Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:5]2[N:14]=[C:13]([C:15]3[CH:16]=[C:17]([S:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=3[O:21][CH2:22][CH3:23])[NH:12][C:10](=[O:11])[C:6]=2[N:7]([CH3:9])[N:8]=1.C(C(O)(C(O)=O)CC(O)=O)C(O)=O.CO.[ClH:49]>C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[C:5]2[NH:14][C:13]([C:15]3[CH:16]=[C:17]([S:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)(=[O:25])=[O:26])[CH:18]=[CH:19][C:20]=3[O:21][CH2:22][CH3:23])=[N:12][C:10](=[O:11])[C:6]=2[N:7]([CH3:9])[N:8]=1.[ClH:49]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CO
Product: CCCc1nn(C)c2c(=O)nc(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)[nH]c12

Procedure:
Sildenafil citrate (9.5 g) is dissolved in a mixture of ethanol (10 mL) and HCl (1N, 60 mL), then reacted at 50° C. for 10 mins. Under room temperature, the methanol is added for incubating over night and crystallization. Then, the crystal is filtrated to obtain precipitate of Sildenafil HCl (6.4 g) for use.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Li]CCCC.[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].ICC>C1COCC1>[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:1][CH3:2])[C:21]([OH:23])=[O:22]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)Cc1ccccc1I
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1ccccc1I
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of diisopropylamine (5.6 mL, 40 mmol) in dry THF (60 mL) at -10° C. was added 1.6M BuLi (25 mL, 40 mmol). After 30 min, a solution of 2-iodophenylacetic acid (5.24 g, 20 mmol) in THF (20 mL) was slowly added. The solution was stirred for 1 h, at which point iodoethane (1.6 mL, 117 mmol) was added. After 2 h at r.t. the reaction was quenched with 0.5M NH4OAc solution and 6M HCl (10mL) and the product was extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to give an oily residue which was purified by flash chromatography (15:85 EtOAc:hexane containing 5% AcOH) to give 4.37 g of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[OH-].[Na+].Cl[CH2:59][CH:60]([OH:63])[CH2:61][OH:62]>>[O:63]1[CH2:59][CH:60]1[CH2:61][O:62][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(OCC3CO3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine with sodium hydroxide and 3-chloro-1,2-propanediol.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:36][CH2:35][CH2:34][CH:33](Br)[CH2:32][C:31]=2[CH:38]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:36][CH2:35][CH2:34][CH:33]([O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[C:32](=[O:7])[C:31]=2[CH:38]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Reactant: BrC1CCOc2ccc(OCc3ccccc3)cc2C1
Product: COC(=O)c1cccc(OC2CCOc3ccc(OCc4ccccc4)cc3C2=O)c1

Procedure:
By the method of Example 27, substituting the phenol with a molar equivalent of methyl 3-hydroxybenzoate, 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxepin-(5(2H)-one (17.3 g) was converted to present title product, 10.9 g, m.p. 134°-136° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:29])=[O:28])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:28])=[O:29])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Yield: 82.6 %

Procedure:
A solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (4.05 g, 9.61 mmol) in a mixture of ethanol (250 ml) and ethyl acetate (250 ml) was hydrogenated over 10% palladium on activated carbon (0.9 g) and under 1 atmosphere of hydrogen for 1 h. The catalyst was then filtered and the solvent was evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave 2.63 g (82% yield) of the title ester as white crystals; mp 186–189° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.42 (3H, t, J=7.0 Hz, CH3), 1.6–1.63 (1H, m, CH), 2.3–2.6 (3H, m, CH2 and CH), 3.2 (1H, m, CH), 3.55–3.75 (2H, m, CH2), 3.65 (3H, s, NCH3), 3.95–4.05 (1H, m, CH), 4.44 (2H, q, J=7.0 Hz, OCH2). HRMS (FAB POS) calculated for C12H18N3O6S [M+H+]: 332.091632. found: 332.092342.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[C:6](OC)=[O:7].O.[NH2:21][NH2:22]>C(O)C>[NH2:21][N:22]1[CH2:3][CH:2]([OH:1])[CH2:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[C:6]1=[O:7]
Reactant: COC(=O)C(CC1CO1)c1ccccc1C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN1CC(O)CC(c2ccccc2C(F)(F)F)C1=O

