Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]=2[S:10][C:9]=1[C:23]([O:25]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCCO)C.[NH3:34]>>[NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[C:11]=2[S:10][C:9]=1[C:23]([NH2:34])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccsc2)c1Nc1ccccc1
Reactant: N
Solvent: CCOCCO
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccsc2)c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of Example 64 (129 mg), 2-ethoxyethanol and liquid ammonia was placed in a sealed pressure vessel and heated at 80° C. and 400 p.s.i. for 24 h. The volatiles were removed in vacuo and the residue purified by column chromatography (silica, 50% to 100% EtOAc in hexane) to give the title compound (20 mg). δH (CDCl3) 8.75 (1H, br s), 7.36-7.34 (2H, m), 7.16-7.11 (2H, m), 7.03 (1H, d, J 9.7 Hz), 6.99-6.88 (4H, m), 6.17 (1H, d, J 9.7 Hz), 5.47 (2H, br s). LCMS (ES+) RT 2.927 minutes, 368 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]1([CH3:43])[CH2:33][CH2:32][CH2:31][CH:30]([O:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH2:29]1>O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH:30]2[CH2:31][CH2:32][CH2:33][C:28]([CH3:43])([CH3:27])[CH2:29]2)=[CH:36][CH:37]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC1(C)CCCC(Oc2ccc(CN)cc2)C1
Solvent: C1COCCO1
Product: CC1(C)CCCC(Oc2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)C1
Yield: 49 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (387 mg, 0.91 mmol) with (±)-4-(3,3-dimethyl-cyclohexyloxy)-benzylamine (233 mg, 1 mmol) in anhydrous 1,4-dioxane (14 mL). Purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (19:1 to 1:1 gradient) to obtain (±)-7-chloro-6-[4-(3,3-dimethyl-cyclohexyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (227 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:15]#N)=[CH:12][N:13]=[CH:14][C:5]=3[C:4]=2[CH:3]=1.Cl[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](CC#N)=[CH:21]2.C(OCC)(=[O:33])C=C>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:6]4[C:11](=[CH:12][N:13]=[CH:14][C:5]=4[C:4]=2[CH:3]=1)[C:15](=[O:33])[C:19]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:18]3
Reactant: N#CCc1cc2cc(Cl)ccc2[nH]1
Reactant: C=CC(=O)OCC
Reactant: N#Cc1cncc2c1[nH]c1ccc(Cl)cc12
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Cl)cc3c3cncc1c32
Yield: 47 %

Procedure:
According to Example 5<step 1>, 8-chloro-4-cyano-5H-pyrido[4,3-b]indole (1.26 g) prepared from 5-chloro-2-cyanomethylindole by the procedure described in literature (Synthesis, 743 (1992) and Chem. Pharm. Bull., 29, 1280 (1981)) was reacted with ethyl acrylate (1.8 mL) to obtain the title compound (850 mg; 47%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=O)(C)(C)C.C1C=CC(/C(/C2C=CC([N+]([O-])=O)=CC=2)=N/O)=CC=1.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH2:58][NH2:59]>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([N:8]2[CH2:12][CH2:11][S:10][CH:9]2[C:13]([NH:59][CH2:58][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[O:51][CH3:50])=[O:15])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: COc1ccccc1CN
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=[N+]([O-])c1ccc(/C(=N\O)c2ccccc2)cc1
Product: COc1ccccc1CNC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general solid phase method as outlined Example 33, starting from 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid, Kaiser oxime resin, 1,1′-biphenyl-4-sulfonyl chloride and (2-methoxyphenyl)methanamine, the title compound was obtained in 98.5% purity by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#N.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[OH-:20].