Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH:4]=1.[CH3:13][C:14]([C:22]1[CH:23]=[C:24](O)[CH:25]=[C:26]([CH:28]=1)[OH:27])=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[OH:27][C:26]1[C:25]2[C@H:5]3[CH2:4][C:3](=[O:2])[CH2:8][CH2:7][C@H:6]3[C:9]([CH3:11])([CH3:10])[O:12][C:24]=2[CH:23]=[C:22]([C:14]([CH3:13])=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:28]=1
Reactant: COC1=CCC(C(C)(C)O)=CC1
Reactant: CCCCCC(C)=C(C)c1cc(O)cc(O)c1
Solvent: ClCCl
Product: CCCCCC(C)=C(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21
Temperature: 24 °C
Reaction time: 4 h

Procedure:
A solution of 1-methoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene in dichloromethane containing 5-(1,2-dimethyl-1-heptenyl)resorcinol was stirred at 0° C. while stannic chloride was added in one portion. The reaction mixture was then stirred for four hours at 24° C., and then washed with hydrochloric acid and water. The solution was dried and the solvent was removed by evaporation under reduced pressure to provide dl-cis-1-hydroxy-3-(1,2-dimethyl-1-heptenyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O.[CH3:12][N:13]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].[Zn]>[NH:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:12]#[N:13])[C:7]=2[CH:8]=[CH:9]1
Reactant: CN1CCCC1=O
Reactant: Clc1nccc2[nH]ccc12
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1nccc2[nH]ccc12
Temperature: 120 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine (500 mg, 3.28 mmol), zinc cyanide (422 mg, 3.61 mmol), Pd2(dba)3 (600 mg, 0.656 mmol), dppf (729 mg, 1.312 mmol), and Zn powder (21 mg, 0.328 mmol) in NMP (30 mL) under nitrogen was stirred at 120° C. for 18 h. The reaction mixture was cooled, poured into water (150 mL), extracted with DCM (3×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (1:1) as eluting solvents to afford 1H-pyrrolo[3,2-c]pyridine-4-carbonitrile as a white solid (150 mg, 32%). MS (ESI) m/z: 144.3 [M+1]+.
Reaction SMILES: OC(=CC([O-])=O)C.CS(Cl)(=O)=O.C(C1SC2C(C(=O)N2C(=C(OS(C)(=O)=O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1.[CH2:58]([C:65]1[S:71][CH:70]2[CH:67]([C:68](=[O:97])[N:69]2[C:72](=[C:89]([N:91]2[CH2:96][CH2:95][O:94][CH2:93][CH2:92]2)[CH3:90])[C:73]([O:75][CH:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[N:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[Br:98]Br>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:58]([C:65]1[S:71][CH:70]2[CH:67]([C:68](=[O:97])[N:69]2[C:72](=[C:89]([N:91]2[CH2:92][CH2:93][O:94][CH2:95][CH2:96]2)[CH2:90][Br:98])[C:73]([O:75][CH:76]([C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[N:66]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: BrBr
Reactant: CC(=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Agent: CC(O)=CC(=O)[O-]
Agent: CC(OS(C)(=O)=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(CBr)N1CCOCC1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 3.5 h
Yield: 70 %

Procedure:
One dissolves diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxy-ethylideneacetate (4.84 g) in tetrahydroufran (60 ml), cools to -20° C., adds triethylamine (2.84 ml) with stirring, adds dropwise methanesulfonyl chloride (0.82 ml) to the yellow solution, and lets react for 30 minutes. To the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.96 ml) at -40° C., stirs for 3.5 hours, adds pyridine (0.77 ml) to the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes, to give diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl] -α-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one adds dropwise 5% hydrochloric acid (72 ml) and methanol (60 ml), stirs for 3 hours at room temperature, and keeps in a refrigerator overnight. The reaction mixture is evaporated to give residue which is dissolved in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. Purification of the obtained residue (5.83 g) by chromatography over silica gel containing 10% water (150 g) gives from the fraction eluted with a mixture of benzene and ethyl acetate (4:1) diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70%. IR: νmaxCHCl3 3410, 1782, 1674, 1610 cm-1. NMR: δCDCl3 3.20s2H, 3.64s2H, 4.97d(4 Hz)1H, 5.66dd(9:4)1H, 6.77d(9 Hz)1H, 6.90s1H, 7.35 ml 5H.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:33]([F:36])([F:35])[F:34])[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28](F)=[C:27]([CH3:32])[CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:33]([F:35])([F:34])[F:36])[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]4[CH:11]=[CH:10][CH:9]=[N:8]4)=[C:27]([CH3:32])[CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: c1cn[nH]c1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cccn1
Temperature: 120 °C
Reaction time: 36 h

Procedure:
