Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.BrC1C=C(C2[N:32]=C(N)SC=2)C=CC=1>>[N+:18]([C:10]12[CH2:17][CH:2]([C:21]([NH2:32])=[O:23])[CH:3]([C:4]3[C:9]1=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:16]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: Nc1nc(-c2cccc(Br)c2)cs1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Product: NC(=O)C1CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Yield: 92.4 %

Procedure:
In a similar manner to Example 1, Step 2, the coupling reaction of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (200 mg, 0.647 mmol) and 4-(3-bromo-phenyl)-thiazol-2-ylamine (214 mg, 0.841 mmol) afforded 15-methyl-N-[4-(3-bromo-phenyl)-thiazol-2-yl]-]-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxamide (176 mg, 49% yield). LC/MS (m/z 548.08 (M+H)+); HPLC Rt: 4.385 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47].CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:40][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])=[O:39])=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:28])([F:29])[F:30])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)OCC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a stirring suspension of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (207 mg, 0.345 mmol) and 2-bromo-1-(4′-methyl-[1,1′-biphenyl]-4-yl)ethanone (100 mg, 0.345 mmol) in acetonitrile (4 mL) at 0° C. was added DIEA (70.0 μl, 0.379 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred for 16 h. The reaction mixture was poured onto citric acid (50 mL, 0.1 N aqueous solution) and extracted with EA (3×20 mL). The combined organic extracts were washed successively with NaHCO3 (20 mL), brine (20 mL) then dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 254 mg (91%) of 2-(4′-methyl-[1,1′-biphenyl]-4-yl)-2-oxoethyl 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoate INT-38 as a white foam. LCMS-ESI (m/z) calculated for C46H43F3N2O8: 808; found 831 [M+Na]+, tR=3.10 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.C[O:59][C:60](=[O:64])[CH2:61][CH2:62][NH2:63]>CN(C=O)C.CO.C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:26][CH:25]=3)[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:63][CH2:62][CH2:61][C:60]([OH:64])=[O:59])=[O:20])=[CH:22][CH:23]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(CC(c2ccc(OC(F)(F)F)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(CC(c2ccc(OC(F)(F)F)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
4-[2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-(4-trifluoromethoxyphenyl)ethyl]benzoic acid (0.16 g, 0.31 mmol) was dissolve in DMF (5 mL) and 1-hydroxybenzotriazole (51.48 mg, 0.38 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (73 mg, 0.38 mmol) were added and the mixture was stirred at room temperature for 1.5 hours. DI PEA (0.123 g, 0.95 mmol) and 3-aminopropionic acid methyl ester hydrochloride (66 mg, 0.48 mmol) were added to the mixture. The mixture was heated at 40° C. for 2 hours and left with stirring for 16 hours at room temperature. Ethyl acetate (5 mL) was added and the mixture was washed with water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL). The combined organic phases were washed with brine (5 mL) and water (5 mL) and concentrated in vacuo to afford crude intermediary ester compound. The ester was dissolved in a mixture of methanol (4 mL) and THF (1 mL) and 4M sodium hydroxide (0.2 mL) was added. The mixture was stirred for 16 hours at room temperature and the solvents were removed by evaporation in vacuo. Water (6 mL) was added and the pH was adjusted (1-2) by the addition of 1M hydrochloric acid. The precipitate was filtered off, washed with water and dried to afford 126 mg (69%) of the title compound as a solid.
Reaction SMILES: O[C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.C[Si](C#[N:18])(C)C.S(=O)(=O)(O)O>C(OCC)(=O)C.O.CCOCC.[OH-].[Na+]>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([NH2:18])([CH3:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5]1
