Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[O:34][C:33]4=[N:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][N:32]4[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>>[N+:38]([C:36]1[N:35]=[C:33]2[N:32]([CH:37]=1)[CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH2:13][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:2]([F:1])([F:6])[F:7])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)=[CH:26][CH:25]=1)[O:34]2)([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (6.0 ml) was added to 4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (200 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (2.0 ml) and triethylamine (2.0 ml) were added to the residue, followed by stirring at room temperature for 5 minutes. The reaction mixture was reconcentrated under reduced pressure. 1,2-Dichloroethane (5 ml), 4-(trifluoromethoxy)benzaldehyde (124 μl) and sodium triacetoxyborohydride (185 mg) were added to the residue, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=10:0→methylene chloride:methanol=9:1) and recrystallized from methylene chloride-isopropyl ether to afford the title compound as a white powder (211 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][N:28]([CH3:34])[CH2:29][CH2:30][NH:31][CH2:32][CH3:33]>C(Cl)Cl>[CH3:27][N:28]([CH3:34])[CH2:29][CH2:30][N:31]([CH2:32][CH3:33])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CCNCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCN(C)C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N,N-dimethyl-N′-ethylethylenediamine (1.2 ml; 7.42 mmol; 5.00 eq) are added. After 30 minutes at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (22) as a beige solid (544 mg; 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(C)=O.C(OCC)(=O)C>[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 60 °C
Yield: 60.9 %

Procedure:
To a solution of 2-Chloromethyl quinoline (2 g, 9.3 mmole) in acetone (47 ml, 0.2M) was added 4-hydroxy benzoic acid methyl ester (1.42 g, 1.0 eq.) and potassium carbonate (3.86 g, 3 eq.). The reaction mixture was heated at 60° C. for 16 h under N2 atmosphere, cooled to ambient temperature and poured into 1N sodium hydroxide (50 ml)/ethyl acetate (100 ml). The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Biotage MPLC was run using a 5-30% ethyl acetate/hexane gradient on a 40 M column to provide the title compound as a white solid (1.66 g, 61%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.7 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.95 (M, 2H), 7.82 (d, J=7.9 Hz, 1H), 7.74 (dt, J=7.1, 1.7 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.55 (dt, J=7.9, 1.2 Hz, 1H), 7.03 (d, J=9.1, 2H), 5.41 (s, 2H), 3.84 (s, 3H); MS: (M+H m/z=294.2).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[NH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22][C:21]3=O)[CH:7]=1>>[Cl:3][C:21]1[C:20]2[C:25](=[C:16]([C:8]3[CH:7]=[N:6][C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:17]=[CH:18][CH:19]=2)[N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[N:22]=1
Reactant: O=c1nc(C(F)(F)F)[nH]c2c(-c3cnc4ccccc4c3)cccc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nc(Cl)c2cccc(-c3cnc4ccccc4c3)c2n1

Procedure:
A suspension of compound (114a) (0.57 g), 3-quinolineboronic acid (0.45 g), Pd2dba3 (0.031 g), X-Phos (0.064 g), and potassium phosphate (1.4 g) in butanol was stirred at 100° C. for 15 hours in a nitrogen atmosphere. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g) as a white solid. Phosphorus oxychloride (5 ml) was added to the obtained 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g), and the mixture was heated to reflux for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The reaction solution was neutralized with an aqueous sodium bicarbonate solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline (0.43 g) as a white solid. Compound (114) was obtained as a yellow solid (yield based on 4 steps: 25%) according to Example 1(5) using the obtained 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline instead of compound (1d) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C(O)CO.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][SH:31])=[CH:28][CH:27]=1>C(O)(C)C.C(Cl)(Cl)Cl>[CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([S:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(I)cc1
Reactant: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: OCCO
Product: CCNS(=O)(=O)c1ccc(SCc2ccc(OC)cc2)cc1
Temperature: 80 °C