To a mixture of potassium carbonate (1.0 g, 7.24 mmol) and pyrazole (0.50 g, 7.35 mmol) in N,N-dimethylformamide (5 mL) was added 5-(3,5-dichlorophenyl)-3-(4-fluoro-3-methylphenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product from Step B) (0.50 g, 1.27 mmol). The reaction mixture was stirred vigorously for 36 h at 120° C. Then the reaction mixture was absorbed onto silica gel, concentrated, and purified by flash chromatography on silica gel and eluted with a gradient of 0-25% ethyl acetate in hexane to afford the title product, a compound of the present invention, as a yellow oil (32.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:25](=[O:26])[CH2:24][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=3)[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)Cc3ccc([N+](=O)[O-])cc3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.1 %

Procedure:
A mixture of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol), 4-nitrophenylacetic acid (22 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) were dissolved in chloroform (1.5 ml). N, N-Diisopropylethylamine (0.02 ml, 0.13 mmol) was added and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured into brine and the organic layer washed with further brine, dried over magnesium sulphate and then concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate-toluene, 1:1), giving the title compound (9 mg, 18%). Rf 0.19 (ethyl acetate-toluene, 1:1).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]1[CH2:23][CH2:22]N2[C:16](=NCCC2)[CH2:15][CH2:14]1.C1(Br)CCCCC1>CN(C=O)C>[CH:13]1([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:14][CH2:15][CH2:16][CH2:22][CH2:23]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: BrC1CCCCC1
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
N-hydroxylphthalimide (61.3 mmol, 10.0 g) was dissolved in anhydrous DMF (60 mL) under nitrogen. To the stirring solution, DBU (92.0 mmol, 13.75 mL) was injected followed by cyclohexyl bromide (76.6 mmol, 9.43 mL) and the reaction was warmed to 55° C. After stirring for 15 hours, the reaction was warmed to 80° C. for 5 hours, then cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 1N NaOH, brine and dried over magnesium sulfate. The solvent was removed under vacuum and the crude product was triturated with hexanes providing 2.89 g (19%) of a yellow solid. Rf: 0.7 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.80 (2H,m), 7.73(2H,m), 4.21 (1H,m), 2.02-1.98 (2H,m), 1.87-1.82 (2H,m), 1.59-1.53 (4H,m), 1.30-1.24 (2H,m).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][OH:17])=[CH:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:17][CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=[CH:9][C:10]4=[N:15][CH:14]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: OCc1cnc2ccc(-c3ccccc3)nn12
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(OCc3cnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
In a microwave vessel, (6-phenylimidazo[1,2-b]pyridazin-3-yl)methanol (0.075 g, 0.33 mmol), 4-chloro-7-methoxyquinoline (0.19 g, 1.00 mmol), Cs2CO3 (0.22 g, 0.67 mmol) and 0.7 mL DMSO were combined and the vessel sealed. The mixture was pre-stirred for 2 min, followed by microwave heating for 2 h at 120 C, then 1 h at 130 C. The mixture was allowed to cool to rt, diluted with water to precipitate a cream solid. The solid was collected and rinsed with water. The solid was purified via flash chromatography using a 0% to 5% MeOH in EtOAc gradient to afford the title compound as a yellow solid. M/Z=383.2 [M+H], calc 382.4212 for C23H18N4O2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a mixture of 4,5-dichloro-2H-pyridazin-3-one (3.3 g, 20.0 mmol) and Cs2CO3 (9.77 mg, 1.5 eq) were added DMF (15 mL) and benzyl bromide (3.10 mL, 1.3 eq), which was then stirred for 3 h at 60° C. under nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was extracted twice with ethyl acetate (200 mL). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (NaHCO3, 100 mL×2) and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was separated by column chromatography (10% ethyl acetate-hexane) to give 4.48 g (88%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[CH2:12]([N:9]1[CH2:10][CH:11]=[C:6]([C:4]2[CH:5]=[N:1][NH:2][CH:3]=2)[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: c1cc(-c2cn[nH]c2)ccn1
Solvent: CC(C)O