Reactant: C[Si](C)(C)C#N
Reactant: CC1(C)CC(C)(C)CC(C)(O)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)CC(C)(C)CC(C)(N)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a vigorously stirred solution of 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane (3.4 g; 20 mmol) and trimethylsilyl cyanide (2.58 g; 26 mmol; 1.3 eq.) in ethyl acetate (4 ml), 95% sulfuric acid (3.2 ml; 60 mmol; 3.1 eq) are added during 1 hour keeping the temperature at −10° C. for 15 min, and then allowing the mixture to reach ambient temperature. After stirring at ambient temperature for 15 hours, the mixture is diluted with 20 ml ice water. Subsequently, the mixture is refluxed with stirring for 10 hours, cooled to ambient temperature, diluted with 40 ml water and 20 ml ether and neutralized with 20% aqueous sodium hydroxide until a pH of 10. The organic phase is separated and dried. Dry hydrogen chloride is passed through the solution until the ether becomes acidic. Solvent is removed and the residue is washed with ether to give 3.1 g Neramexane in the form of its hydrochloride.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[F:16][C:17]([F:35])([F:34])[C:18]([C:20]1[S:24][C:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])=[CH:22][CH:21]=1)=[O:19]>C(O)=O>[CH3:1][CH:2]1[N:7]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:23]3[S:24][C:20]([C:18](=[O:19])[C:17]([F:16])([F:34])[F:35])=[CH:21][CH:22]=3)[CH:26]=2)[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Solvent: O=CO
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Yield: 39 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described for example 37 step 3 (95 mg, yield 39%). 1H NMR (400 MHz, MeOD) δ 8.42 (d, J=1.9 Hz, 1H), 7.97-7.96 (m, 1H), 7.80-7.77 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.75-7.74 (t, J=1.5 Hz, 1H), 7.68-7.65 (dd, J=9.1 Hz, 2.4 Hz, 1H), 7.58-7.54 (t, J=7.6 Hz, 1H), 7.48-7.45 (m, 2H), 6.64-6.62 (d, J=9.1 Hz, 1H), 4.40-4.23 (m, 4H), 3.42-3.37 (m, 2H), 3.16-3.09 (m, 1H), 1.33-1.31 (m, 3H). MS (ESI) m/z: Calculated for C24H19F3N4O2S: 484.12. found: 529.7 (M+HCOOH)−
Reaction SMILES: [I:1]Cl.[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Si](C)(C)C)=[CH:26][CH:25]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]>ClCCl>[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([I:1])=[CH:26][CH:25]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: ClI
Reactant: C[Si](C)(C)c1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Solvent: ClCCl
Product: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 M solution of iodine monochloride in dichloromethane (0.9 mL) is added to 4-(β-D-glucopyranos-1-yl)-2-(4-trimethylsilyl-benzyl)-benzonitrile (0.26 g) dissolved in dichloromethane (5 mL). The solution is stirred at room temperature for 1 h and then quenched by the addition of aqueous Na2S2O3 solution and aqueous NaHCO3 solution. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH:12](O)[C:11]=2[C:18]=1[CH3:19])=[O:5].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]=2[C:18]=1[CH3:19])=[O:5]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a mixed solution of 3,3-dimethyl-N-(3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide (2.0 g, 6.55 mmol) obtained in Example 338 in trifluoroacetic acid (3 mL) was added dropwise with ice-cooling triethylsilane (2.09 g, 13.10 mmol). The reaction solution was warmed to room temperature and stirred for 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous 1 N sodium hydroxide solution and an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 1.75 g (yield: 92%) of the title compound. Melting point: 181-182° C. (THF-hexane).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:27]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:42][CH:41]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.1 %