Procedure:
Methyl 3-oxiranyl-2-(2-trifluoromethylphenyl)propionate (2.61 g) was dissolved in ethanol (20 mL). Hydrazine monohydrate (2.3 mL) was added at room temperature, and the mixture was reacted for 24 hours. Concentration under reduced pressure gave an oil which was partitioned with methylene chloride and water. The aqueous layer was extracted with methylene chloride four times. After drying over magnesium sulfate, concentration under reduced pressure gave the title compound (1.8 g) as a pale yellow solid.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.C(OCC)(=O)C>[C:7]1([C:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCO1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCC(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A solution of butyrolactone (10.5 g, 122 mmol) in anhydrous THF (500 mL) was chilled to −78° C. under nitrogen atmosphere. Phenylmagnesium bromide (3M in ether, 100 mL, 300 mmol) was added via syringe at a rate that keeps the reaction temperature below −40° C. After the addition was complete, the reaction was stirred at −78° C. for two hours then the cold bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The solution was then re-cooled to 10° C. on an ice bath before adding 2N aqueous ammonium chloride (200 mL) to quench the reaction. The resulting mixture was diluted with ethyl acetate (1 L) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. Evaporation of solvent from the filtrate afforded crude 1,1-diphenylbutan-1,4-diol as an oil, which was purified by chromatography on silica gel, eluting with a gradient of 50% to 60% ethyl acetate in hexane. Evaporation of solvents gave a colorless solid that was triturated with hexane and collected by filtration to afford 18.2 g of pure 1,1-diphenylbutan-1,4-diol. MS (EI+): 243 (M+1); 225 (M-H2O+1).
Reaction SMILES: C(N)C1C=CC=CC=1.C(O)(=O)C.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:31][O:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][N:42]([CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]2[C:59]3[C:60]4[C:65]([NH:66][C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:64][CH:63]=[CH:62][CH:61]=4)CC2C=CC=CC=2)=[CH:37][CH:36]=[CH:35][CH:34]=1>C1OCCOC1>[CH3:31][O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][NH:42][CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[NH:66][C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:59]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Reaction time: 8 h

Procedure:
To 5 ml dioxane 1.4 g (0.0054 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 0.07 g (0.00125 moles) of acetic acid and 0.5 g (0.0021 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 24 hrs (TLC control for checking conversion to N-benzyl carvedilol). To this reaction mixture, a second lot of 0.07 g (0.00125 moles) of acetic acid and 0.5 g (0.0021 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is further heated to 70-75° C. for 24 hrs (TLC control for checking conversion to N-benzyl carvedilol). Dioxane is distilled off from the reaction mixture and to the concentrated reaction mixture 10 ml ethylacetate is added and subjected the reaction mass to hydrogenation. To this solution of N-benzyl carvedilol in ethylacetate, (0.14 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 8 hours. The reaction mixture is filtered and the filtrate is washed with 12-15% v/v aqueous ammonia (1 volume w. r .t. to the carbazole). The product enriched organic layer is separated and concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (2 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (1 ml) and toluene (1 ml) to obtain carvedilol (0.9 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (0.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH3:10][CH2:11][CH2:12][CH2:13][CH:14]([CH:16]([CH3:18])C)C.[CH3:19][CH2:20]CC(CC(C)C)C.CC(CC(C(C)C)C)C>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:19][CH2:20][CH2:18][CH2:16][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: COc1ccccc1O
Reactant: CCCCC(C)C(C)C
Reactant: CCCC(C)CC(C)C
Agent: CC(C)CC(C)C(C)C
Product: CCCCCCCCCc1ccc(O)c(OC)c1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
2-Methoxyphenol (5 mol, 621 g), dry Amberlyst 15 (50 g) and tripropylene (5.5 mol, 694 g, 951 ml) were placed in a 3000 ml 3N RBF. The mixture was heated and maintained at 120° C. under vigorous stirring for 7 hrs. After cooling to ambient temperature, the reaction mixture was filtered and distilled to obtain 2-methoxy-4-nonylphenol in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]2[CH2:12][CH2:11][CH:10]2CC(O)=O)[N:5]=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][C@@H:22]2[CH2:24][C@@H:20]([C:21]2([CH3:26])[CH3:25])[C@H:19]1[CH3:27].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1.CN(C)[CH:57]=[O:58]>C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2([C:57]([NH:54][CH2:53][C:50]3[CH:51]=[CH:52][N:47]=[CH:48][CH:49]=3)=[O:58])[CH2:12][CH2:11][CH2:10]2)[N:5]=[CH:4][C:3]=1[NH:17][C@@H:18]1[CH2:23][C@@H:22]2[CH2:24][C@@H:20]([C:21]2([CH3:25])[CH3:26])[C@H:19]1[CH3:27]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCC3CC(=O)O)c(=O)c1Br)C2(C)C
Reactant: CN(C)C=O
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3(C(=O)NCc4ccncc4)CCC3)c(=O)c1Br)C2(C)C
Yield: 41 %