Product: C1=C(c2cn[nH]c2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a hot (80° C.) solution of 4-(1H-pyrazol-4-yl)pyridine (4.8 g) in 2-propanol was added benzyl bromide (10 mL, 2.5 equiv.) and the resulting mixture heated at reflux for 10 minutes. After cooling in an ice bath, the precipitate was filtered and washed with more 2-propanol and air dried. The solid was suspended in ethanol at 0° C. and sodium borohydride (6.5 g) was added in several portions over 30 minutes, and the mixture was stirred for an additional 30 minutes. The reaction was quenched by carefully addition of water, and the ethanol was removed by evaporation, and the residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO4, and filtrated and evaporation gives 1-benzyl-4-(1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridine (7.5 g)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:10](O)=O.C=O.[ClH:15]>>[ClH:15].[ClH:15].[CH3:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: OCCN1CCNCC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: CN1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A total of 100 g (0.77 mol) of 1-(2-hydroxyethyl)piperazine was added dropwise to a stirred solution of 78.6 g (1.54 mol) of 90% formic acid at 0° C. To the resulting solution, 63.2 g (0.77 mol) of 37% formaldehyde was added dropwise. The solution was stirred at 0° C. for 15 minutes and heated on a stream bath for 3 hours. The solution was acidified with 150 ml of concentrated hydrochloric acid. The water was removed and the resulting residue dissolved in 200 ml of 25% NaOH, and extracted with chloroform. The organic layer was dried over MgSO4, filtered, and the solvent removed. The resulting residue was distilled to give 84.7 g (76%) (b.p. 96°-97° C./3 Torr) of the alcohol as a colorless liquid. The dihydrochloride salt was prepared by acidifying the free base to a pH of 1 and removing the water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(F)c(F)c1
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1ccc(F)c(F)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.72 mmol) of 1-(3,4-Difluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXVII), 78.2 mg (1.45 mmol) of sodium methylate and 60.9 mg (0.72 mmol) methyl propiolate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([O:26]CC)=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.O[Li].O.Cl>C1COCC1.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=[O:25])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OCC2CC2)nc2sccn12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of Step 4 intermediate (495 mg, 1.242 mmol) in THF (10 ml) was added LiOH.H2O (105 mg, 2.484 mmol) dissolved in water (10 ml). The mixture was stirred for 2 h at room temperature. Solvent was evaporated under reduced pressure and the residue obtained was acidified with 1 N HCl to pH 4 and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with water (2×25 mL) and dried (Na2SO4). Evaporation of solvent under reduced pressure afforded 0.381 g of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.49-0.53 (m, 2H), 1.16-1.22 (m, 1H), 3.75 (d, J=7.5 Hz, 2H), 3.79 (s, 3H), 6.95-6.99 (m, 1H), 7.04 (t, J=7.8 Hz, 1H), 7.16-7.27 (m, 1H), 7.39 (d, J=3.9 Hz, 1H), 7.71 (d, J=15.9 Hz, 1H), 7.79 (d, J=15.9 Hz, 1H), 8.10 (d, J=3.9 Hz, 1H), 13.44 (br s, 1H); ESI-MS (m/z) 369.08 (M−H)−.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1[C@@H]1CCCC[C@H]1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 74.6 %

Procedure:
To a solution of trans-3-[2-(2-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (157 mg) in 20 ml of dichloromethane was added pyridinium dichromate (307 mg) and molecular sieves 4A (144 mg) at 5° C. The reaction mixture was allowed to stir at room temperature for 28.5 hours. Insoluble material was filtered off using celite and the filtrate was washed with 1N hydrochloric acid (10 ml), saturated aqueous sodium bicarbonate (10 ml), and brine (10 ml), dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (2 g) eluted with a mixture of dichloromethane and ethyl acetate (4:1) to give 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (116.5 mg). The nmr spectrum for this compound was identical with that of the authentic sample prepared by the method described in Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C@H:16]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([N:15]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:24][C@H:16]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CN
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.05 cm3 of 3-methylphenyl isocyanate is added to a solution of 0.08 g of tert-butyl (2S,5R)-1-(2-aminoacetyl)-5-phenylprolinate in 10 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 3 hours at a temperature in the vicinity of 25° C., the solvent is then evaporated under reduced pressure at 45° C. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (98/2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure. 0.04 g of tert-butyl (2S,5R)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate is thus obtained, the analytical data for which are in agreement with those for the dextrorotatory enantiomer prepared by chiral stationary phase chromatography of the racemic product, ([α]D20 =±35.6°±0.8° (C=0.11%; MeOH)).
