Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=[O:25])[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[N:3]=1.[ClH:38].C([N:41]([CH2:44][CH3:45])CC)C>O1CCOCC1.C(#N)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([NH:41][C:44]5[CH:45]=[CH:12][C:11]([Cl:38])=[CH:10][CH:9]=5)=[O:25])[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[N:3]=1
Reactant: Cl
Reactant: CCN(CC)CC
Reactant: CN1CCN(c2cc(N3CCc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4C3)nc(N)n2)CC1
Solvent: CO
Solvent: C1COCCO1
Solvent: CC#N
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCN(C(=O)Nc6ccc(Cl)cc6)CC5)cc4C3)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperazine-1-carboxylate (16 mg, 0.031 mmol) was treated with 4M HCl in dioxane (0.5 mL) at r.t. for 1 h. The reaction mixture was concentrated to dryness. 1-Chloro-4-isocyanatobenzene (5.0 uL, 0.041 mmol, Aldrich, Cat. No. 152277) was added to a mixture of above residue and triethylamine (22 uL, 0.16 mmol) in acetonitrile (1.0 mL). After stirring at r.t. for 2 h., the reaction mixture was diluted with MeOH and purified by RP-HPLC (pH=10 system) to afford the desired compound. LCMS(M+H)+: m/z=562.3.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(Cc3ccccc3)C2)cc1

Procedure:
2.39 g (12.4 mmoles) of toluene-4-sulfonyl chloride, dissolved in 10 ml of pyridine, were added dropwise, under nitrogen atmosphere, to a stirred solution of 2.0 g (11.3 mmoles) of N- benzyl-3-hydroxypyrrolidine [J. Med. Pharm. Chem. 1, (1959) 73,76,77]in 15 ml of pyridine, cooled below -10° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:24][O:25][CH2:26][C:27](O)=[O:28].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:28]
Reactant: O=C(O)COCCOC1CCCCO1
Reactant: O=C(COCCO)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Product: O=C(COCCOC1CCCCO1)OCCOCC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
A solution of the alcohol 4 (685 mg, 3.26 mmol), the acid 2 (932 mg, 4.57 mmol), DIC (680 μl, 4.57 mmol) and DMAP (39 mg, 0.32 mmol) was stirred overnight at room temperature. The mixture was then filtered and concentrated. Flash chromatography on silica gel (EtOAc/pentane 1/1) afforded compound 5 as an oil (1.06 g, 82%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(CN)cn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(CN)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of ethyl 2-(6-(5-(aminomethyl)pyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.18 g, 3.31 mmol) in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 3 using 1 M HCl. The precipitate was collected and washed with water and dried to give the product as a white solid (0.85 g, yield 78%). No right mass was observed and the structure was confirmed by NMR. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (b, 1H), 9.80 (b, 2H), 9.22 (s, 1H), 8.26 (d, J=2 Hz, 1H), 8.07 (m, 1H), 7.21 (d, J=2 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.01 (m, 1H), 5.51 (dd, J=9.2, 4 Hz, 1H), 4.15 (s, 2H), 3.07 (dd, J=15.6, 2.4 Hz, 1H), 2.28 (s, 3H), 2.12 (dd, J=15.2, 9.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:67]([NH:74][CH2:75][CH2:76][CH2:77][NH2:78])([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:78][CH2:77][CH2:76][CH2:75][NH:74][C:67](=[O:68])[O:69][C:70]([CH3:72])([CH3:71])[CH3:73])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-Boc-1,3-propanediamine (57 mg, 0.33 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate as white solid. Yield: 120 mg, 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)C(O)=O)(=[O:13])=[O:12])[CH2:6][CH2:5]2.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CN([CH:38]=[O:39])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:22]=[CH:21][C:20]([C:38]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[N:30]=3)=[O:39])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:6][CH2:5]2
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3cc(Cl)ccc32)c1
Reactant: CN(C)C=O