Procedure:
2-(5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)cyclobutaneacetic acid (108.7 mg, 0.256 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98.2 mg, 0.512 mmol), 1-hydroxybenzotriazole anhydride (10.8 mg, 0.08 mmol) and triethylamine (71.4 μL, 0.512 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (51.3 μL, 0.512 mmol) at room temperature for 22 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=20/1) to give the desired product (53.8 mg, 41% yield).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-:28].[Na+].[OH:30]O.CC(O)=O>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26](=[O:30])[NH2:27])=[CH:24][CH:25]=2)[C:14]([C:17]([NH2:18])=[O:28])=[N:15][CH:16]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)cc1
Reactant: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-cyanophenylamino)pyrazine-2-carbonitrile (36 mg, 0.100 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (40 mg). MS 406.0 (M+H); UV 204.2, 267.1, 320.0 nm; t 0.365 min.
Reaction SMILES: C(OC[CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:12][S:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.[CH3:29][OH:30].C(Cl)Cl>C(Cl)Cl>[OH:30][CH2:29][SH:11]1[CH2:10][CH2:15][O:14][CH:13]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:12]1
Reactant: CO
Reactant: Cc1cn(C2CSC(COCc3ccccc3)CO2)c(=O)[nH]c1=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1cn(C2C[SH](CO)CCO2)c(=O)[nH]c1=O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
1-(5-Benzyloxymethyl-1,4-oxathian-2-yl)thymine (0.14 g) was dissolved in methylene chloride (10 ml), and the solution cooled to -78° C. To the solution, 1M boron trichloride (4.1 ml) was added dropwise, and the mixture stirred at the same temperature for 4 hours. After adding a mixed solution of methanol-methylene chloride (1/1, 8 ml), the temperature of the reaction mixture was raised to room temperature. Upon concentrating the reaction mixture under reduced pressure, the resultant dark brown oil was purified on a silica gel column (eluent: chloroform/methanol=20/1) to obtain the desired product (0.07 g) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH2:11][CH3:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1c(F)cc(Cl)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOc1c(F)cc(Cl)c([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of 30-3 (48.6 g, 192 mmol) in concentrated H2SO4 (240 mL) stirred at room temperature was added HNO3 (19 mL) dropwise. The mixture was allowed to stir at room temperature for two hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate (3×800 mL). The organic layer was combined and concentrated under vacuum to get a crude product which was purified on silica gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 1:1) to afford 30-4 (22.9 g, 40%) as a yellow solid. LRMS: calc 296.9 and found: 297.9 [M+1].
Reaction SMILES: [Na].CO[CH:4]([CH3:7])[C:5]#[N:6].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]2[O:20][CH2:19][O:18][C:17]=12)[CH:13]=O.[CH3:21][OH:22]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]2[O:20][CH2:19][O:18][C:17]=12)[CH:13]=[C:4]([CH2:7][O:22][CH3:21])[C:5]#[N:6]
Reactant: COC(C)C#N
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: CO
Agent: [Na]
Product: COCC(C#N)=Cc1cc(OC)c2c(c1)OCO2

