Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.C([BH-](CC)CC)C.[Li+].C(=O)(O)[O-].[Na+].OO>C1COCC1>[OH:1][CH:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: O=C([O-])O
Agent: OO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
93 g of di-tert-butyl (S)-5-oxopyrrolidine-1,2-dicarboxylate were dissolved in 600 ml of THF and cooled to −78° C. 392 ml of a 1N solution of lithium triethylborohydride in THF were added dropwise over the course of 90 min. The mixture was then stirred at −70° C. for 30 min. Subsequently, 240 ml of saturated sodium bicarbonate solution were added dropwise to the solution. The temperature was allowed to rise to −15° C. and then 160 ml of a 30% strength hydrogen peroxide solution were added dropwise. The mixture was then stirred at room temperature for 30 min. The phases were then separated, and the organic phase was concentrated in vacuo. The residue was taken up in 500 ml of tert-butyl methyl ether and washed 3 times with 300 ml of a 10% strength solution of sodium bicarbonate in water each time and twice with 300 ml of a saturated sodium chloride solution each time. The organic phase was dried with sodium sulfate, and the solvents were removed in vacuo. The crude product obtained in this way was employed without further purification in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:24])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Product: O=C(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (45%, crystals. HPLC-MS m/z=369.1 (M+1), Rt: 4.3 min.
Reaction SMILES: O.Cl.[NH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][N:6]=1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:20]([O:19][C:17](=[O:16])[NH:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][N:6]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: NCc1n[nH]c(=O)c2ccccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1n[nH]c(=O)c2ccccc12
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A mixture of 4-(aminomethyl)phthalazin-1(2H)-one hydrochloride hydrate (0.300 g, 1.31 mmol), BOC2O (0.314 g, 1.44 mmol), and triethylamine (0.46 mL, 3.3 mmol) in DCM (4.5 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and chromatographed (70% EtOAc/hexanes) to give 313 mg of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.62-12.50 (m, 1H), 8.30-8.22 (m, 1H), 8.01 (s, 1H), 7.92 (dd, J=11.0, 4.1, 1H), 7.89-7.80 (m, 1H), 7.41-7.26 (m, 1H), 4.44 (d, J=5.8, 2H), 1.39 (s, 9H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[CH:9][C:8](=[O:21])[NH:7][C:6]1=[S:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:47]([O:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]1[N:5]([CH2:4][CH2:3][NH:2][C:56](=[O:57])[CH2:55][NH:54][C:52](=[O:53])[O:51][C:47]([CH3:48])([CH3:49])[CH3:50])[C:6](=[S:22])[NH:7][C:8](=[O:21])[CH:9]=1
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCNC(=O)CNC(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of 1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one hydrochloride (123 mg, 0.4 mmol)(the product of Example 6) in dry methylene chloride (4 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (182 mg, 0.48 mmol) and tert-butoxycarbonylamino-acetic acid (70 mg, 0.4 mmol) and diisoproplyethylamine (336 mg, 1.6 mmol). After stirring overnight at RT the reaction mixture was concentrated under reduced pressure and the residue purified by preparative thin layer chromatography (1:1 petroleum ether:ethyl acetate) to provide tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate (120 mg, 65%).
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.[NH:31]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[OH:36][C@H:33]1[CH2:34][CH2:35][N:31]([C:8](/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)=[O:30])[CH2:32]1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: O[C@H]1CCNC1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CC[C@H](O)C2)s1

