Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9](I)=[CH:8][N:7]3[C:13]=2[CH3:14])[CH2:3][CH2:2]1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:13]([CH3:14])=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[CH:8]=2)[C:25](=[O:29])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1c(C2CC2)nc2ccc(I)cn12
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cn12
Temperature: 110 °C
Yield: 55.6 %

Procedure:
A mixture of 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (1482 mg), 4-(benzyloxy)pyridin-2(1H)-one (1000 mg), copper iodide (946 mg), N,N′-dimethylethylenediamine (0.534 ml), potassium carbonate (2061 mg) and DMSO (13 ml) was heated 110° C. for 1 h under microwave irradiation. The residue was quenched with 28% NH3 solution, and extracted with EtOAc/THF. The organic layer was separated, washed with water and brine, dried over MgSO4, passed through silica gel pad (EtOAc only) and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH) and recrystallized from EtOH (80 ml) to give the title compound (1027 mg) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[Br:1][C:2]1[C:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2Br)cc1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2cc(Br)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1

Procedure:
Following the procedure described for Intermediate 3 with 4-bromo-3-(4-nitrophenyl)-1H-pyrazole and p-methoxybenzylchloride provided the title product. ESMS [M+H]+: 388.2
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:39]=[CH:38][C:9]([O:10][C:11]2[C:12]([C:34]([O:36][CH3:37])=[O:35])=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[N:16](COCC[Si](C)(C)C)[C:15]=3[CH:33]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([S:3]([C:6]1[CH:39]=[CH:38][C:9]([O:10][C:11]2[C:12]([C:34]([O:36][CH3:37])=[O:35])=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[NH:16][C:15]=3[CH:33]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3c(cc2C(=O)OC)nc(-c2ccccn2)n3COCC[Si](C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(=O)OC)cc1

Procedure:
Methyl 6-[4-(ethylsulfonyl)phenoxy]-2-(2-pyridinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5-carboxylate was reacted with trifluoroacetic acid to obtain the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=1)=[O:4]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1ccncc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccncc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
Pd(OH)2/C (0.4 g) was added to a solution of 3′,6′-dihydro-2′H-[3,4′]bipyridinyl-4,1′-dicarboxylic acid 1′-t-butyl ester 4-methyl ester (500 mg, 1.2 mmol, 1.0 eq.) in EtOAc (15 mL), maintained under hydrogen at 1 atm. The resulting solution was stirred over night at room temperature. The solids were filtered. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:3) to yield 3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-4,1′-dicarboxylic acid 1′-t-butyl ester 4-methyl ester (240 mg) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[F:29].[C-:30]#[N:31].[K+].C1OCCOCCOCCOCCOCCOC1>CN1C(=O)CCC1>[C:30]([C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[F:29])#[N:31]
Reactant: CN(C)C(=O)c1ccc(Nc2nnc(Cl)c(NCc3cccc(F)c3F)n2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1ccc(Nc2nnc(C#N)c(NCc3cccc(F)c3F)n2)cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-(6-Chloro-5-(2,3-difluorobenzylamino)-1,2,4-triazin-3-ylamino)-N,N-dimethylbenzamide (20 mg) was dissolved in 2 mL NMP. To it was added KCN (100 mg) and 18-crown-6 (20 mg). The mixture was stirred in a sealed tube at 130° C. for overnight. It was cooled to RT and subjected to reverse phase preparative HPLC to isolate the cyanation product, 4-(6-cyano-5-(2,3-difluorobenzylamino)-1,2,4-triazin-3-ylamino)-N,N-dimethylbenzamide. It was dissolved in 2 mL DMSO and 10 mL methanol. To it was added 100 mg KOH and then 1 mL H2O2 (50%). The mixture was stirred at RT for 1 h. It was treated with acetonitrile and TFA, concentrated and subjected to reverse phase preparative HPLC to isolate the title compound (3 mg). MS found for C20H19F2N7O2 as (M+H)+ 428.3. UV: λ=244, 278 nm. Proton NMR: (CD3OD) δ 7.53 (2H, d, J=8.8 Hz), 7.43 (2H, d, J=8.4 Hz), 7.20 (1H, m), 7.14-7.11 (2H, m), 4.84 (2H, s), 3.11 (3H, s), 3.04 (3H, s) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1) to give the title compound as a colorless oil, MS (ESI+): m/z=410.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25].[CH3:28][NH2:29]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:29][CH3:28])=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25]
Reactant: COc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(OC)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 66 h
Yield: 95.2 %

