Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([OH:10])=[O:9]>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[OH:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:14]=1)[C:8]([O-:10])=[O:9]
Reactant: CCNCC
Reactant: O=C(O)C(O)CCc1ccc(-c2ccccc2Cl)cc1
Solvent: CCCCCC
Product: CC[NH2+]CC
Product: O=C([O-])C(O)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyric acid (0.10 moles) in 100 ml. of n-hexane at 0°C. The precipitated diethylammonium salt is collected on a filter washed with n-hexane and dried in a vacuum desiccator to obtain α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyric acid, diethylammonium salt.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.F[B-](F)(F)F.[Li+].[C:16](#[N:18])[CH3:17].[C:19]([OH:28])(=[O:27])[C@@H:20]([C@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21].[CH2:29]([OH:31])[CH3:30]>O>[C:24]([C@@H:22]([C@H:20]([C:19]([OH:28])=[O:27])[OH:21])[OH:23])([OH:26])=[O:25].[S:1]1[C:9]2[CH2:8][CH2:7][N:6]([CH2:20][C@@H:22]([OH:23])[CH2:24][O:26][C:4]3[CH:9]=[CH:8][CH:7]=[C:17]([C:16]4[C:30]5[S:1][CH:2]=[CH:3][C:29]=5[O:31][N:18]=4)[CH:5]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CC#N
Reactant: CCO
Reactant: c1cc2c(s1)CCNC2
Agent: F[B-](F)(F)F
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Li+]
Solvent: O
Product: O[C@@H](COc1cccc(-c2noc3ccsc23)c1)CN1CCc2sccc2C1

Procedure:
Stir a solution of the example 4 epoxide (0.79 g, 0.0029 mol), 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine free base (0.40 g, 0.0029 mol), lithium tetrafluoroborate (0.27 g, 0.0029 mol) and acetonitrile (50 mL) overnight at room temperature. Pour into water (300 mL) and extract with ethyl acetate. Dry (Na2SO4), filter and concentrate the organic phase, and purify the residue by flash chromatography (silica gel, elute with 3% methanol in dichloromethane) to afford a yellow oil. Dissolve the oil in ethanol, treat with L-tartaric acid (1 molar equivalent), heat to afford a solution, and cool and collect the title compound (0.34 g, 21%) as crystals, m.p. 81–83° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13](O)=[CH:12]2.IC.C(OCC)(=O)C>CC(C)=O>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:4][CH3:1])=[CH:14][N:15]=2)[N:10]=1
Reactant: COc1ccc2ncc(O)cc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cnc2ccc(OC)nc2c1
Reaction time: 4 h
Yield: 54.6 %

Procedure:
Potassium carbonate (13.84 g, 100.1 mmol, 2.0 eq) is added at room temperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol (9.8 g, 50.06 mmol, 1.0 eq) in acetone (300 mL), followed by iodomethane (3.74 mL, 60.1 mmol, 1.2 eq). After 4 hours stirring under reflux conditions, the solid is removed by filtration and the filtrate is concentrated to give a residue that is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 6:1, v/v) to afford 2,7-dimethoxy-[1,5]naphthyridine as a yellow solid (5.2 g, 52% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(N2CCCC2=O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Yield: 51.3 %

Procedure:
A stirred mixture of 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (D12, 50 g, 0.20 mole) and 4-boronobenzoic acid (32 g, 0.20 mole) in DME (500 ml) was treated with a solution of sodium carbonate (94 g, 0.88 mole) in water (500 ml), then de-gassed by bubbling argon through for 0.25 hrs. Tetrakis (triphenylphosphine)palladium (0) (5 g) was added and the mixture heated under reflux for 22 hours, then allowed to cool and concentrated in vacuo to approx. 50% volume. The aqueous residue was diluted with water to approx. 1000 ml, washed with ethyl acetate, then acidified with conc. HCl acid. The precipitate was filtered off, washed with water, dried and recrystallised from ethanol to afford the title compound as a cream solid (30.3 g, 52%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:3]=2)=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccc(Cl)cc2)c1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1