Reactant: Nc1nc(-c2ccccn2)cs1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1ccc(S(=O)(=O)N2CCc3cc(Cl)ccc32)cc1

Procedure:
3-(5-chloroindolin-1-ylsulfonyl)benzoic acid (8) (100 mg, 0.30 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (44 mg, 0.25 mmol) in DMF (2 mL) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(5-chloroindolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 53 mg (43%). 1H-NMR: 8.63-8.59 (m, 1H), 8.25 (d, J=8.5 Hz, 2H), 8.02-7.86 (m, 5H), 7.49 (d, J=8.5 Hz, 1H), 7.34 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.29-7.24 (m, 2H), 4.00 (t, J=8.5 Hz, 2H), 2.94 (t, J=8.5 Hz, 2H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1OC
Solvent: O
Product: COc1cc(C(=O)CN2CCN(c3ccncc3)CC2)ccc1OCC(=O)O
Yield: 47 %

Procedure:
In a similar manner to Example 2, but starting from the product of Example 5, the title compound was prepared in 47% yield: m.p. 218°-224° C.; NMR(d6DMSO) δ8.16(2H,d), 7.65(1H,dd), 7.53(1H,d), 6.92(1H,d), 6.85(2H,d), 4.73(2H,s), 3.86(2H,s), 3.82(3H,s), 3.36(4H,t), 2.63(4H,t); m/e 386(M+H)+ ; calculated for C20H23N3O5. H2O: C, 59.5; H, 6.2; N, 10.4. found: C, 59.5; H, 5.9; N, 10.1%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][O:13][C@H:14]1[CH2:17][C@H:16]([NH2:18])[CH2:15]1.CCN(C(C)C)C(C)C>CC#N.[Pd]>[F:8][C:6]1[CH:7]=[C:2]([NH:18][C@H:16]2[CH2:17][C@H:14]([O:13][CH3:12])[CH2:15]2)[C:3]([NH2:9])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CO[C@H]1C[C@H](N)C1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CO[C@H]1C[C@H](Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.2 mL, 1.7 mmol) in CH3CN (3 mL) were added trans-3-methoxycyclobutylamine (0.18 g, 1.7 mmol) and DIPEA (0.3 mL, 1.7 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The resulting residue was carried to the next step without further purification (0.41 g, quantitative). To a solution of the product thus obtained (1.7 mmol) in EtOAc (15 mL) was added Pd/C (350 mg) and the reaction mixture was stirred at RT for 18 h under a hydrogen atmosphere. The suspension was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford the title compound as a dark oil (0.36 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.68-6.59 (1H, m), 6.33 (1H, dt, J=19.6 Hz, 2.7 Hz), 6.18 (1H, dd, J=13.6 Hz, 2.7 Hz), 4.00-3.90 (1H, m), 3.76-3.63 (1H, m), 3.53 (3H, br s), 3.27 (3H, s), 2.49-2.37 (2H, m), 2.36-2.12 (2H, m).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].[Cl-].[NH4+]>CCOCC.C1COCC1>[O:19]=[C:13]1[CH2:18][CH:17]2[CH2:16][CH2:15][CH:14]1[CH2:22][CH:21]2[C:20]([O:24][CH3:25])=[O:23]
Reactant: O=C1C=CCCC1
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1CC2CCC1CC2=O
Temperature: -11 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a cooled solution of diisopropylamine (7.72 mL, 54.62 mmol) in ether (40 mL) at −78° C. was added 2.5M n-butyllithium (21.8 mL) dropwise. The reaction mixture was allowed to warm to −11° C. A solution of cyclohex-2-en-1-one (5.04 mL, 52.01 mmol) in diethyl ether (60 mL) was added over 45 minutes. During the addition, the temperature was maintained between −11° C. and −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl prop-2-enoate (4.68 mL, 52.01 mmol) in THF (40 mL) was added dropwise over 60 minutes. The reaction mixture was stirred at this temperature for 1 h and stored in a freezer overnight. The reaction mixture was poured into saturated ammonium chloride solution (200 mL) and stirred for 15 minutes. A brown sticky polymer was formed and removed using tweezers. The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (Biotage; 0-60% ethyl acetate in heptane) in 2 batches, to afford the title compound (2.98 g, 31%) as the trans isomer as a clear colourless liquid. δH (500 MHz, CDCl3) 3.70 (s, 3H), 2.76 (ddt, J 10.6, 6.4, 1.8 Hz, 1H), 2.53-2.48 (m, 1H), 2.47-2.38 (m, 1H), 2.37-2.31 (m, 1H), 2.22 (ddt, J 14.2, 6.3, 2.5 Hz, 1H), 2.13 (ddd, J 19.1, 2.9, 1.8 Hz, 1H), 2.02 (ddd, J 14.3, 11.0, 3.5 Hz, 1H), 1.89-1.74 (m, 3H), 1.70-1.60 (m, 1H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:16]([OH:18])=[O:17]>CC(C)=O>[C:1]([NH:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:16]([OH:18])=[O:17])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)cc(C(=O)O)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1cc(NC(=S)NC(=O)c2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