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 0.1 g, 0.18 mmol), (S)-pyrrolidin-3-ol (0.016 g, 0.18 mmol) and Hunig's base (0.023 g, 018 mmol) in dry acetonitrile (5 mL) was heated to 60° C. for three hours. After cooling, the mixture was diluted with CH2Cl2 (50 mL) and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and dried. After evaporation under reduced pressure, the residue was chromatographed over silica using CH2Cl2 and then 2% MeOH/CH2Cl2 to give the titled compound. 1H NMR (CDCl3) δ ppm 1.99 (2H), 2.20 (3H), 3.40-3.70 (4H), 4.42 (1H), 6.60 (1H), 7.20-7.50 (3H); MS (ESI) m/z 434(M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S.C(OCC)(=O)C>[Cl:12][CH2:13][CH2:14][C:15]([C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9])=[O:16]
Reactant: Cc1csc2ccc(F)cc12
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: S=C=S
Product: Cc1c(C(=O)CCCl)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-fluoro-3-methylbenzo[b]thiophene (9.97 g) and 3-chloropropionyl chloride (7.45 ml) in carbon disulfide (100 ml) was added AlCl3 (16.00 g) at 0° C. The mixture was stirred at room temperature for 2 hours, poured onto crushed ice, and diluted with ethyl acetate. The extract was washed with 1N HCl, water and brine, dried over MgSO4, and concentrated. The residue was washed with ethanol and hexane to give the titled compound as colorless crystals (12.75 g).
Reaction SMILES: C1(N)CC1.[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:7]=1.[F:19][C@@H:20]1[C@@H:24]([CH2:25][OH:26])[O:23][C@@H:22](N2C=C(C)C(=O)NC2=O)[CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>CN(C=O)C.CS(C)=O>[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:7]=1.[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[C@@H:22]2[O:23][C@H:24]([CH2:25][OH:26])[C@@H:20]([F:19])[CH2:21]2)=[C:8]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:7]=1
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: NC1CC1
Agent: Nc1nc(NC2CC2)c2nc[nH]c2n1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 37 °C
Reaction time: 552 h
Yield: 72.1 %

Procedure:
2-Amino-6-(cyclopropylamino)-9H-purine was prepared by the displacement of the clorine group on 2-amino-6-chloropurine (Aldrich Chemical Company) by cyclopropylamine (Aldrich Chemical Company) 2-Amino-6-(cyclopropylamino)-9H-purine (0.50 g, 2.7 mmoles) was dissolved in DMF (5 ml) and DMSO (5 ml). 3'-Deoxy-3'-fluorothymidine (0.81 g, 3.3 mmoles) and potassium phosphate buffer (10 mM, 30 ml), pH 6.8, containing 0.04% potassium azide were added. Purified purine nucleoside phosphorylase (7500 I.U.) and thymidine phosphorylase (37.50 I.U.) adsorbed onto 5 ml DEAE-cellulose resin were added to the reaction and the suspension stirred at 37° C. After 23 days, the reaction was filtered and the filtrate applied to a series of coupled columns. The initial column contained AG1-X2 (OH-form, 2.5×10 cm) while the second column contained Amberlite XAD-2 resin (2.5×20 cm). After sample application, the columns were washed with water (700 ml) and the product eluted with methanol. Product-containing fractions were then flash chromatographed down a silica gel column (4.8×24 cm) using ethyl acetate:methanol (95:5) as eluant. The product was further purified by flash chromatography down a silica gel column (2.5×40 cm) using dichloromethane:methanol(9:1) as eluant. Solvent was evaporated in vacuo and lyophilisation yielded 0.30 g of 2-amino-6-(cyclopropyl-amino)-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (33%): mp 75° C.;
Reaction SMILES: C(C1[CH:24]=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.CC1C(CCl)=C(C)[O:28][N:27]=1>>[CH3:4][C:5]1[C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[C:23]([CH3:24])[O:28][N:27]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: Cc1noc(C)c1CCl
Product: COCOc1cc(SCc2c(C)noc2C)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 3,5-dimethyl-4-chloromethyl-1,2-oxazole instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.FC1C=CC(C=O)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]
Yield: 99.1 %

Procedure:
A mixture of 4-amino-3-nitrophenol (1.54 g; 10.0 mmol), 4-fluorobenzaldehyde (1.05 mL; 10.0 mmol) and Cs2CO3 (3.91 g; 12.0 mmol) in anhydrous dimethylsulfoxide (10 mL) was heated at 80 degrees Centigrade, under nitrogen. An additional portion of 4-fluorobenzaldehyde (0.050 mL; 0.50 mmol) was added after 1 hour and heating was continued. After 2 hours the mixture was cooled, poured into water and extracted three times with ethyl acetate. Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexanes), affording 2.56 g of 4-[(4-Amino-3-nitrophenyl)oxy]benzaldehyde as an orange solid. 1H NMR (400 MHz, CDCl3) delta ppm 6.11 (br. s, 2H), 6.90 (d, J=9.1 Hz, 1H), 7.04 (m, 2H), 7.20 (dd, J=9.0, 2.8 Hz, 1H), 7.86 (m, 2H), 7.89 (d, J=2.7 Hz, 1H), 9.93 (s, 1H) ppm. (M+H) 259, 2.33 min (LC/MS method A).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:19])[CH:3]=1.[CH3:20][S-:21].[Na+].CN(C)C(=O)C>>[CH3:19][C:4]1[CH:3]=[C:2]([S:21][CH3:20])[N:7]=[CH:6][C:5]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(F)ncc1-c1ccc2cc(N)ncc2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CSc1cc(C)c(-c2ccc3cc(N)ncc3c2)cn1