Procedure:
8-Chloro-6,7-difluoro-1-(2,4-difluoro-5-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (90 mg) and an aqueous solution (about 40%; 200 mg) of methylamine were added to pyridine (520 mg), and the mixture was stirred at room temperature for 66 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (88 mg) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[NH:4][N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:6](=[O:22])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17](O)(=[O:19])=[O:18])=[CH:12][C:11]=1[CH3:21])#[N:2].C(#N)C.P(Cl)(Cl)([Cl:35])=O>CN(C)C(=O)C>[Cl:35][S:17]([C:13]1[C:14]([CH3:16])=[CH:15][C:10]([N:9]=[N:8][C:7]2[C:6](=[O:22])[N:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[NH:4][C:3]=2[C:1]#[N:2])=[C:11]([CH3:21])[CH:12]=1)(=[O:19])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(S(=O)(=O)O)c(C)cc1N=Nc1c(C#N)[nH]n(-c2ccccc2C)c1=O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)Cl)c(C)cc1N=Nc1c(C#N)[nH]n(-c2ccccc2C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8.6 g of the azo obtained in step (2) above, 35 ml of acetonitrile, and 8.6 ml of N,N-dimethylacetamide were put into a 100 ml three-necked flask and 8.6 ml of phosphorus oxychloride was added dropwise to the mixture at a temperature of 50° C. or below. After completion of the dropwise addition, the mixture was stirred for 30 minutes and then poured into ice water. The crystals thus deposited were collected by filtration.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN([CH:17]=[O:18])C.[Cl-].[NH4+]>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([CH:17]=[O:18])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)n1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
To THF(60 ml) was added at −70° C. n-butyllithium (1.59M hexane solution, 63 ml, 100 mmol). To the mixture was added dropwise (taking about 1 hour) a solution of 2,6-dibromo-pyridine (23.69 g, 100 mmol) in THF (140 ml) at −60° C., and the mixture was stirred at −70° C. for 15 minutes. To the mixture was added DMF (12 ml), and the mixture was stirred at the same temperature for 15 minutes. To the mixture was added 20% ammonium chloride solution (100 ml), and the organic layer was separated. The aqueous layer extracted with ethyl acetate (100 ml), and the organic layer was mixed with the previous organic layer. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 150 g, ethyl acetate/hexane=1/20), and the desired fraction was concentrated under reduced pressure. To the residue was added duisopropyl-ether (15 ml), and insoluble materials were filtered, which were washed with diisopropylether (5 ml×3) and dried under reduced pressure to give 6-bromo-2-pyridinecarbaldehyde (2.05 g, 11.0 mmol, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:20][CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cl-].[Na+].O>[N:25]1([CH2:24][CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]34[NH:20][CH2:19][CH2:18][N:9]3[C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH2:13]4)=[CH:4][CH:3]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C1c2cccn2CC2(c3ccc(O)cc3)NCCN12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cccn2CC2(c3ccc(OCCN4CCOCC4)cc3)NCCN12
Temperature: 100 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
10a-(4-hydroxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.19 mmol), 4-(2-chloroethyl)morpholine hydrochloride (106 mg, 0.57 mmol) and potassium carbonate (105 mg, 0.76 mmol) were suspended in DMF (1 mL) and the mixture heated at 100° C. The reaction was complete after 3 hours. Brine (5 mL) and water (1 mL) were then added. The mixture was then extracted with ethyl acetate (3×3 mL) and the extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to yield a residue that was purified by flash chromatography (Biotage SP4, gradient 0 to 10% methanol-dichloromethane). The material isolated required a second purification by reverse phase chromatography (Biotage SP4, C18 column, 5 to 100% 10 mM NH4OAC (aq)-MeOH) to give 10a-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (75% pure, 22 mg, yield: 22%). The product was used in the next step without further purification. ESI-MI m/z [M+H]+ 383.2.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1Cl>O1CCOCC1>[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of phenol (5.64 g, 60 mmol) and potassium t-butoxide (6.74 g, 60 mmol) in 50 mL 1,4-dioxane was stirred at room temperature for 0.5 h. To the mixture was added 2-chloro-5-nitro-benzoic acid methyl ester (10.78 g, 50 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography with EtOAc:hexanes, 1:4, as eluant, yielding (11.739 g, 86%) 5-nitro-2-phenoxy-benzoic acid methyl ester. A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (2.0 g, 7.32 mmol) in 30 mL ethanol and Pd/C (200 mg) were hydrogenated at 40 psi overnight to yield 5-amino-2-phenoxy-benzoic acid methyl ester (1.672 g, 94%). A mixture of 5-amino-2-phenoxy-benzoic acid methyl ester (0.95 g, 3.9 mmol) and hydrazine (4 mL, 80%) was refluxed for 4 h to yield 5-amino-2-phenoxy-benzoic acid hydrazide (0.722 g, 76%). The title compound was prepared from 5-amino-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (CDCl3): 10.81 (s, 1H), 8.15 (s, 1H), 8.0 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.40 (m, 2H), 7.19 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.8, 2H), 6.80 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCCO)OCc1ccccc1
Yield: 27.4 %