Procedure:
The title compound was prepared 2-chloro-6-(4-chloro-phenyl)-4-trifluoromethyl-pyridine (example A.16) (10.14 g, 35 mmol) and commercially available 4-iodo-imidazole (8.081 g, 42 mmol) according to the general procedure IVa. Obtained as a white solid (2.80 g, 18%). MS (ISP) 450.0 [(M+H)+] and 452 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].COCCCOCCCO.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CN(C)C1C=CC=CC=1>>[CH3:10][O:9][C:3]1[C:4]([CH3:8])=[N:5][CH:6]=[CH:7][C:2]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: COc1c(Cl)ccnc1C
Reactant: C1CNCCN1
Agent: COCCCOCCCO
Solvent: CN(C)c1ccccc1
Product: COc1c(N2CCNCC2)ccnc1C
Temperature: 140 °C
Reaction time: 72 h
Yield: 94.1 %

Procedure:
4-Chloro-3-methoxy-2-methyl-pyridine (0.47 g, 3 mmol) was mixed with dipropyleneglycolmonomethylether (3 ml), piperazine (1.1 g, 7.2 mmol) and N,N-dimethylaniline (0.36 g, 3 mmol) and stirred at 140° C. for 72 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (prepacked silica column, gradient ethyl acetate/methanol with the addition of 1% ammonia). The raw product was dissolved in 1M NaOH and extracted with a mixture of diethylether, dichloromethane and ethylacetate (1:1:1) several times. The combined organic phases were washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure to yield 585 mg of a yellow solid (2.8 g, 94%). MS (APCI): m/z=208.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].ClC(Cl)(Cl)C(O)=O.[N-:19]=[N+]=[N-].[Na+]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:19][C:6]2=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2c1CCC2=O
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Product: Cc1cccc2c1CCNC2=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 4.7 g (32.2 mmol) of 2,3-dihydro-4-methyl-1H-inden-1-one and 53 g of trichloroacetic acid was heated to 65°. To the resulting solution was added 4.2 g (64.4 mmol) of sodium azide and the mixture was kept at 65° for 18 hours. An additional 1.0 g of sodium azide was then added and heating continued for another four hours. The mixture was diluted with 200 ml of ice water and extracted with ether. The ether extracts were washed with water, saturated sodium hydrogen carbonate, dried (MgSO4), and concentrated. The residue was chromatographed (SiO2, ether to ether/methanol 95/5). The resulting product was recrystallized from toluene to give 2.45 g (47%) of product; mp 141°-143°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[C:32](=[O:33])[CH2:31][CH2:30][C@H:29]1[C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:58]([NH:60][C@H:61]([C:64](O)=[O:65])[CH2:62][OH:63])=[O:59])[CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH:11][C:62](=[O:63])[C@H:61]([CH2:64][OH:65])[NH:60][C:58](=[O:59])[C@H:47]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[NH:46][C:44](=[O:45])[C@H:37]([CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)[NH:36][C:34](=[O:35])[C@@H:29]1[CH2:30][CH2:31][C:32](=[O:33])[NH:28]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CO)C(=O)O)N1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
O-Benzyl-L-tyrosine benzyl ester (VIII) hydrochloride (0.397 g) and L-pyroglutamyl-L-histidyl-L-tryptophyl-L-serine (VII) (0.539 g) in dry dimethylformamide (50 ml) is treated with triethylamine (0.14 ml) and dicyclohexylcarbodiimide (0.227 g) in dry dimethylformamdie (5 ml) at 0° C. After stirring at room temperature for 24 hours, the reaction mixture is evaporated to dryness. The residue is triturated in methanol and the dicyclohexylurea is removed by filtration. The filtrate is concentrated to L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-O-benzyl-L-tyrosine benzyl ester (IX).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:23])[N:4]=1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:23])[N:4]=1)=[N+:30]=[N-:31]
Reactant: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-(bromomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)-quinoxaline (0.7173 g, 1.786 mmol) in DMF (8.930 mL, 1.786 mmol) was added sodium azide (0.2322 g, 3.572 mmol) at room temperature and the mixture was stirred at room temperature. After 30 min, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give bluish-brown syrup. The bluish-brown syrup was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 2-(azidomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)quinoxaline: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1 H, dd, J=8.6, 1.2 Hz), 8.10-8.14 (1 H, m), 7.99 (1 H, d, J=7.8 Hz), 7.95 (1 H, dd, J=8.4, 7.6 Hz), 7.79-7.91 (3 H, m), 4.41-4.67 (2 H, m); LC-MS (ESI) major peak of m/z 364.0 [M+H]+. The crude product was carried on crude without pufrification for the next step.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH:6]([S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:8])[CH3:7].[CH:17]1([CH2:23][CH2:24][NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:2].[CH:17]1([CH2:23][CH2:24][NH:25][CH2:1][CH:3]([OH:5])[CH2:4][O:16][C:13]2[CH:14]=[CH:15][C:10]([S:9][CH:6]([CH3:8])[CH3:7])=[CH:11][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCCC1CCCCC1
Reactant: CC(C)Sc1ccc(O)cc1
Reactant: ClCC1CO1
Product: CC(C)Sc1ccc(OCC(O)CNCCC2CCCCC2)cc1
Product: Cl
Yield: 18 %

