Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[F:10][CH:11]([F:32])[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([CH:26]=[O:27])=[C:14]([C:28]([F:31])([F:30])[F:29])[N:13]=1.Cl>CCOCC.O>[F:32][CH:11]([F:10])[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([CH:26]([OH:27])[C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)=[C:14]([C:28]([F:31])([F:29])[F:30])[N:13]=1
Reactant: Brc1cccs1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2cccs2)c1CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
This example illustrates the preparation of Compound Number 53. To a suspension of magnesium (1.4 g, 58 mmol) in anhydrous ether (40 mL) containing several iodine crystals was added dropwise a solution of 2-bromothiophene (10 g, 62 mmol) in anhydrous ether (20 mL). The reaction was exothermic; the mixture was stirred at ambient temperature for 1.5 h. The resulting Grignard reagent was cooled to 0°-5° C. and a solution of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)6-(trifluoromethyl)-3-pyridinecarboxylate (6.8 g, 20 mmol) in anhydrous ether (20 mL) was added. The mixture was stirred for 2 h, poured into iced water, and acidified with conc. HCl. The organic layer was separated, washed with water and brine, dried (MgSO4), and conc. The residue was eluted on a silica gel column with 15% ethyl acetate/cyclohexane to yield 6.6 g of methyl 2-(difluoromethyl)-5-(hydroxy-2-thienylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate, a 77.6 % yield. m.p. 78°-88° C.
Reaction SMILES: C(=O)C1C=CC=CC=1.[C:9]([C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][CH:38]=1)[CH2:15][NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([N:27]1[CH:31]=[C:30]([C:32]([OH:34])=[O:33])[CH:29]=[N:28]1)[NH:21][C:20]2=[O:35])(=O)[NH2:10].NC1C=C2C(=CC=1)N=C(N1C=C(C(O)=O)C=N1)NC2=O>>[C:9]([C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][CH:38]=1)[CH2:15][NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([N:27]1[CH:31]=[C:30]([C:32]([OH:34])=[O:33])[CH:29]=[N:28]1)[NH:21][C:20]2=[O:35])#[N:10]
Reactant: NC(=O)c1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1
Agent: Nc1ccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2c1
Solvent: O=Cc1ccccc1
Product: N#Cc1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 171, substituting 3-cyanobenzaldehyde for benzaldehyde in step A. Step C yielded a mixture of the titled compound, 1-[6-(3-carbamoyl-benzylamino)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, and 1-[6-amino-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, which was separated by reverse-phase HPLC.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]=[O:16])=[CH:11][C:10]([O:17][CH3:18])=[CH:9][CH:8]=2.CC(C)=O.ClCCl>C(O)C.CO>[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][OH:16])=[CH:11][C:10]([O:17][CH3:18])=[CH:9][CH:8]=2
Reactant: COc1ccc2ncc(Cl)c(CC=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(Cl)c(CCO)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Sodium borohydride (2.09 g, 55.2 mmol, 1.0 eq) is added portionwise at 0° C. to a stirred suspension of (3-chloro-6-methoxy-quinolin-4-yl)-acetaldehyde (13.0 g, 55.2 mmol, 1.0 eq) in ethanol (200 mL). After 1 hour stirring at 0° C., acetone (50 mL) is added to quench the reaction. Solvents are removed and the resulting crude product is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1, v/v) to afford 2-(3-chloro-6-methoxy-quinolin-4-yl)-ethanol as a yellow solid (13.1 g, 99% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.O.CC#N>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described for the title compound under E in Scheme 5 from (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. TLC, Rf (CH2CO2/MeOH 95:5)=0.3. tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.16 min.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH3:15])=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:22])[CH3:19].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu](I)I>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:2]2[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH3:15])=[CH:4][CH:3]=2)[CH:27]=1)=[O:22])[CH3:19]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(I)cc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Temperature: 25 °C

Procedure:
A suspension of (2R)-1-[3-(4-iodophenoxy)propyl]-2-methylpyrrolidine obtained in Example 1-(2) (1.60 g), 1H-pyrazole-4-carboxylic acid ethyl ester (0.779 g), (rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.263 g), copper iodide (0.088 g) and cesium carbonate (3.02 g) in N,N-dimethylformamide (2.5 mL) was stirred at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=3:1) to give the titled compound (1.11 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[CH:19]=[CH:18][C:17]5[O:23][CH2:24][CH2:25][N:26](C(=O)C)[C:16]=5[C:15]=4[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:30])=[N:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[CH:19]=[CH:18][C:17]5[O:23][CH2:24][CH2:25][NH:26][C:16]=5[C:15]=4[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:30])=[N:4][CH:3]=1
Reactant: CC(=O)N1CCOc2ccc3ccc(CCc4nc5c(C)ncc(C)n5n4)nc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3ccc4ccc5c(c4n3)NCCO5)nc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(9-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-2,3-dihydro-[1,4]oxazino[2,3-h]quinolin-1-yl)ethanone (10 mg, 0.025 mmol) in methanol (1 mL) was added 2 M NaOH (0.05 mL, 0.1 mmol) at room temperature. After stirring the mixture at 100° C. for 12 h, the solvent was removed. The crude product was purified using reverse phase column chromatography (7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C2C=CC(F)=CC=2)=[C:4]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=2)[CH:3]=1.NC1C=CC(Cl)=CC=1[C:35](C1C=CC=C(OC)C=1)=[O:36].[OH-].[Na+]>CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:18]([C:19]1[CH:20]=[CH:21][C:22]([O:36][CH3:35])=[CH:23][CH:24]=1)=[O:26]
Reactant: COc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)c2cc(Cl)ccc2N)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide (6.0 g, 16 mmol), prepared as described above for compound 1s, in MeOH (400 mL) was added 5N NaOH (50 mL) and the resulting solution was allowed to reflux for 16 h. The solution was cooled to room temperature and concentrated in vacuo. The aqueous portion was extracted with CH2Cl2 (2×100 mL). The combined organic portions were washed with H2O (3×50 mL), dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, 5 to 25% EtOAc/hexanes) and recrystallized from MeOH to provide 1u (3.5 g, 83%) as a light yellow powder MS m/z=262 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N:10]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]#[N:10])[CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(O)c(Cl)c1
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 103.2 %

Procedure:
At from −5 to −10° C., a suspension of 123 g (858 mmol) of 2-chloro-4-aminophenol in 190 ml of conc. HCl was added dropwise to a solution of 71 g (1 mol) of NaNO2 in 190 ml of water. At from −5 to −10° C., this suspension was added to a solution of 354 g (1.72 mol) of SnCl2*2H2O in 800 ml of conc. HCl. The mixture was stirred at about 20-25° C. for approximately 14 hours and the crystalline material was filtered off and washed with water. After drying, 85 g of 3-chloro-4-hydroxyphenyldiazonium hydrochloride were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1.[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH2:14]([O:8][C:7]1[CH:6]=[C:5]([CH:11]=[CH:10][CH:9]=1)[O:4][CH2:3][CH2:2][OH:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCOc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCOc1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of O-(2-Hydroxyethyl)resorcinol (4 g) and sodium hydroxide (1.04 g) dissolved in methanol (60 mL) was added benzyl bromide (4.44 g), and the resulting reaction mixture was stirred overnight. After this time, approximately 30 mL of the methanol was removed in vacuo, and the mixture was diluted with methylene chloride (100 mL). The organics were washed with water and aqueous 1N NaOH, dried, and concentrated to provide 2-(3-benzyloxy-phenoxy)ethanol (5.03 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=O)[CH2:8][CH2:9][C:10](O)=[O:11])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1C(C(=O)CCC(O)=O)=CN=C1C1C=CC=CC=1.O.[NH2:40][NH2:41]>C(O)C.C(O)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH2:8][CH2:9][C:10](=[O:11])[NH:40][N:41]=2)[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: Cn1cc(C(=O)CCC(=O)O)nc1-c1ccccc1