Reaction SMILES: Br[CH:2]([CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:17][C:18]([NH2:20])=[S:19].C([O-])(=O)C.[Na+]>>[CH2:13]([C:2]1[S:19][C:18]([NH2:20])=[N:17][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(Br)C(=O)c1ccc(OC)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCCc1sc(N)nc1-c1ccc(OC)cc1
Yield: 57.2 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-methoxy-phenyl)-hexan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 3 hours, followed by post-treatment to give a crude product, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 1:1 (V:V) to obtain a product as a white solid in a yield of 57.2%, mp: 118-119 └. 1H-NMR (CDCl3, 400 M.Hz) δ: 0.90 (3H, t, J=7.2 Hz, CH3), 1.36 (2H, sextuple, J=7.20 Hz, CH2), 1.59 (2H, quintuple, J=7.20 Hz, CH2), 2.74 (2H, t, J=7.2 Hz, CH3), 3.83 (3H, s, OCH3), 4.93 (2H, br, NH2), 6.93 (2H, d, J=8.80 Hz, ArH), 7.45 (2H, d, J=8.80 Hz, ArH); EI-MS m/e (%): 262.0 (M+, 55), 219.0 (100), 177.0 (36); HREI-MS Calcd. for C14H18N2OS: 262.1140. found: 262.1140. Anal. Calcd. for C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. found: C, 64.19; H, 7.02; N, 10.63.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]3)O1.CC1(C)C(C)(C)OB(C2C=CC=C3C=2CN(C(OC(C)(C)C)=O)CC3)O1.FC(F)(F)S(O[C:59]1[CH:60]=[N:61][C:62]([C:65]([F:68])([F:67])[F:66])=[N:63][CH:64]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.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.[Fe+2].CCO.C1(C)C=CC=CC=1>[F:66][C:65]([F:68])([F:67])[C:62]1[N:63]=[CH:64][C:59]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:13][CH2:12]3)=[CH:60][N:61]=1
Reactant: O=S(=O)(Oc1cnc(C(F)(F)F)nc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)OC(=O)N1CCc2cccc(B3OC(C)(C)C(C)(C)O3)c2C1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3cnc(C(F)(F)F)nc3)ccc2C1
Temperature: 81 °C
Yield: 48 %

Procedure:
A 4:1 mixture (0.10 g, 0.28 mmol) of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, 2-(trifluoromethyl)pyrimidin-5-yl trifluoromethanesulfonate (0.083 g, 0.28 mmol), PdCl2×dppf (0.0048 g), 2M sodium carbonate (1.1 mL), toluene (4.0 mL) and EtOH (1.0 mL) was purged with dry argon for ten minutes then heated in a sealed vial at 81° C. for 6 h. The black solution was filtered through glass-wool, taken up in water-brine and washed twice with EtOAc. The combined organic phases were dried, filtered and concentrated with silica (5 g). Column chromatography with EtOAc-heptanes (1:8 through 1:5) gave 0.051 g (48%) of the title product as white solid.