Benzoyl isothiocyanate (169 μl, 1.25 mmol) was added to a solution of 3-amino-5-methoxy-benzoic acid (0.2 g, 1.19 mmol) in acetone (10 mL). The reaction was stirred at ambient temperature and a thick precipitate formed after 10 minutes. LCMS indicated complete conversion of the starting material. The solvent was removed in vacuo and the crude material triturated with iso-hexane, dried under reduced pressure and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](C)[CH:18]=3)[NH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:22]C1C=CC(SC2C3C(=CC=C(C)C=3)NC=2C)=CC=1>>[Cl:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])=[C:12]([CH3:21])[NH:13]2
Reactant: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Reactant: Cc1ccc2[nH]c(C)c(S(=O)(=O)c3ccc(Cl)cc3)c2c1
Product: Cc1[nH]c2cccc(Cl)c2c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 part (b) using the product from part (a). Product was purified using Flash column chromatography (33% EtOAc/hexane as eluent).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:21])[CH:19]=[CH2:20].S(=O)(=O)(O)O.C1(C=CC(O)=CC=1)O>C1C=CC=CC=1>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: C=CC(=O)O
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Yield: 54.3 %

Procedure:
4.8 g of 4-(6-hydroxyhexyloxy)benzoic acid and 5.8 g of acrylic acid were heat-refluxed for 40 hours together with 1 ml of sulfuric acid in the presence of hydroquinone in benzene, followed by distilling-off of the solvent and recrystallization to obtain 3.2 g of the product. (Yield: 55 %)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN(C=O)C.CCN(CC)CC.[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C>[CH2:33]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=3)[CH:6]=2)[CH2:1]1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)cc1
Reactant: CCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCN1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Yield: 76.8 %

Procedure:
Combine 4-(1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-benzamide (80.0 mg, 0.30 mmol), DMF (4 mL), Et3N (0.2 mL, 1.32 mmol), and pentylbromide (0.1 mL, 0.66 mmol) in a 7 mL vial. Place the vial on a shaker at 70° C. for 72 hours and then add ethyl acetate to the reaction vial. Wash with water and several times with 10% LiCl (aq), and dry over Na2SO4. Concentrate the organic mixture and flash chromatograph using 2% 1.0 N NH3 in MeOH, 20% THF, 78% CH2Cl2 to afford 78.0 mg (77% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.9-1.0 (3H, m), 1.3-1.4 (4H, m), 1.5-1.7 (2H, m), 2.4-2.6 (2H, m), 2.7-2.8 (2H, m), 2.8-3.0 (2H, m), 3.5-3.6 (2H, m), 6.8-6.8 (2H, m), 6.9-7.1 (3H, m), 7.7-7.9 (2H, m); MS m/z 339 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:6])=[O:4].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>ClCCl>[C:34]([NH:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:6])=[O:4])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3c2nc(C)n3C)c1Cl
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-[3-(N-glycyl-N-methylamino) -2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (80 mg) in dichloromethane (0.8 ml) were added pyridine (23.3 mg) and acetic anhydride (30.1 mg) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed with toluene azeotropically three times. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1, v/v) to give 4-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (75 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O-:26].[Na+]>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([O:26][CH3:25])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:21])[CH3:22]