[Na+]>C(OCC)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1ccccc1N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: Nc1ccccc1C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-aminobenzonitrile (4.25 g, 36 mmol) in anhydrous diethyl ether (40 ml) at 0° C. is treated under argon with benzylmagnesium chloride (2M in tetrahydrofuran; 50 ml; 100 mmol). The reaction medium is maintained under agitation for 1 hour at ambient temperature, then hydrolyzed at 0° C. by adding hydrochloric acid at 10%, agitated for 1 hour, and neutralized with sodium hydroxide. The resulting mixture is extracted with ethyl acetate. The combined extracts are washed with water and with a saturated solution of sodium chloride, then dried over magnesium sulphate and concentrated to produce 3.5 g of the desired product, in the form of a white solid (m.p.: 100–101° C.).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:16]1.CO.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:20]1
Reactant: COCOc1ccc([C@H]2CC[C@H](CC(=O)OC)CC2)c(OCOC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added cis/trans-methyl {4-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}acetate (1.00 g, 2.84 mmol) and methanol (20 ml). The stirred solution was heated to reflux temperature and aqueous hydrochloric acid (20 ml, 1 M) was added in aliquots (4×5 ml) at 10 min intervals. After 2 hr, the reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate (50 ml) added. The reaction mixture was poured into a separating funnel containing ethyl acetate (100 ml) and water (30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:2, v/v) afforded the title compound (0.51 g, 69%) as a mixture of diastereoisomers. m/z (ES+) 265 (M+H+); δH(CD3OD) 1.33-1.91 (9H, m), 2.30 (2H, m), 2.79 (1H, m), 3.72 (3H, s), 6.28 (2H, m), 6.95 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]([O:19][CH2:20][CH2:21]Cl)=[O:18]>C(#N)C>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([N:1]2[CH2:21][CH2:20][O:19][C:17]2=[O:18])=[N:3][CH:4]=1
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cc(N)ncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N2CCOC2=O)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2-amino-4-methyl-5-bromo-pyridine (3 g, 16 mmol) and K2CO3 (5.5 g, 40 mmol) were added into acetonitrile (35 mL), cooled to 0° C. on ice-salts cooling bath. 2-chloroethyl chloroformate (2.75 g, 19.2 mmol) was added dropwise, and after its completion, the mixture was raised to room temperature, agitated for 1 hr, and refluxed under heat for 3 hrs. TLC (petroleum ether/ethyl acetate=3:1) was employed to monitor the reaction. After the starting materials completely reacted, acetonitrile was removed by evaporation. The resulting mixture was diluted by adding dichloromethane (100 mL), washed sequentially with water and saturated saline solution, and dried over anhydrous sodium sulfate. Column chromatography afforded 2.6 g of white solid, yield 63%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[C:20]=3[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>[Pd].C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(CC(=O)N2CCc3c2ccnc3Cl)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(CC(=O)N2CCc3cnccc32)CCN1C(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 51.3 %

Procedure:
10% Pd/C (62 mg, 0.06 mmol) and (R)-4-[2-(4-chloro-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (232 mg, 0.6 mmol) were mixed with THF (5.82 mL) and triethylamine (1.22 mL, 0.87 mmol) was added. The reaction was hydrogenated at 1 bar for 5 h at ambient temperature then filtered under vacuum and the solvent evaporated in vacuo. The residue was dissolved in MeOH and loaded onto SCX column eluting with MeOH then 2 M ammonia in MeOH to release the amine and concentrated, to give the title compound (111 mg, 53%) as a yellow oil, 1H NMR (Me-d3-OD): 8.35 (1H, s), 8.31 (1H, d), 8.05 (1H, s), 4.33 (2H, t), 4.28-4.17 (1H, m), 3.83 (1H, d), 3.28 (2H, d), 3.24-3.08 (1H, m), 3.00-2.79 (3H, m), 2.36 (1H, dd), 2.26-2.12 (1H, m), 1.48 (9H, s), 1.31 (3H, d).