Procedure:
To a solution of 2-amino-4-methyl-thiazole-5-carboxylic acid benzylamide (0.054 g, 0.22 mmol) and diisopropylethylamine (0.40 mL, 2.3 mmol) in dichloromethane (5 mL) was added 4-benzylbenzoic acid (0.057 g, 0.27 mmol), followed by the addition of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.11 g, 0.28 mmol). The reaction was stirred at ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by preparative HPLC (acetone/water gradient) to afford the title compound (0.003 g); MS (ES+) m/z 442 (M+1).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:23]([O:22][C:20]([C:18]1[O:19][C:15]([CH2:14][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[Cl:1])=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 24 h

Procedure:
Alternately, combine 2-chlorobenzimidazole (20 mmol) and sodium hydride (20 mmol) in dimethylformamidle (30 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (20 mmol) and stir. After 1 day, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[CH:7]=1.BrC1C=C(C(O)=O)C=C(C=1)C(O)=O>CO>[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: O=C(O)c1cc(Br)cc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add a solution of NaOH pellets (3.66 g, 91.5 mmol) in methanol (200 mL) to dimethyl-5-bromoisophthalate (25 g) and stir the resulting solution overnight at room temperature. Add water (300 mL) and extract with dichloromethane (3×200 mL). Acidify the aqueous with 5 N HCl (20 mL), filter the precipitate and dry to give a mixture of the title compound and 5-bromo-isophthalic acid in about a 6:4 ratio by LCMS (18.2 g crude).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([CH:24]2[CH2:26][CH:25]2[C:27]#[N:28])=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-:33])(C)C.[K+]>C(O)(C)(C)C>[C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([CH:24]2[CH2:26][CH:25]2[C:27]([NH2:28])=[O:33])=[N:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CC1c1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)C1CC1c1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Yield: 22.5 %

Procedure:
To a solution of (±)-2-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (550 mg, 1.50 mmol) in t-butanol (30 mL) was added KOtBu (842 mg, 7.51 mmol). The reaction mixture was heated to reflux at 90° C. for 12 h. t-Butanol was evaporated under reduced pressure and water (25 mL) was added to the reaction mixture. The aqueous layer was acidified with aqueous citric acid solution and extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (Condition B-108 as described in general methods) to obtain (±)-2-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarboxamide (130 mg, 22.0%) which was resolved by chiral HPLC (Condition B-109 as described in general methods) to obtain enantiomer-1 (42 mg) and enantiomer-2 (46 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH2:26][CH2:27]Br)=[C:17]([O:20][CH2:21][CH:22]4[CH2:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:29][NH:30][CH:31]1[CH2:35][O:34][C:33](=[O:36])[CH2:32]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH2:26][CH2:27][N:30]([CH:31]4[CH2:35][O:34][C:33](=[O:36])[CH2:32]4)[CH3:29])=[C:17]([O:20][CH2:21][CH:22]4[CH2:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC1COC(=O)C1
Reactant: Fc1ccc(Nc2ncnc3cc(OCCBr)c(OCC4CC4)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCC1CC1)C1COC(=O)C1
Temperature: 25 °C

Procedure:
300 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-bromoethoxy)-quinazoline and 400 mg of 4-methylamino-dihydro-furan-2-one in 20 ml acetonitrile are combined with 240 mg of potassium carbonate and 70 mg of sodium iodide and refluxed for 24 hours. After cooling to ambient temperature the reaction mixture is filtered and the filtrate is evaporated down in vacuo. The flask residue is chromatographed over a silica gel column with methylene chloride/methanol/concentrated aqueous ammonia solution (97:3:0.05) as eluant. The title compound is obtained as a light beige solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][N:2]=1.B.CSC>C1COCC1>[OH:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=[N:2][CH:3]=1
Reactant: O=Cc1cncc2ccccc12
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1cncc2ccccc12

Procedure:
4-Isoquinolinecarboxaldehyde (1 mmole) (prepared by the method of: J. B. Wommack, T. G. Barbee, Jr., D. J. Thoennes, M. A. McDonald and D. E. Pearson, J. Heterocyclic Chem., 1969, 6, 243-245.) is dissolved in anhydrous THF (50 mL) and treated with borane-methyl sulfide (0.3 mmoles) (as described in: E. Mincione, J. Org. Chem., 1978, 43, 1829-1830) at 0° C. for 0.5-1 h and worked up in the usual way to give the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][Br:23])=[CH:16][CH:15]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3n2C(=O)C(F)(F)F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(n1c(-c2ccc(CBr)cc2)nc2ccccc21)C(F)(F)F
Temperature: 25 °C

