Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: BrCCCc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(CCCc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.3 g--see EP-A-0178947), 1-bromo-3-phenylpropane (0.238 g), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.4g.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([O:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])(=[O:13])=[O:12])=[N:8][CH:9]=1.[CH2:30]([O:34][C:35](Cl)=[O:36])[CH:31]([CH3:33])[CH3:32]>COCCOC>[Br:3][C:4]1[N:5]=[C:6]([O:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:7]([N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])(=[O:12])=[O:13])[C:35](=[O:36])[O:34][CH2:30][CH:31]([CH3:33])[CH3:32])=[N:8][CH:9]=1
Reactant: CC(C)COC(=O)Cl
Reactant: O=S(=O)(Nc1ncc(Br)nc1OCc1cccnc1)c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)COC(=O)N(c1ncc(Br)nc1OCc1cccnc1)S(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
Sodium hydride (0.045 g of a 60% dispersion in oil) was added to N-[5-bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide (Example 34) (0.5 g) in 1,2-dimethoxyethane (3 mL). Iso-butylchloroformate (0.15 mL) was added. After 2 h, the mixture was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and evaproated to yield the product (0.65 g). Used directly.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:26]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:30]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate (0.96 g) in a mixed solvent of acetone (10.0 mL)-acetonitrile (10.0 mL)-water (10.0 mL) were added osmium oxide (fixed catalyst I) (0.34 g) and sodium periodate (2.86 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The insoluble substance was removed by filtration, and the filtrate was washed with saturated aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.17 g).
Reaction SMILES: [C:1]([NH:8][O:9][CH2:10][CH:11]=[CH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:16][CH2:17][CH3:18]>C1COCC1>[C:1]([N:8]([CH2:16][CH2:17][CH3:18])[O:9][CH2:10][CH:11]=[CH2:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C=CCONC(=O)OC(C)(C)C
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCON(CCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Boc-O-allylhydroxylamine (6.5 g) from the above procedure was dissolved in dry THF (25 mL) and the solution cooled to 0° C. in an ice bath. Sodium hydride (1.5 g, 60% dispersion in oil) was added portionwise over 5 min. The resulting mixture was stirred for 30 min at 0° C. 1-Iodopropane (3.8 mL) was added dropwise to the mixture. The reaction was stirred at 0° C. for 1 hour, then stirred overnight at room temperature. The THF was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1×50 mL), saturated sodium bicarbonate solution (3×50 mL), 1N phosphoric acid (3×50 mL), and brine (1×50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was purified by flash chromatography on silica gel eluting with 5% EtOAc/hexanes to give the title compound as a colorless oil (6.0 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:45])=[O:44])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 79.3 %

Procedure:
The title compound was prepared by a similar method to example 3 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)-tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol), benzenesulfonyl chloride (36 mg, 0.20 mmol) and triethylamine (0.1 ml, 0.72 mmol) to afford the title compound as a solid (100 mg). MS: 631 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: COc1cccc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3cccc(OC)c3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (75% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 25 mg (0.17 mmol, 1.1 eq.) of 3-methoxybenzoic acid were reacted according to General Method 1. Yield: 47 mg (72% of theory)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O>C1COCC1>[F:1][C:2]([F:12])([F:13])[CH2:3][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)CNc1ccccc1
Yield: 91.6 %

Procedure:
To a solution of 2,2,2-trifluoro-N-phenylacetamide (5.0 g, 26 mmol) in THF (10 mL) was added BH3 in THF (130 mL, 130 mmol, 1.0 M). The resulting mixture was refluxed overnight. The mixture was quenched with water and methanol, concentrated to remove most of THF, and extracted with EtOAc. Organics were washed with brine, dried (Na2SO4), and concentrated to give 4.17 g (92%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.71-3.75 (2H, m), 6.66 (2H, d, J=8.0 Hz), 6.79 (1H, t, J=7.2 Hz), 7.20 (2H, t, J=8.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:13][CH3:14])[CH:7]=[C:6]([CH3:15])[C:5]=1[OH:16])[CH3:2].[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:7]1[C:8]([O:12][CH2:13][CH3:14])=[C:9]([O:10][CH3:11])[C:4]([O:3][CH2:1][CH3:2])=[C:5]([OH:16])[C:6]=1[CH3:15]
Reactant: BrBr
Reactant: CCOc1cc(C)c(O)c(OCC)c1OC
Solvent: ClC(Cl)Cl
Product: CCOc1c(O)c(C)c(Br)c(OCC)c1OC
Temperature: 0 °C

Procedure:
40 g of 2,4-diethoxy-3-methoxy-6-methylphenol prepared in Referential Example 6 was dissovled in 200 ml of chloroform, and 10 ml of bromine was added thereto and cooled by ice while stirring. Ice water was added to the reaction mixture, and the mixture was subjected to liquid-liquid separation. The organic phase was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off to prepare 54 g of the product compound as a light yellow oleaginous substance.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][CH:12]([C:16](OC)=[O:17])[CH:11]1[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][CH:12]([CH2:16][OH:17])[CH:11]1[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC(CO)C(c2c(Cl)cccc2Cl)N1Cc1ccccc1
Reaction time: 8 h
Yield: 129.6 %