Procedure:
A mixture of 7-(6-fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine (389 mg; 1.536 mmol) and sodium thiomethoxide (344 mg; 4.66253 mmol) in N,N-dimethylacetamide (3.0 mL; 32 mmol) was subjected to microwave irradiation at 150° C. for 30 minutes to produce a mixture of the desired product and the demethylated thiol product. To the reaction mixture was added a 10 mol/L solution sodium hydroxide in water (1.5 mL; 15 mmol) followed by iodomethane (0.10 mL; 1.6 mmol). The reaction mixture was stirred at room temperature for 4 hours, and then additional iodomethane (0.05 mL; 0.8 mmol) was added. After an additional 4 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield 419.9 mg of the title compound, which was carried forward without purification. LCMS (ESI): M+H=282.2; 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.30 (s, 1H), 7.79 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.27 (s, 1H), 6.66 (s, 1H), 5.98 (s, 2H), 2.54 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl-].[Li+].CN(C)C=O.CS([Cl:37])(=O)=O>CCCCCC.C(OCC)(=O)C.CCOCC.O>[Cl:37][CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CO)C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Reaction time: 5 h
Yield: 88 %

Procedure:
To a mixture of ethyl 14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate (71.0 mg, 0.20 mmol), τ-collidine (26.7 mg, 0.22 mmol), lithium chloride (8.5 mg, 0.20 mmol), and dimethylformamide (1 ml) was added with stirring methanesulfonyl chloride (25.2 mg, 0.22 mmol) on an ice-water bath and under nitrogen atmosphere. The stirring was continued at the same temperature for 5 hours. After confirmation of disappearance of the starting material, water and ether were added to the reaction mixture. The organic layer was separated, washed with water, dried over MgSO4, and condensed to give a residue, which was then subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate (10:1)). Relevant fractions gave the aimed ethyl 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate (64.6 mg, 86% ). ##STR46##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: N#Cc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-cyano-phenylboronic acid to give 4-[3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 312(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[N:7]1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CC([O-])(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1COCC1.CS(C)=O.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[O:13][C:12]([C:8]3[N:9]=[C:10]([CH3:11])[N:6]([CH2:5][C:4]4[CH:27]=[CH:28][CH:29]=[C:2]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH:3]=4)[N:7]=3)=[N:16][N:15]=2)=[CH:18][CH:19]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)nn1Cc1cccc(Br)c1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1nc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)nn1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 4.3 %