Reactant: C[O-]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Yield: 3.4 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 100 mg, 0.302 mmol) and sodium methoxide (1.2 mL from 2M solution in methanol, 0.605 mmol) in DMF (3 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (3.4 mg, 6%). 1H NMR (DMSO-d6) δ: 11.10 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.01-8.03 (m, 1H), 7.98-8.01 (m, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.55 (s, 1H), 6.41 (d, J=2.3 Hz, 1H), 5.19 (s, 1H), 4.21 (s, 3H), 1.46 (s, 6H). ESI-MS: m/z 327.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O[CH2:10][CH:11]([CH2:13]O)O>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:13][CH:11]=[CH:10]2
Reactant: Nc1ccc(F)cc1
Reactant: OCC(O)CO
Product: Fc1ccc2ncccc2c1

Procedure:
4-Fluoroaniline (ex Aldrich) and anhydrous glycerol (ex Fluka) were reacted together in a Skraup reaction according to Sveinbjornsson et al, J. Org. Chem., 16, 1450 (1951) to give 6-fluoroquinoline. The latter (3.82 g) in glacial acetic acid (22 ml) was treated with 30% hydrogen peroxide (7 ml) for 4 hours at 70°-80° C. Additional 30% hydrogen peroxide (7 ml) was added and the mixture kept for 16 hours at 70°-80° C. The solvents were removed at reduced pressure and the residue neutralized with solid sodium carbonate and extracted with chloroform. The organic phase was washed with hexane and dried to give 6-fluoroquinoline-N-oxide (3.13 g). The latter (1 g) was heated under reflux with acetic anhydride (6 ml) in the absence of moisture for 1 hour, the hot mixture treated with water (6 ml), boiled for 1 hour and poured onto fresh ice. After neutralisation with aqueous sodium carbonate the solid product, 2-hydroxy-6-fluoroquinoline, was collected by filtration and dried (0.39 g). 2-chloro-6-fluoroquinoline was obtained by analogy with Example IV and used in Stage a.
Reaction SMILES: [Cl-].[C:2](=[O:5])([O-])[OH:3].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([C:31]([NH:33][C@H:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]([CH3:44])[CH3:43])[CH:37]=4)[CH3:35])=[O:32])=[CH:28][CH:29]=3)[C:24]([CH3:45])=[C:23]2[CH3:46])=[CH:17][CH:16]=1)#[N:8].[N:47]12CCCN=C1CCCCC2>C(OCC)(=O)C.CS(C)=O>[CH:42]([C:38]1[CH:37]=[C:36]([C@@H:34]([NH:33][C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:7]4[NH:47][C:2](=[O:5])[O:3][N:8]=4)=[CH:20][CH:19]=2)[C:23]([CH3:46])=[C:24]3[CH3:45])=[O:32])[CH3:35])[CH:41]=[CH:40][CH:39]=1)([CH3:43])[CH3:44]
Reactant: O=C([O-])O
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C#N)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of hydroxylammoium chloride (0.2 g, 2.88 mmol), sodium hydrogen carbonate (0.3 g, 3.57 mmol) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min. (S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide (0.1 g, 0.19 mmol) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with brine, and dried over anhydrous sodium sulfate. Thvent was evaporated under reduced pressure, and the residue was dissolved in THF (3 mL), N,N′-carbonyldiimidazole (0.055 g, 0.29 mmol) and then 1,8-diazabicyclo[5,4,0]undec-7-ene (0.05 mL, 0.29 mmol) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative-HPLC to obtain the title compound. ESI-MS (m/z): 585 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@@H:15]1[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)(C)C>[OH:14][C@@H:15]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture containing 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (410 mg, 2.1 mmol), tert-butyl [(3R,4R,5S)-4-hydroxy-5-methylpiperidin-3-yl]carbamate (240 mg, 1.0 mmol) and triethylamine (0.5 mL, 4 mmol) in isopropyl alcohol (3.0 mL) was stirred at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a CombiFlash® apparatus (eluting with 0 to 80% EtOAc in hexanes) to give the sub-title compound as pale yellow powder (200 mg, 50%). LCMS calc. for C19H29N4O5 (M+H)+: m/z=393.2. Found: 393.2.