Reaction SMILES: C(OC(N1CC(=C)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)C.[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78](Br)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57].[CH3:84][O:85][C:86](=[O:121])[NH:87][CH:88]([C:92]([N:94]1[CH2:98][CH2:97][CH2:96][CH:95]1[C:99]1[NH:103][C:102]2[C:104]3[C:109]([CH2:110][CH2:111][C:101]=2[N:100]=1)=[CH:108][C:107](B1OC(C)(C)C(C)(C)O1)=[CH:106][CH:105]=3)=[O:93])[CH:89]([CH3:91])[CH3:90]>>[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78]([C:107]4[CH:108]=[C:109]5[C:104](=[CH:105][CH:106]=4)[C:102]4[NH:103][C:99]([CH:95]6[CH2:96][CH2:97][CH2:98][N:94]6[C:92](=[O:93])[CH:88]([NH:87][C:86]([O:85][CH3:84])=[O:121])[CH:89]([CH3:91])[CH3:90])=[N:100][C:101]=4[CH2:111][CH2:110]5)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1CC2)C(C)C
Agent: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc1CC2)C(C)C
Yield: 73.9 %

Procedure:
This compound was synthesized using the procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.641 g, 1.449 mmol) and (2-Methyl-1-{2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (1.06 g, 2.029 mmol) to give 2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.812 g, 74% yield) as a solid. LCMS-ESI+: calc'd for C44H51N7O5: 757.40 (M+); Found: 758.75 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([C:38]1[O:42][N:41]=[C:40]([C:43](O)=[O:44])[CH:39]=1)[CH:35]([CH3:37])[CH3:36].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>>[CH2:34]([C:38]1[O:42][N:41]=[C:40]([C:43]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:44])[CH:39]=1)[CH:35]([CH3:37])[CH3:36]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)Cc1cc(C(=O)O)no1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1cc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)no1
Yield: 11.7 %

Procedure:
(5-Isobutyl-isoxazol-3-yl)-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone (8 mg, 12%) was prepared as a white solid using the conditions described in Example 152, by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27, 63 mg, 0.13 mmol) with 5-isobutyl-isoxazole-3-carboxylic acid (Matrix Scientific, Columbia, S.C., USA; 26 mg, 0.15 mmol) in the presence of TSTU (O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 78 mg, 0.26 mmol) and diisopropylethylamine (0.14 mL, 0.8 mmol).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>CN(C=O)C>[I:24][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of Example 219B (5 g, 15.7 mmol) in DMF (100 mL) was treated with N-iodosuccinimide (4.23 g, 18.8 mmol), stirred at ambient temperature for 2 hours, concentrated to half the original volume, and poured into 5% sodium thiosulfate (400 mL). The mixture was filtered and the filter cake was washed with water and dried. The solids were dissolved in dichloromethane (300 mL), treated with silica gel (80 g), and concentrated. The residue was transferred to a silica gel column (600 g) and chromatographed with ethyl acetate/heptane (1:6) to provide 5.2 g (75%) of the desired product. 1H NMR (CD2Cl2, 400 MHz) δ 7.95 (s, 1H), 7.33-7.29 (m, 4H), 7.12 (s, 1H), 7.10 (t, 1H), 7.02-6.99 (m, 4H), 4.76 (br s, 1H); 13C NMR (CD2Cl2, 400 MHz) δ 158.4, 156.8, 154.7, 154.4, 148.6, 138.4, 131.3, 131.2, 130.4, 124.4, 122.9, 120.0, 119.9, 118.8, 72.0.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:23][C:21]([C:18]1[CH:17]=[N:16][C:15]([N:13]2[CH2:12][CH2:11][C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:2]([C:36]5[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH2:14]2)=[N:20][CH:19]=1)=[O:22]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(Br)cc4c3C2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)cc5)cc4c3C2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a 0° C. solution of Example 33 (1.5 g, 3.37 mmol) in THF:H20 (4:1) were added Cs2CO3 (10.07 g, 30.99 mmol) and 4-formylphenylboronic acid (1.158 g, 7.75 mmol). The reaction mixture was thoroughly degassed and freshly prepared tetrakis(triphenylphosphine)palladium(0) (1.119 g, 0.96 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture temperature was raised to 80° C. and continued stirring for 12 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the THF was removed under reduced pressure. The mixture was partitioned between ethyl acetate (100 mL) and water (15 mL). The organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide Example 102 (1.0, 62.6%). 1HNMR (CDCl3, 200 MHz) δ: 10.11 (s, 1H), 8.90 (s, 2H), 8.17 (s, 1H), 8.00-7.92 (m, 2H), 7.85-7.80 (m, 2H), 7.64-7.38 (m, 4H), 5.15 (s, 2H), 4.39 (t, 2H, J=5.4 Hz), 3.88 (s, 3H), 2.98 (t, 2H, J=5.4 Hz); m/e=413(M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]3[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][CH2:22][N:21]3[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:14][CH:15]=2)[N:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:35]([O:34][C:13]1[CH:12]=[C:11]2[C:16]([C:17]3[N:21]4[CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:20]4=[N:19][C:18]=3[C:9]([NH2:8])=[N:10]2)=[CH:15][CH:14]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (50 mL of a 10% solution in dichloromethane) was added to tert-butyl 6-amino-3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (2.07 g, 4.50 mmol), and the reaction was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the residue was recrystallized from methanol to provide 2.2 g of 3-benzyloxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine trifluoroacetate.
