ended, the catalyst was filtered out and the remaining mixture concentrated by evaporation in vacuo. The residue was purified by column chromatography (NM silica gel 60; 0.063-0.2 mm particle size; eluent; ethyl acetate/methanol=9:1) and 3.2 g (91% of theory) of 5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-dibenzo[b,e][1,4]diazepin-11-one was obtained, which was identical, according to thin layer chromatography, elementary analysis and IR spectrum, to the product obtained using the method of Example 4.
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([C:1]1([C:4]#[N:5])[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N#CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopropyl cyanide (3.0 mL, 40 mmol) in 20 mL THF was dropwise added to a stirred, freshly prepared, mixture of lithium diisopropylamide (40 mmol) in THF (100 mL) at −78° C. After 30 min, a solution of benzyl bromide 7.8 mL, 60 mmol) in THF (20 mL) was dropwise added. The resulting mixture was warmed slowly over several hrs and stirred at rt 48 hr. The reaction was quenched (250 mL saturated NH4Cl), extracted with ether (3×100 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated to afford a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1>CN(C)C=O>[ClH:15].[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:20][N:21]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: Clc1ccc(CN2CCOCC2)cn1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Reaction time: 0.25 h
Yield: 6 %

Procedure:
To a suspension of 5-cyanooxindole (720 mg, 4.55 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (248 mg, 6.2 mmol, 60% dispersion in oil). After 15 min, was added 4-[(6-chloropyridin-3-yl)methyl]morpholine (323 mg, 1.52 mmol; described in: Maienfisch, P. et al. J. Med. Chem. 2000, 43, 5003) to the solution. The reaction mixture was heated at reflux for 1 h. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. A 2 M aqueous HCl solution was added to the ethyl acetate and water mixture until slightly acidic pH, and then NaHCO3 (s) was added until saturation. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and the solvent was removed in vacuo. The crude product was dissolved in a mixture of methanol and ethyl acetate and was cooled on ice. A solution of HCl in diethyl ether was added until acidic pH. Approximately half of the solvent volume was removed in vacuo. The precipitated hydrochloride salt was filtered, washed with ethyl acetate, and dried in vacuo. The salt was converted back to the base by partitioning between ethyl acetate and an aqueous saturated NaHCO3 solution. The obtained material (142 mg) was purified on a silica gel column using chloroform/ethanol, (9:1), as the eluent affording 34 mg (7% yield) of the title compound as the base as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 14.96 (br s, 1 H), 8.83 (br s, 1 H), 7.79 (dd, J=9, 1 Hz, 1 H), 7.69 (s, 1 H), 7.63 (s, 1 H), 7.50 (d, J=9 Hz, 1 H), 7.29-7.26 (m, 1 H), 7.06 (d, J=8 Hz, 1 H), 3.75-3.72 (m, 4 H), 3.44 (s, 2 H), 2.50-2.49 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].[Na].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C@H:15]([C:16]([OH:18])=[O:17])[CH:19]([CH3:21])[CH3:20])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C)C(Br)C(=O)O
Agent: [Na]
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)c(F)c1)C(=O)O