Procedure:
A mixture of 2-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazole (100 mg, 0.22 mmol), 1-methylpiperazine (37 μL, 0.33 mmol), NaOtBu (46.7 mg, 0.48 mmol), dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (10.3 mg, 0.022 mmol) and chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(17.7 mg, 0.022 mmol) in THF (1 mL) was degassed (freeze-pump-thaw, under N2). The reaction mixture was stirred at 65° C. for 2 h, and then the solvent was removed under reduced pressure. The crude reaction mixture was dissolved in DMSO and was purified by pre-HPLC (Mobile phase: A=0.1% CF3CO2H/H2O, B=MeCN; Gradient: B=30%-70% in 12 min; Column: Waters C18) to afford 2-(4-(tert-butyl)phenyl)-5-(5-methyl-1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-1,3,4-oxadiazole (4.5 mg, 4.3%) as a white solid. MS (ES+) C27H33N7O requires: 471. found: 472 [M+H]+; 1H-NMR (500 MHz, CDCl3) δ ppm 8.13 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.25 (d, J=7.9 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.78 (t, J=2.0 Hz 1H), 6.70 (d, J=7.8 Hz, 1H), 5.38 (s, 2H), 3.27-3.20 (m, 4H), 2.67-2.58 (m, 4H), 2.51 (s, 3H), 2.40-2.37 (m, 3H), (1.36 (s, 9H).
Reaction SMILES: [CH:1]1[C:17]2[C:5](=[C:6]3[CH:51]=[CH:50][CH:49]=[CH:48][C:7]3=[C:8]3[C:16]=2[CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:39]=[CH:38][C:32]([C:33](OCC)=[O:34])=[CH:31][CH:30]=2)[C:14]2[C:9]3=[C:10]3[CH:47]=[CH:46][CH:45]=[CH:44][C:11]3=[C:12]3[CH:43]=[CH:42][CH:41]=[CH:40][C:13]3=2)[CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH:40]1[C:13]2[C:12](=[C:11]3[CH:44]=[CH:45][CH:46]=[CH:47][C:10]3=[C:9]3[C:14]=2[CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:33][OH:34])=[CH:38][CH:39]=2)[C:16]2[C:8]3=[C:7]3[CH:48]=[CH:49][CH:50]=[CH:51][C:6]3=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]3=2)[CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Ethyl 4-[[10-(17H-tetrabenzo[a,c,g,i]fluoren-17-yl)decyl]oxy]benzoate (9) (2.03 g, 3.03 mmol) was charged to an oven-dried flask along with freshly distilled THF (40 mL) and the resultant solution stirred at room temperature under an atmosphere of nitrogen. Diisobutyl aluminum hydride (12.0 mL, 12.00 mmol) was added via syringe and the resulting mixture stirred at room temperature under nitrogen for 2 hours, after which time, TLC analysis showed that all the starting material had been consumed. The reaction was quenched with the addition of HCl (2 M, 40 mL), and the organic products were extracted with ethyl acetate (3×50 mL), washed with saturated Na2CO3 (40 mL) and water (40 mL), and dried over MgSO4. Excess solvent was removed in vacuo to yield 4-[[10-(17H-tetrabenzo[a,c,g,i]fluoren-17-yl)decyl]oxy]-benzenemethanol (1.7765 g, 2.82 mmol, 94%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14].N(CCO)(CCO)CCO.[NH4+].[Cl-]>O1CCCC1.O.CN(C=O)C>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCOCCN1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(CCOCCO)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
1-[2-(2-hydroxyethoxyl)ethyl]piperizine (12.36 g, 71.8 mmol) in tetrahydrofuran (THF) (60 mL) was added to bromoacetic acid tert-butyl ester (14.00 g, 71.8 mmol) in THF (10 mL). Triethanolamine (TEA) (22 mL, 143.5 mmol) was then added. DMF (30 mL) was added to the mixture to dissolve any solids. The reaction mixture was stirred at 50° C. for approximately 16 hours (overnight). NH4Cl (20 g, 370 mmol) and water (20 mL) were added to the mixture. The organic layer was extracted with ethylacetate (EtOAc). The organic layers were combined, concentrated, and purified by silica gel column chromatography (5-10% methanol (MeOH) in ethylacetate) to give of the target product as an oil (16 g, 77% yield). 1H NMR (400 MHz, CDCl3) (ppm) 3.70-3.55 (m, 7H), 3.09 (s, 2H), 2.52-2.80 (m, 10H), 1.44 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])([O-])=O>C(O)(C)C.C(N(CC)CC)C.[Pd]>[OH:26][C:13]1[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Yield: 77 %

Procedure:
When using the general procedure of Example 5, a 23% by weight suspension of 2-nitro-2'-hydroxy-3',5'-di-tert-butylazobenzene in isopropanol/triethylamine (1/0.18) was hydrogenated at 45° C. at 1 atmosphere pressure for 3 hours in the presence of 3% of a 5% palladium on charcoal catalyst the above noted product was obtained in a yield of 77%.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[SH:6][C:7]1[C:8]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:9]=2[S:10][C:11]=1[C:12]([NH2:14])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:14][C:12]([C:11]1[S:10][C:9]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:8]=2[C:7]=1[S:6][CH2:2][C:3]([OH:5])=[O:4])=[O:13]
Reactant: O=C(O)CBr
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2sc(C(N)=O)c(SCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
Bromoacetic acid (72 mg, 0.52 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (50 mg, 0.21 mmol) in 3 mL of THF followed by NaHCO3 (219 mg, 2.60 mmol) and the reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane provides [[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]acetic acid in 54% yield; mp=126°-127° C.