Procedure:
A solution of 4-amino-1-butanol (7.68 g) and pyridine (7.00 g) in dichloromethane (100 mL) was chilled in an ice bath and a solution of benzylchloroformate (14.37 g) in dichloromethane (100 mL) was slowly added with stirring over a period of thirty minutes. The ice bath was removed and the reaction was stirred for an additional 16 hours. Hydrochloric acid (1.2 M, 200 mL) was added and phases were separated. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was recrystallized from toluene and dried under vacuum to provide 5.15 g of benzyl (4-hydroxybutyl)carbamate.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:9]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>COCCOC>[C:22]([C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:19]=1[OH:26])[N:9]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Reactant: O=C1CCCC(=O)O1
Solvent: COCCOC
Product: CC(C)(C)c1cc(N(C(=O)CCCC(=O)O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
1.1 g (0.010 mole) of glutaric anhydride, 3.0 g (0.010 mole) of the known compound 4-anilino-2,6-di-t-butylphenol, and 30 ml of 1,2-dimethoxyethane were combined and heated at reflux for 24 hours. The volume of the reaction was reduced by two-thirds under a stream of nitrogen, and the reaction was heated for another 24 hours. The remaining solvent was removed under vacuum on a rotary evaporator. The resulting solid was recrystallized twice from a mixture of benzene and hexane and then twice from a mixture of ethanol and water to give 0.6 g of off-white crystalline 5-(3,5-di-t-butyl-4-hydroxy-N-phenylanilino)- 5-oxopentanoic acid, m.p. 168°-170° C. Analysis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4: Found: % C, 73.2; % H, 8.0; % N, 3.0.
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].[H-].[Na+].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1>CN(C=O)C>[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([CH:48]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:29][CH:28]=2)=[CH:50][CH:51]=1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5.51 g (13.29 mmol) of (4-cyanobenzyl)-triphenylphosphonium chloride in 100 ml of dry DMF under positive nitrogen atmosphere is cooled to 0° C. and 0.50 g (20.77 mmol) of an 80% NaH in oil dispersion is added in o small portions. The suspension is aged for 15 minutes at 0° C. followed by 45 minutes at room temperature to assure complete anion formation. The flask is cooled back to 0° C. and 3.5 g (13.29 mmol) of 4-(2-quinolinylmethyloxy)benzaldehyde in 20 ml of DMF is dropped in over a period of 15 minutes. The reaction is allowed to equilibrate to room temperature and stirred for 2 hours. The resultant mixture is poured into ice water and filtered. The precipitate is dissolved in CH2Cl2, dried, and concentrated in vacuo. The crude product is recrystallized from ether to give 4-(4-(2- quinolinylmethyloxy)styryl)benzonitrile. (M.P. 116° C.-112 ° C.)
Reaction SMILES: [NH2-:1].[Na+].N.[Na].[CH2:5]([C:8]([CH2:12][CH2:13][CH3:14])(Cl)[C:9]#[CH:10])[CH2:6][CH3:7]>C(OCC)C>[CH2:5]([C:8]([NH2:1])([CH2:12][CH2:13][CH3:14])[C:9]#[CH:10])[CH2:6][CH3:7]
Reactant: [NH2-]
Reactant: C#CC(Cl)(CCC)CCC
Agent: N
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Product: C#CC(N)(CCC)CCC
Reaction time: 1 h