Procedure:
3.8 g. of sodium were dissolved in 120 ml. of methanol under reflux. 56 g. of methoxypropionitrile and 60 g. of 3-methoxy-4,5-methylenedioxybenzaldehyde were then added and refluxed in the methanol mixture for 5 hours. Upon chilling, 3-methoxy-4,5-methylenedioxy-α-methoxymethyl-cinnamonitrile crystallized in needles of m.p. = 115°, in a yield of 68 g. = 83 percent. A sample of analysis was recrystallized from methanol, m.p. 115.5°-116.5°.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Br:17])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:18][CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]>>[Cl-:18].[NH2:1][C:2]1[N:6]([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Br:17])=[CH:10][C:4]=2[N+:3]=1[CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:28])([F:29])[F:30]
Reactant: FC(F)(F)c1ccccc1SCCl
Reactant: Nc1nc2ccc(-c3ccccc3Br)cc2[nH]1
Product: Nc1n(CSc2ccccc2C(F)(F)F)c2ccc(-c3ccccc3Br)cc2[n+]1CSc1ccccc1C(F)(F)F
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5-(2-bromophenyl)benzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-trifluoromethylphenyl chloromethyl sulfide, the title compound is obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:33][CH2:34][CH3:35]>>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:33][CH2:34][CH3:35])[C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 0.75 h

Procedure:
A solution of 5-cyclohexyl-1,3-dihydro-3(R,S)-[(benzyl oxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (Intemediate 1, step 2, 2 g) in anhydrous dimethylfomamide (15 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.22 g of a 55-60% dispersion in mineral oil), at 0° C. After 45 min at 0° C., 1-iodopropane (0.55 ml) was added in one portion and the solution allowed to reach ambient temperature and stirred overnight. After this time the solvent was removed under reduced pressure, and the crude residue partitioned between water (25 ml) and dichloromethane (25 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (3×25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (1.74 g) as a solid. mp 160°-163° C.; 1H NMR (360 MHz, CDCl3)δ0.82 (3H, t, J=10.5 Hz), 0.94-1.48 (5H, m), 1.50-1.76 (5H, m), 1.79-1.90 (1H, m), 1.96-2,08 (1H, m), 2.70-2,84 (1H, m), 3.46-3.59 (1H, m), 4.22-4.35 (1H, m), 5.06-5.16 (3H, m), 5.07 (1H, d, J=12.0 Hz), 7.21-7.40 (7H, m), 7.44-7.59 (2H, m).
Reaction SMILES: O1CCCC1.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]1[C:20]([O:22]C)=[O:21].[OH-].[Li+].Cl>O>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([OH:6])[CH:8]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flask, tetrahydrofuran (1.01 mL) was added to 1-tert-butyl 3-methyl 4-hydroxypiperidine-1,3-dicarboxylate (0.079 g, 0.303 mmol). A solution of lithium hydroxide (0.0254 g, 0.607 mmol) in water (0.505 mL) was added to the reaction. The reaction was allowed to stir at room temperature for 4 hrs. Using 1N hydrochloric acid, the reaction was neutralized to pH 6 and was concentrated in vacuo. The crude product was purified using prep LC/MS. LC-MS: 190.1 [M−t-butyl]. LC/MS RT=2.58 min.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:27]2[C:28]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:24]=[CH:25][CH:26]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc2ccc3c(-c4cccc5ccccc45)ccc4ccc1c2c43
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 27.2 g (75.6 mmol) of 1,6-dibromopyrene, 13 g (75.6 mmol) of naphthalen-1-ylboronic acid, 0.87 g(0.756 mmol) of Tetrakis(triphenylphosphine)Palladium, 57 ml of 2M Na2CO3, 120 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 14 g (yield 45.5%) of beige product which was recrystallized from 1,4-Dioxane.