Procedure:
To 580 ml of methanol was added 72 g. of sodium borohydride at 0°-5°. After the addition, 40 g of methyl 1-benzyl-2-(2,6-dichlorophenyl)-5-oxopyrrolidin-3-carboxylate was then added in portions at 0°-5°. The reaction was stirred at 10°-15° and then left standing overnight at ambient temperature. After concentrating the mixture in vacuo to a solid, the crude product was suspended in water at 50° and stirred for 30 minutes. The resulting solid was collected by filtration and dissolved in chloroform. Drying (Na2SO4), filtration, and concentration in vacuo provided 48 g of off-white crystals, m.p. 122°-126°.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][NH:29][CH3:30])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][N:29]([CH3:30])[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNCc1ccc(F)cc1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(F)cc1
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate and 4-fluoro-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1H NMR (400 MHz, DMSO): δ 2.18 (3H, s), 2.69 (2H, t, J=6 Hz), 3.51 (2H, s), 4.00 (1H, t, J=5.7 Hz), 4.15 (1H, t, J=5.9 Hz), 7.03 (2H, t, J=8.9 Hz), 7.20 (2H, dd, J=8.7 Hz and 2.8 Hz), 7.52 (1H, s), 7.72 (1H, d, J=1.7 Hz), 7.78 (1H, s), 8.26 (1H, s), 8.46 (1H, d, J=4.3 Hz). [M+H] Calc'd for C19H19FN4O2, 355. Found, 355.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]1.[N+:21]([O-])([O-:23])=[O:22].[K+].C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C@:8]1([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:15])([F:16])[F:17])[C:10]([NH2:19])=[N:9]1
Reactant: O=[N+]([O-])[O-]
Reactant: C[C@@]1(c2ccccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,5R)-5-(2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (1.035 g, 3.57 mmol) in H2SO4 (6 ml) was added in portions KNO3 (0.379 g, 3.74 mmol) under ice-water cooling. The reaction mixture was stirred for 2 h at 25° C., diluted with water and basified with K2CO3 under cooling. The product was extracted with EtOAc. Combined extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. Purification via chromatography on silica gel (hexane-EtOAc 4:1 to 1:1 containing 0.05% NEt3) gave the title compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.50; UPLC RtH5=0.749 min; ESIMS: 336 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 8.48 (dd, 1H), 8.14 (m, 1H), 7.15 (dd, 1H), 4.20 (br s, 2H), 4.04 (dd, 1H), 3.91 (dd, 1H), 1.54 (s, 3H), 1.49 (s, 3H).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>O1CCCC1>[C:1]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=1)(=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of cinnamic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 7. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.51 g, 91%). HRMS calcd for C17H15NO3: 281.3242. Found: 281.3240. MA calcd for C17H15NO3: C, 72.58%; H, 5.38%; N, 4.98%. Found: C, 72.42%; H, 5.37%; N, 4.87%.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]2[N:13]=[C:14]([CH2:16]Cl)[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:27]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][CH:37]2[C:46]3[N:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:40][CH2:39][CH2:38]2)=[CH:31][CH:30]=1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][N:36]([CH2:16][C:14]2[NH:13][C:12]3[CH:18]=[CH:19][C:9]([C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[N:15]=2)[CH:37]2[C:46]3[N:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:40][CH2:39][CH2:38]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=C(c1ccccc1)c1ccc2nc(CCl)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc2[nH]c(CN(Cc3ccc(CNCc4ccccn4)cc3)C3CCCc4cccnc43)nc2c1
Yield: 75.9 %