Procedure:
Reaction of the epichlorohydrin derivative of 4-(isopropylthio)phenol (5.0 g., 0.022 mole) with cyclohexylethylamine (3.3 g., 0.026 mole) according to the procedure of Example 2(b) and crystallization of the crude product from isopropyl alcohol affords an 18% yield of analytically pure 1-[(2-cyclohexylethyl)amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol hydrochloride, m.p. 180°-182° (corr.).
Reaction SMILES: ClCCl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:22])[CH:14]=[CH:15][C:16]=2[O:18][CH2:19][CH2:20][CH3:21])[C:11](=[O:23])[C:10]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:9]1.C(N(CC)CC)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>O>[Cl:39][CH2:40][C:41]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[C:13]([F:22])[CH:14]=[CH:15][C:16]=2[O:18][CH2:19][CH2:20][CH3:21])[C:11](=[O:23])[C:10]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:9]1)=[O:42]
Reactant: O=C(Cl)CCl
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN)c12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCNC(=O)CCl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
A dichloromethane solution (6 ml) of 1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (645 mg, 1.67 mmol) was ice-cooled. Triethylamine (253 mg, 2.5 mmol) and chloroacetyl chloride (207 mg, 1.83 mmol) were added to the solution and stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction using dichloromethane. The thus-obtained organic layer was condensed, and the residue was then purified using silica gel column chromatography (dichloromethane:ethyl acetate=4:1→2:1). The purified product was concentrated to dryness under reduced pressure, giving a white powder of 2-chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide (372 mg, yield: 48%).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]([CH3:21])[CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[O:11][C:7]=2[C:6](F)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]=1[CH3:29])#[N:2].C(N(CC)CC)C.[CH3:37][N:38]([CH3:44])[C@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>CS(C)=O.ClCCl>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]([CH3:21])[CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[O:11][C:7]=2[C:6]([N:41]2[CH2:42][CH2:43][C@H:39]([N:38]([CH3:44])[CH3:37])[CH2:40]2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]=1[CH3:29])#[N:2]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCCC(=O)N(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)CCCC(=O)N(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
4-[{4-Cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}(methyl)amino]-N,N-dimethylbutanamide (I-156) (0.32 g, 0.81 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.24 ml, 1.73 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.21 ml, 1.66 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, and washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1), then diisopropyl ether was added and the insoluble matter was collected by filtration to obtain a colorless solid (0.22 g, 56%).
Reaction SMILES: [CH2:1]([C:6]1([CH:12]=[CH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[OH:34]O.[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:6]1([CH2:12][CH2:13][OH:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OO
Reactant: C=CC1(CCCCC)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC1(CCO)CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
A solution of 2-5 (90 mg, 0.50 mmol) in THF (3.4 mL) was added to a solution of 9-BBN dimer (206 mg, 0.84 mmol) in THF (3 mL). The reaction was placed in a 60° C. oil bath and after 2.5 h, a solution of H2O2 (35%, 1.4 mL)/NaOH (0.5 M, 1.4 mL)/H2O (0.35 mL) was added. The reaction was heated to reflux for 1 h and then allowed to cool to room temperature. H2O (20 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The combined ethyl acetate solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a Combiflash system by Teledyne Isco (4 g silica gel, 0→30% ethyl acetate/hexanes) which gave the title compound (70 mg, 71%).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([OH:16])=O)=[CH:2]1.C1C=CC2N(O)N=[N:23]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([NH2:23])=[O:16])=[CH:2]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c[nH]c2c1CCc1cnccc1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1c[nH]c2c1CCc1cnccc1-2
Yield: 30 %