Agent: Cn1c(C(=O)CCC(=O)O)cnc1-c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1cc(C2=NNC(=O)CC2)nc1-c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 1-methyl-γ-oxo-2-phenyl-1H-imidazole-4-butanoic acid and of 1-methyl-γ-oxo-2-phenyl-1H-imidazole-5-butanoic acid (as obtained by method B, ca 60:40 ratio) in 150 ml of ethanol and 25 ml of glacial acetic acid is treated with 12 ml of hydrazine hydrate at 85° C. for six hours and then is allowed to stand overnight at room temperature. The solid is collected, washed with water, then with cold ethanol, and finally with ether giving 4.2 g of pure 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone as nearly white crystals, mp 271°-272° C., dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C[O:28][B:29](OC)[O:30]C>C1COCC1>[CH3:19][C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:29]([OH:30])[OH:28])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Br)c2)CC1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromophenyl)methyl]-1-piperazinecarboxylate (6.55 g) in THF (20 mL) at −70° C. was added dropwise n-butyl lithium (15.4 mL, 2.5M solution in hexanes) over 10 minutes. After stirring for 30 mins at that temperature, the resulting orange solution was treated with trimethylborate (8.02 g). The reaction mixture was then allowed to warm up to room temperature and quenched with saturated ammonium chloride (15 mL). The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and further extracted with ethyl acetate (20 mL). The organic phases were combined, dried (MgSO4) and evaporated under vacuum to give the title compound (5 g) which was used directly for the preparation of 1,1-dimethylethyl 4-[(3′-cyano-3-biphenylyl)methyl]-1-piperazinecarboxylate without further purification. LC/MS: m/z, 321 (M+H), 1.91 min.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: Fc1cccc(Br)c1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 1-bromo-3-fluorobenzene
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][C:10]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 3-(4-fluorophenyl)propionyl chloride (287.6 g, 1.5 mol) in dichloromethane (1.4 L) was added dropwise during 3 h to an ice-cold, mechanically stirred suspension of aluminum chloride (226.0 g, 1.7 mol, Aldrich) in dichloromethane (2.2 L) under nitrogen. The resulting yellowish-black solution was refluxed for 5 h and allowed to cool to room temperature. The solution was washed successively with water (2 L), 1N sodium hydroxide (2 L), water (2 L) and brine (2 L). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a tan solid (229.1 g, 99%). The solid was recrystallized from dichloromethane-hexane to give 215.7 g (93%) of 6-fluoro-1-indanone as off-white crystals, m.p., 57°-59° C.; NMR (DMSO-d6): d 7.36-7.66 (m, 3H, Ar), 2.65-2.72, 3.06-3.10 (2m's, 4H, 2XCH2).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>C1COCC1>[F:30][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(cc1Br)C(C)(C)CC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)C(C)(C)CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of 6-bromo-5-methoxy-1,1-dimethyl-indan (2.77 g, 10.8 mmol) (see Example 5) in THF (40 mL) at −78° C. was slowly added n-butyllithium (5.56 ml, 2.5M). The resulting solution was stirred at −78° C. for 0.5 h and a solution of N-fluorobenzenesulfonimide (4.11 g, 13.0 mmol) in THF (40 mL) was added. After an additional 2 h at −78° C., the reaction was warmed to room temperature, poured into water (50 mL), and extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with water (100 mL), dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography (2% ethyl acetate/heptanes) afforded 1.40 g of the title compound as yellow oil.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O>CN(C=O)C>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][CH:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[C:6]1=[O:15]
Reactant: NC1Cc2ccccc2NC1=O
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2C(=O)C(N)Cc3ccccc32)O1
Temperature: 80 °C
Yield: 52.6 %

Procedure:
Sodium hydride (60% in oil, 191 mg, 4.70 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985; 1511–16,450 mg, 2.27 mmol), in anhydrous DMF (6 mL) at 0° C. over a period of 5 min keeping the internal temperature at <10° C. The reaction was stirred for a further 30 min before addition of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (J. Med. Chem. 35, 1992, 1650–62; 528 mg, 2.50 mmol) and the reaction has then heated to 80° C. for a period of 5 h. The reaction was then cooled and evaporated before addition of sat. aqueous NaHCO3 (20 mL) and EtOAc (50 mL). The organic layer was then dried (MgSO4), filtered and evaporated and the residue was purified by column chromatography (MeOH:DCM 1:19) to afford the title compound (330 mg, 53%) as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:11]([C:23]3[CH:40]=[CH:39][C:26]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=4[O:37][CH3:38])=[C:25]([N+:41]([O-])=O)[CH:24]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCO.CCOC(C)=O>C1COCC1.C(Cl)Cl.O=[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[CH:11]([C:23]3[CH:24]=[C:25]([NH2:41])[C:26]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=4[O:37][CH3:38])=[CH:39][CH:40]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(Br)cc4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])c(OC)c1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(Br)cc4)N3c3ccc(C(C)(C)C)cc3)cc2N)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from