Reaction SMILES: N12CCCN=C1CCCCC2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C@@H:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23](O)[CH2:22]2)=[CH:13]1.C1(P([N:45]=[N+:46]=[N-:47])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1COCC1>[N:45]([C@@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][CH:13]=2)[CH2:22]1)=[N+:46]=[N-:47]
Reactant: O[C@@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (4.8 mL, 32.1 mmol, 1.45 equiv) was added to (1R,3S)-3-(1H-indol-3-yl)-indan-1-ol (22.2 mmol ) and diphenyl phosphoryl azide (6.0 mL, 27.8 mmol, 1.25 equiv) in 150 mL dry THF at 0° C. The reaction was stirred 0.5 hours at 0° C., then 2 hours at room temperature—TLC showed full conversion. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with 100 mL 0.5 N HCl, sat. NaHCO3, dried over MgSO4 and concentrated in vacuo to give the 3-((1S,3S)-3-azido-indan-1-yl)-1H-indole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH2:2]1.[C:7]([O:10]C(=O)C)(=[O:9])[CH3:8].S(=O)(=O)(O)O.[C:19]([O-])(=[O:21])[CH3:20].[Na+]>>[C:19]([O:1][CH2:6][CH2:5][CH2:4][O:3][CH2:2][O:10][C:7](=[O:9])[CH3:8])(=[O:21])[CH3:20]
Reactant: CC(=O)[O-]
Reactant: C1COCOC1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)OCCCOCOC(C)=O
Temperature: 20 °C
Reaction time: 14 h
Yield: 50174.4 %

Procedure:
To a mixture of 1,3-dioxan (3 ml, 0.035 mmol) and acetic anhydride (3.3 ml, 0.035 mmol) at 0° C., was added a drop of concentrated sulphuric acid. The mixture was then stirred for 14 h at 20° C., added with sodium acetate (2 g) and filtrated. The residue, distilled in vacuo (120° C., 16 mmHg), gave 1-acetoxy-3-acetoxymethoxypropane (3.34 g, 50%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12](=O)[CH2:13][C@H:14]2[NH:17][C:16](=[O:18])[C@@H:15]2[C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(N([CH2:35][CH3:36])CC)C.O.[C:38]([O:41][CH2:42]C)(=[O:40])[CH3:39]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:13][C@H:14]3[N:17]([C:16](=[O:18])[C@@H:15]3[C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[C:39]=2[C:38]([O:41][CH2:42][CH:35]=[CH2:36])=[O:40])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CCOC(C)=O
Reactant: C=CCOC(=O)N1CCC(C(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C1
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(C2CCN(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S,4R)-4-[2-(1-allyloxycarbonylpyrrolidin-3-yl)-2-oxoethyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (2.13 g) and triethylamine (1.4 ml) in dichloromethane (30 ml) was added allyl oxalyl chloride (1.1 g) at -20° C. under nitrogen, and the resulting mixture was stirred for 30 minutes at -20° C. The reaction mixture was taken up into a mixture of water and ethyl acetate. The organic layer was separated, washed in turn with water, aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and evaporated. To a solution of the residue in xylene (30 ml) was added triethyl phosphite (5.2 ml). The resulting mixture was heated at 90° C. for 15 hours under nitrogen, and then to the mixture was added hydroquinone (0.9 g) and the mixture was heated at 130° C. for 2 hours under nitrogen. Evaporation of the solvent gave a residue, which was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (4:1, V/V) to give allyl (5R,6S)-3-(1-allyloxycarbonylpyrrolidin-3-yl)-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.9 g).