Procedure:
To a suspension of sodium amide in liquid ammonia, prepared from 6.9 g of sodium and 250 ml of liquid ammonia, were added 17 g of 1,1-di-n-propyl-1-chloro-2-propyne in 50 ml of anhydrous ethyl ether. The operation of adding the chlorinated derivative lasted one hour. Stirring of the mixture was maintained for 2 hours and then 300 ml of anhydrous ethyl ether were added.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])([O:13][CH3:14])[O:11][CH3:12]>CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:10]([O:13][CH3:14])([O:11][CH3:12])[CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COC(CBr)(OC)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(Cn1cncn1)(OC)c1ccc(Cl)cc1Cl
Yield: 44 %

Procedure:
To a stirred mixture of 19 parts of 1H-1,2,4-triazole and 225 parts of N,N-dimethylformamide are added 8.4 parts of sodium hydride dispersion 78% and stirring is continued till foaming has ceased. Then there are added 29 parts of 1-(2-bromo-1,1-dimethoxyethyl)-2,4-dichlorobenzene and the whole is stirred and refluxed overnight. The reaction mixture is cooled, poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized from petroleumether (activated charcoal), yielding 12.1 parts (44%) of 1-[2-(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-1,2,4-triazole; mp. 87.7° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:27][C:26]2[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[N:4][C:3]=1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(-c2nc(CBr)sc2Br)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
To a solution of 4-(5-Bromo-2-bromomethyl-thiazol-4-yl)-benzonitrile (0.43 g, 1.20 mmol) in 5 ml of anhydrous DMF was added 2,6-difluoro-3-hydroxy-benzamide (0.20 g, 1.20 mmol) and potassium carbonate (0.58 g, 4.20 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (30:70) as the eluent to provide the title compound as a white solid (0.35 g, 66%). 1H NMR (DMSO-d6, 400 MHz): δ 5.57 (s, 2H), 7.13 (m, 1H), 7.44 (m, 1H), 7.89 (br s, 1H), 8.0 (d, J=8.40 Hz, 2H), 8.10 (d, J=8.40 Hz, 2H) and 8.17 (br s, 1H). MS ES+ (450.09), HPLC (method I) Rt=16.127 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:33].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: CCCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: CCCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 3-propyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.940 g; 6.720 mmol), and purification by FC (DCM/MeOH=25/1) afforded 1-chloro-3-propyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.550 g; 49%). LC-MS: tR=1.09 min.; [M+H]+=472.00 g/mol.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[C].[Pd]>[ClH:1].[C:2]1([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C1=C(c2ccccc2)CCNC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C2CCNCC2)cc1
Yield: 95 %

Procedure:
1,2,3,6-Tetrahydro-4-phenylpyridine hydrochloride (200 mg, 1.0 mmol) and 10% palladium-carbon (30 mg) were stirred in methanol (2 ml) for 19 hours in an atmosphere of hydrogen. The reaction solution was filtered and the resulting residue was thoroughly washed with methanol. Then the filtrate and washed solution were combined and evaporated under a reduced pressure to obtain 190 mg of the title compound (0.95 mmol, 93% in yield).