Procedure:
A mixture of 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid E6 (0.093 mmol), HOBT.NH3 (0.374 mmol), TBTU (0.186 mmol) and DIEA (0.374 mmol) in DMF (5 mL) was stirred 4 h at rt. The solvent was evaporated and the crude residue was purified by preparative HPLC (Phase A: 0.05% NH4OH pH10/AN 95/5, Phase B: AN; gradient phase B 0—50% 8 min, yield 30%). ESI (+) MS: m/z 214 (MH+). 1H NMR: 2.83 (t, J=7.93, 2H), 2.98 (t, J=8.05, 2H), 6.61-7.28 (m, 2H), 7.33 (d, J=5.00, 1H), 7.56 (d, J=2.80, 1H), 8.28-8.38 (m, 2H), 11.85 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=3)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27](=O)[CH3:28]>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=3)[CH:15]=2)[CH2:27][CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1
Product: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CN(C(=O)OC(C)(C)C)C1

Procedure:
Intermediate 104 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[C:19](=[O:21])=[O:20]>CCCCCC.C1COCC1.C(OCC)C.[OH-].[Na+]>[CH:6]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11][C:10]=2[C:9]([C:19]([OH:21])=[O:20])=[CH:8][CH:7]=1
Reactant: O=C=O
Reactant: c1ccc2c(c1)oc1ccccc12
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c1oc1ccccc12
Temperature: 20 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of 1.6M n-butyllithium in hexane (18.5 ml) was added dropwise to a stirred solution of dibenzofuran (5.0 g) in anhydrous THF (25 ml) at −78° C. under a nitrogen atmosphere. The resulting suspension was allowed to warm to 20° C. where it was stirred for 3 h. It was then cooled to −78° C. and added to a mixture of excess solid carbon dioxide in diethyl ether (250 ml) under a nitrogen atmosphere. The resulting white suspension was allowed to stand for 1 h at 20° C. and was then diluted with 2M sodium hydroxide (500 ml). The aqueous extract was washed with ether (3×200 ml), acidified to pH 1 with 6M hydrochloric acid and extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulphate and evaporated in vacuo to give the title compound as a white solid (3.64 g, 58%). LCMS: Rt 5.06 min; m/z 213 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])=[CH:14][CH:15]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C=O)cc2Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzaldehyde (5.0 g, 24.9 mmol; 1 eq) in DCM (10 mL), was added 1-(bromomethyl)-4-methoxybenzene (6.0 g, 29.88 mmol, 1.2 eq, Aldrich, Milwaukee, Wis., USA) and DIEA (8.7 mL, 49.7 mmol, 2 eq). After stirring at room temperature for 18 h, the reaction mixture was diluted with DCM and washed with saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 8.0 g of 4-(4-methoxybenzyloxy)-3-bromobenzaldehyde (32).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc([N+](=O)[O-])ccc2Cl)n1
Temperature: 150 °C
Yield: 67.6 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-5-nitrobenzoyl chloride (0.086 g, 0.390 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.051 g (68% yield) of pure product: MS (ES) m/z 489 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].[C:26]1(=[O:39])[N:30]([CH2:31][CH2:32]Br)[C:29](=[O:34])[C:28]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:27]12>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:20][CH2:32][CH2:31][N:30]2[C:29](=[O:34])[C:28]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:27]3[C:26]2=[O:39])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCCN2C(=O)c3ccccc3C2=O)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
6-Amino-9-benzyl-8-hydroxy-2-mercaptopurine (110 mg, 0.40 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (50 mg, 0.40 mmol) and 2-phthalimidoethyl bromide (108 mg, 0.40 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, water and methanol were added to the residue, and the resulting crystals were taken by filtration to give the subject compound (138 mg, yield 75%).