Procedure:
Following the procedure of Example 38, 3-fluoro-4-trifluoromethylaniline is reacted with the sodium salt of α-bromoisovaleric acid to yield N-(3-fluoro-4-trifluoromethylphenyl)valine, which is esterifed to yield the m-phenoxybenzyl ester of N-(3-fluoro-4-trifluoromethylphenyl)valine.
Reaction SMILES: [CH:1]1([O:4][C:5]2[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8]([O:10]C)=[O:9])[CH2:3][CH2:2]1.[OH-].[Li+].O>C1COCC1.CO>[CH:1]1([O:4][C:5]2[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(OC2CC2)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(OC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of methyl 3-cyclopropoxy-2-nitrobenzoate (4.7 g, 19.81 mmol) in THF (30 mL) and MeOH (30 mL) was treated with a solution of lithium hydroxide (2.88 g, 120 mmol) in water (15 mL, 833 mmol). The mixture was stirred at room temperature for 2 hours. The organic solvents were removed under reduced pressure. The resulting aqueous slurry was diluted with water, acidified with 1M HCl and extracted with ethyl acetate (3×). The extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide 3-cyclopropoxy-2-nitrobenzoic acid (4.35 g, 19.8 mmol, 98% yield) as a yellowish solid. HPLC: RT=2.186 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=246 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.76 (dd, J=7.7, 1.8 Hz, 1H), 7.68-7.46 (m, 2H), 4.02 (tt, J=6.0, 2.9 Hz, 1H), 1.00-0.52 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[CH:29]=[N:28][NH:27][CH:26]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(-c3cn[nH]c3)c21
Product: CC1c2c(cccc2-c2cn[nH]c2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(O[C:4](=[NH:11])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])C.[Cl-:12].[NH4+:13]>C(O)C>[ClH:12].[NH2:13][C:4](=[NH:11])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(=N)CCC(=O)OC
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CCO
Product: COC(=O)CCC(=N)N
Product: Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of methyl 4-ethoxy-4-iminobutanoate (1.34 g, 8.4 mmol) in ethanol (25 mL) was added ammonium chloride (450 mg, 8.4 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction was then cooled to room temperature and filtered, and the filtrate was concentrated to provide methyl 4-amino-4-iminobutanoate hydrochloride (1 g) as a white solid. MS (ESI): m/z 131 [M+H]+.
Reaction SMILES: C(OC(C1C(=O)[C:14]2[C:9](=[CH:10][C:11](C(=O)C)=C(F)C=2)[N:8](C2C=CC(F)=CC=2)C=1)=O)C.[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([C:42](=O)[CH3:43])[C:39]=3Cl)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][C:53]2C=CC=CC=2)[CH2:30][CH2:29]1>[Ni]>[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([CH:42]4[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:43]4)[CH:39]=3)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][CH3:53])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1c(Sc2ccccc2)n(C2CC2)c2c(Cl)c(C(C)=O)c(F)cc2c1=O
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C(C)=O)c(F)cc2c1=O
Agent: [Ni]
Product: CCOC(=O)c1c(SC)n(C2CC2)c2cc(C3CCC(N)CC3)c(F)cc2c1=O

Procedure:
In the described fashion as Example 21 (b and c), replacing ethyl 1-ethyl-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-quinoline carboxylate (9) (A=CH, R10 =C2H5, R=C2H5) with 1-cyclopropyl-2-methylthio-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-3-carboxylate (13) of Example 40 and also replacing the catalyst Raney nickel catalyst in Example 21(c) with pallidium on carbon under an hydrogen atmosphere, one can obtain ethyl 1-cyclopropyl-2-methylthio-6-fluoro-7-(3-aminocyclopentyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylate (16) (A=CH, R11 =CH3, R10 =C2H5, R=cyclopropyl, Z= ##STR137##
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][C:8](=[O:17])[N:7]3[CH2:6]1.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCCl>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:13]1[CH:12]=[C:11]2[C:16]3=[C:15]([CH2:5][CH2:6][N:7]3[C:8](=[O:17])[CH2:9][CH2:10]2)[CH:14]=1)=[O:24]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1CCc2cccc3c2N1CC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCCCl)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (55 g, 410 mmol) was added by portions to a solution of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (30.0 g) and 5-chlorovaleryl chloride (26.8 ml) in 1,2-dichloroethane (70 ml) under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice (500 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol-diethyl ether to give a pale yellow solid (36.5 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals (32.4 g) having a melting point of 110–111° C.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCl>[ClH:26].[NH:14]1[CH2:17][CH:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[CH2:15]1
Reactant: O=C(c1ccc(Cl)cc1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccc(Cl)cc1)C1CNC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (1-Benzhydryl-azetidin-3-yl)-(4-chloro-phenyl)-methanone (19.8 g, 54.8 mmol) in dichloromethane (250 ml), cooled to −4° C., is treated with 1-chloroethylchloroformate (8.0 ml, 73.8 mmol) and allowed to warm to ambient temperature. The reaction mixture is stirred for 18 hours and then evaporated. The residue is dissolved in methanol (220 ml) and stirred at ambient temperature for 3.5 hours. The methanol solution is concentrated and the product precipitated by addition of diethylether. The precipitate is collected by filtration and dries under high vacuum to afford Azetidin-3-yl-(4-chloro-phenyl)-methanone hydrochloride. [MH]+ 195.95.