Procedure:
A stirred solution of 213.0 g (0.7 mole) of 1-trifluoroacetyl-2-(4-methylphenyl)benzimidazole, 125.0 g (0.7 mole) of N-bromosuccinimide, and 3.39 g (2 mole %) of benzoyl peroxide in carbon tetrachloride is heated at reflux for 20 hours. After cooling to room temperature, the reaction is diluted by the addition of carbon tetrachloride, and the solid byproducts are removed by filtration. The filtrate is concentrated in vacuo, and the product is purified by recrystallization from tetrahydrofuran.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.ClC1C=C(Cl)C=CC=1C1[C:28]([C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=2)[N:24]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:28]([C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][N:26]=[C:25]([NH:34][CH2:35][CH2:36][NH:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][N:39]=3)[N:24]=2)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(F)cc3C(F)(F)F)n2)nc1

Procedure:
{4-[4-fluoro-2-(trifluoromethyl)phenyl]-5-imidazol-2-ylpyrimidin-2-yl}{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 4-fluoro-2-(trifluoromethyl)benzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]Br.[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([O:23][CH3:24])=[O:22]>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:21]([O:23][CH3:24])=[O:22])[CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccc(C(=O)c2c[nH]c3ccc(OCc4ccccc4)cc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution 5-benzyloxyindole (2.23 g, 10 mmol) in 5 ml of tetrahydrofuran (THF), cooled in an external ice bath, is added dropwise with stirring 6.15 ml of a 2 molar solution of methyl magnesium bromide in diethyl ether. The resulting mixture is stirred for an additional 15 minutes in the ice bath and a solution of 3-carbmethoxybenzoyl chloride in 10 ml of THF is added dropwise. The cooling bath is removed and the reaction mixture is stirred at room temperature for 18 hours. Water is then added, followed by ethyl acetate. The layers are separated. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue obtained is purified by a silica gel column, eluting with a solvent system of 25% ethyl acetate in hexane to give 5-benzyloxy-3-(3-carbomethoxybenzoyl)indole. NMR confirms this structure.
Reaction SMILES: C1(C(C2C=CC=CC=2)CNC2N=C(N[C@H](CO)CC3C=CC=CC=3)N=[C:15]3[C:11]=2[N:12]=C[N:14]3[C@@H:30]2[CH2:34][C@H:33](NC(=O)CC)[C@@H:32](O)[C@H:31]2O)C=CC=CC=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].Cl[C:56]1[N:64]=[C:63]2[C:59]([N:60]=[CH:61][N:62]2[C@@H:65]2[CH2:69][C@H:68]([NH:70][C:71](=[O:74])[CH2:72][CH3:73])[C@@H:67]([OH:75])[C@H:66]2[OH:76])=[C:58]([NH:77][CH2:78][C:79]2[C:88]3[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH:82]=[CH:81][CH:80]=2)[N:57]=1.N1(CCN)CCCCC1>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[OH:75][C@H:67]1[C@@H:66]([OH:76])[C@H:65]([N:62]2[CH:61]=[N:60][C:59]3[C:63]2=[N:64][C:56]([NH:12][CH2:11][CH2:15][N:14]2[CH2:30][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:57][C:58]=3[NH:77][CH2:78][C:79]2[C:88]3[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH:82]=[CH:81][CH:80]=2)[CH2:69][C@@H:68]1[NH:70][C:71](=[O:74])[CH2:72][CH3:73]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N[C@H](CO)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: NCCN1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 16) by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 4) with N-((1S,2R,3S,4R)-4-{2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (Example 50) and by replacing (S)-2-amino-3-phenyl-propan-1-ol with 2-piperidin-1-yl-ethylamine.