example 191E (1.18 g, 1.831 mmole) was dissolved in a mixture of THF (10 mL):EtOH (10 mL):EtOAc (10 mL), treated with PtO2 (42 mg) and evacuated 10 minutes, followed by introduction of H2 (g) via balloon. The reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was filtered and the solvent removed in vacuo leaving a dark green foamy solid. The solid was dissolved in 10 mL CH2Cl2 applied to a 40 g silica gel column and eluted with a gradient of hexane/EtOAc; 90/10 to 30/70 over 20 minutes. The title compound was isolated as a white foamy solid as a mixture of isomers 0.54 g, 48%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[Cl:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16]Cl>>[Cl:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1ccc2c(c1)OCCC2
Product: OC(CCl)CCOc1ccc2c(c1)OCCC2

Procedure:
The starting 1-chloro-4-(3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-butanol was prepared according to example 1 (b) from 7-hydroxy-3,4-dihydro-2H-1-benzopyrane (J. Chem. Soc. 1190, 1958) and 1,4-dichloro-2-butanol (m.p. 78°-80° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:19][NH2:20])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[CH2:27]([CH:34]([CH2:39][Br:40])[CH2:35][C:36](Cl)=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CO>ClCCl.[Cl-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:19][NH:20][C:36](=[O:37])[CH2:35][CH:34]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:39][Br:40])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CC(CBr)Cc1ccccc1
Reactant: NN=C(Cc1ccnc2ccccc12)c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CC(CBr)Cc1ccccc1)NN=C(Cc1ccnc2ccccc12)c1ccccn1
Reaction time: 2 h

Procedure:
A solution of (1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazine (2.25 g, 8.40 mmol) in anhydrous dichloromethane (100 mL) and pyridine (1.81 mL, 22.4 mmol) is cooled to −78° C., treated with a solution of 3-benzyl-4-bromo-butyryl chloride (2.1 g, 7.8 mmol) in dichloromethane (10 mL), and stirred for 2 h. The mixture is treated with methanol (3 mL), stirred for 10 min, and diluted with saturated ammonium chloride solution (30 mL). The mixture is diluted with dichloromethane (300 mL), washed with water (2×50 mL) and brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is precipitated from ether to yield the title compound, 2.3 g (60%), as a pale yellowish solid.
Reaction SMILES: C([Mg]Br)C.C(NC(C)C)(C)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1[F:19].[C:24](=[O:26])=[O:25].Cl.CC1CCCCC1>C1COCC1>[Cl:12][C:13]1[C:18]([F:19])=[C:17]([CH:16]=[C:15]([C:20]([F:23])([F:21])[F:22])[CH:14]=1)[C:24]([OH:26])=[O:25]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: O=C=O
Agent: CC[Mg]Br
Agent: Cl
Solvent: CC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
To a mixture of ethyl magnesium bromide solution (6.25 ml, 6.25 mmol, 1.25 equiv., 1M in THF) and diisopropyl amine (77.7 μl, 0.5 mmol, 0.1 equiv.) was added 3-chloro-4-fluoro-benzo trifluoride (0.99 g, 5 mmol in THF (2 ml)) at ambient temperature and the mixture was heated in an oil bath to 50° C. for 13 h. The brown clear reaction mixture was cooled to 0-5° C., was transferred into a syringe and added dropwise to a solution of CO2 (2.2 g, 50 mmol, 10 equiv.) in THF (5 ml) at −70° C. and stirred for 15 min. To the brown suspension was added HCl (1M, 14 ml) and the phases were separated. The aqueous phase was extracted with TBME (10 ml), the combined organic phases were dried over sodium sulfate, filtered, washed with TBME and the solvents were removed under vacuum to yield a dark brown oil (0.97 g of the crude product). The crude product was treated with methyl cyclohexane (4.4 ml) and heated in a pre-heated oil bath to reflux. After 5 min, a brown clear solution was obtained, the oil bath was removed, the reaction mixture was cooled to ambient temperature and the formed suspension was stirred overnight at ambient temperature. After 18 h the brown suspension was stirred in an ice bath (0-5° C.) for two hours, the obtained crystals were filtered off, the crystals were washed with cold methyl cyclohexane (1.6 ml) and the crystals were dried until weight constancy to yield the product as white crystals (0.46 g, 38.2% yield).