Procedure:
A solution of 5-benzoyl-2-chloromethylbenzimidazole (284 mg, 1.05 mmol), N-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (476 mg, 1.04 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.08 mmol) were stirred at 80□ C in DMF (4 mL) for 16 hours. The reaction was then cooled, concentrated under reduced pressure and diluted with CH2Cl2 (35 mL) and saturated aqueous NaHCO3 (40 mL). The phases were separated and the aqueous phase was washed with CH2Cl2 (2×25 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (1×40 mL), dried (NaSO4), filtered and concentrated under reduced pressure. Purification of the resultant oil by flash chromatography on silica gel (96:4 CH2Cl2/MeOH) provided the desired alkylated product (468 mg, 65%) as an orange oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([S:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]5)(=[O:36])=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)ccc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidine-4-sulfinyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 206 (35 mg, 0.0731 mmol) in DCM (6 mL) was added TFA (17 μL, 0.306 mmol) followed by a slow addition of a solution of m-CPBA (16 mg, 0.0951 mmol) in DCM (1 mL) and the resulting mixture was stirred for 2 h at 0° C. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 10-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 208 as a white solid (24 mg, 66%). LCMS: RT 2.68 min [M+H]+ 499.1. 1H NMR (DMSO, 400 MHz): δ 8.87 (1H, d, J=2.40 Hz), 7.97 (1H, s), 7.71 (1H, dd, J=10.93, 2.38 Hz), 7.30 (1H, d, J=8.63 Hz), 5.70-5.58 (1H, m), 4.68-4.56 (4H, m), 3.20-3.10 (1H, m), 2.84-2.77 (2H, m), 2.68-2.59 (1H, m), 2.27 (3H, s), 2.09 (2H, bt, J=11.46 Hz), 1.91 (2H, bd, J=12.10 Hz), 1.54-1.34 (8H, m), 0.89 (6H, d, J=6.55 Hz)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[H-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.O>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:17]1[CH:18]=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccccc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(trifluoromethyl)aniline (0.570 g, 3.54 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 0.384 g, 9.6 mmol) was added portion wise at 0° C. under Argon, followed by the addition of 2,4-dichloropyrimidine (0.528 g, 3.54 mmol). The reaction mixture was slowly warmed to room temperature and stirred for a further 24 h. The solvent was removed under reduced pressure to provide a red/orange solid. The residue was slurried with water (30 mL) and solid was filtered and washed with water (10 mL×2). The dried solid was suspended in diethyl ether (5 mL) and sonicated, then filtered and washed with diethyl ether (5 mL), hexane (10 mL) to afford the title compound as a yellow solid. The solid was re-dissolved in ethyl acetate, activated charcoal was added and the mixture was stirred for 20 min at room temperature. The activated charcoal was removed by filtration through a celite/silica bed. The filtrate was collected, the solvent removed under reduced pressure to provide 5f (0.261 g, 28%) as an off-white solid. m.p. 139° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.11 (d, J=5.9 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.57-7.51 (m, 2H), 6.57 (d, J=5.9 Hz, 1H); LC-MS (ESI+) m/z 274.04 (M+H)+; HRMS (ESI+) m/z calculated for C11H8F3ClN3 (M+H)+ 274.0353. found 274.0354.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=CC=C[C:24]=1C=C)[C:13]([O:15]CC[Si](C)(C)C)=[O:14].O=[O+][O-]>C(Cl)Cl.CO>[NH2:3][CH:2]1[C:2](=[O:1])[N:3]([CH:12]([CH2:22][CH:23]([CH3:24])[CH3:28])[C:13]([O:15][C:23]([CH3:28])([CH3:24])[CH3:22])=[O:14])[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:10]1
Reactant: C=Cc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(N)C1=O
Temperature: -78 °C
Yield: 247.1 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (2.61 g, 6.19 mmol) in methylene chloride (70 mL) and methanol (75 mL). Cool to −78° C. and treat with ozone until a blue color persists. Purge with nitrogen and add dimethylsulfide (7 mL) and pyridine (0.35 mL). Allow to warm to room temperature gradually overnight. Partition between methylene chloride (100 mL) and water (40 mL). Extract the aqueous with methylene chloride (50 mL), dry (Na2SO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate) to give the title compound as a colorless viscous oil (2.65 g, 100%). Step h: 2-(2-(2-(1,3,-Dioxo-1,3,dihydro-isoindol-2-yl)-2-(2-trimethylsilanyl-ethoxycarbonyl)-ethyl)-benzylamino)-4-methyl-valeric acid, tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][OH:11].[CH:12]([O:14][CH2:15][CH3:16])=[CH2:13].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13]
Reactant: C=COCC
Reactant: COc1ccc(Br)c(CO)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(C)OCc1cc(OC)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Dissolve (2-bromo-5-methoxy-phenyl)methanol (5.0 g, 23 mmol) in dry dichloromethane (120 mL) and cool to 0° C. under nitrogen. Add ethyl vinyl ether (2.5 g, 34 mmol) followed by pyridinium p-toluenesulfonate (580 mg, 2.3 mmol). Warm to room temperature and stir for 2 hours. Pour reaction into saturated aqueous sodium bicarbonate and extract twice with dichloromethane. Combine organic layers and wash with water and brine. Dry with sodium sulfate, filter and concentrate in vacuo to yield 6.6 g (100%) of title compound as a clear colorless oil. 1H NMR (CDCl3) δ 7.41 (d, J=8.6 Hz, 1H), 7.08 (d, J=3.1 Hz, 1H), 6.71 (dd, J=8.8, 3.1 Hz, 1H), 4.88 (q, J=5.3 Hz, 1H), 4.65 (ab, Jab=13.3 Hz, H), 4.55 (ab, Jab=13.3 Hz, 1H), 3.8 (s, 3H), 3.71 (m, 1H), 3.55 (m, 1H), 1.41 (d, J=5.3 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1.O>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9])=[O:17]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1c(Cl)cncc1Cl)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-amino 3,5-dichloro pyridine in THF (0.5M) at 0° C. was added NaH (1.5 eq). The mixture was stirred at 0° C. for 30 min then 3-bromo benzoyl chloride (2.0 eq.) was added dropwise. The resulting mixture was stirred 12 hours at room temperature, poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2 SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:1) afforded the desired compound a yellow solid.