Procedure:
To a suspension of N-ethyl-4-iodo-benzenesulfonamide 6 g in isopropanol 26 ml was added ethylene glycol 1.9 ml, potassium carbonate 4.68 g, cuprous iodide 320 mg and then 4-methoxybenzyl mercaptan 3.55 g. The mixture was heated at ˜80° C. for 16 h and then cooled, diluted with chloroform 250 ml and washed with water ×3, (any solid at the interface was filtered off). The organic solution was dried, MgSO4 and evaporated. The solid was triturated with cyclohexane ×2 and dried to give N-ethyl-4-(4-methoxy-benzylsulfanyl) -benzenesulfonamide, 5.98 g 92%. 1HNMR 7.63 (2H, d), 7.28 (2H, d), 7.18 (2H, d), 6.79 (2H, d), 4.40 (1H, m), 4.08 (1H, s), 3.72 (3H, s), 2.90 (2H, m), 1.03 (3H, t).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:43]=[CH:42][C:18]([C:19]([NH:21][C:22]3[C:23]4[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C:24]=4[N:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:43]=[CH:42][C:18]([C:19]([NH:21][C:22]3[C:23]4[CH2:34][NH:33][CH2:32][C:24]=4[N:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c2c1CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c2c1CNC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 4N solution of hydrochloric acid in dioxane (122 ml, 488 mmol) was added dropwise to a stirred solution of 5-tert-butyl 1-ethyl 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (19.5 g, 39.2 mmol), as prepared in Example 2, in dry DCM (240 ml); precipitation of a white solid occurred almost immediately. The resulting mixture was stirred at room temperature for 24 hours; after dilution with Et20 (100 ml), the solid was filtered, extensively washed with Et20, and dried under vacuum at 50° C. to give 20.1 g of the title compound, used in the next step without further purification. [M+H]+ 399.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:4]([Cl:28])[CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([S:14](=[O:16])(=[O:15])[NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][C:4]=2[Cl:28])=[CH:18][CH:19]=1)[CH3:31]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Br)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3[C:15]4[C:14]([CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=4[NH:9][C:8]=32)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:23]>C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:19]=[C:18]2[C:5](=[CH:4][CH:3]=1)[C:6]1[N:9]([CH3:23])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[C:15]=3[C:7]=1[CH2:8]2
Reactant: Cc1cc(C)c2c3c([nH]c2c1)-c1cc(F)ccc1C3
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3
Temperature: 40 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of 47b (2.74 g, 10.9 mmol) in benzene (59 mL) was added aqueous sodium hydroxide (50% by mass, 5.9 mL), tetrabutylammonium iodide (289 mg, 0.78 mmol), and iodomethane (5.42 mL, 87.1 mmol). The reaction mixture was stirred vigorously at 40° C. for 16 hours and then cooled to room temperature. The mixture was diluted with benzene (20 mL) and H2O (20 mL), and the aqueous layer was extracted 2×20 mL ethyl acetate. Organic layers were combined, washed 1×25 mL H2O, dried over anhydrous magnesium sulfate and concentrated to yield a brown solid. Crude product was purified by flash column chromatography (15:1 hexanes-ethyl acetate followed by a second column 40:1 to 26:1 hexanes-ethyl acetate) to give 48b in 39% yield (1.12 g, 4.24 mmol). 1H NMR (400 MHz, CDCl3): δ 7.51-7.53 (dd, 1H, J=8.2, 5.2 Hz), 7.237-7.260 (m, 1H), 7.99-7.06 (td, 1H, J=9.2, 2.4 Hz), 6.99 (s, 1H), 6.78 (s, 1H), 3.97 (s, 3H), 3.80 (s, 2H), 2.60 (s, 3H), 2.46 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.5 (d, J=361.5 Hz), 150.4 (d, J=13.5 Hz), 142.42, 141.72, 131.6 (d, J=3.0 Hz), 131.3, 129.0, 121.9, 121.6, 119.5 (d, J=4.5 Hz), 117.1 (d, J=13.5 Hz), 113.2 (d, J=34.5 Hz), 113.5 (d, J=34.1 Hz), 107.1, 31.2 (d, J=2.9 Hz), 30.8, 21.8, 19.0; 19F NMR (CD3CD, 376 MHz): δ −118.0 (m); FTIR: cm−1 3011, 2917, 1588, 1527, 1449, 1417, 1360, 1267, 1212.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>[Ti](Cl)(Cl)(Cl)Cl.C1(OC)C=CC=CC=1>[CH3:23][C:21]1[CH:20]=[CH:19][C:3]2[NH:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:1][C:2]=2[CH:22]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1c(sc3ccccc13)N2

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4-methylanilino)benzo[b]thiophene-3-carboxylate (3.7 g), 1-methylpiperazine (19 ml), anisole (60 ml) and titanium tetrachloride (3.0 ml), 9-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.18 g) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[C:27]([CH:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:26][C:25]3[C:20](=[CH:21][C:22]([O:38][CH3:39])=[C:23]([O:36][CH3:37])[CH:24]=3)[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40].CCO>>[ClH:40].[CH3:37][O:36][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:38][CH3:39])[N:19]=[C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:27]([CH:28]=[CH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[N:26]2
Reactant: COc1cc2nc(C=Cc3ccccc3)c(NCCCC3CCN(C(=O)OC(C)(C)C)CC3)nc2cc1OC
Agent: Cl
Solvent: CCO
Product: COc1cc2nc(C=Cc3ccccc3)c(NCCCC3CCNCC3)nc2cc1OC

Procedure:
A solution of the product from Step A above (150 mg, 0.28 mmol) in conc HCl/EtOH (1:2 mixture, 3 mL) was stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum and the residue was azeotroped twice with ethanol to give the desired product as an amorphous solid. API-MS: 433 (M+1). 1H NMR (300 MHz, d4-MeOH): d 8.0 (d, 2 H), 7.75 (d, 2 HO, 7.66 (d, 2 H), 7.4 (m), 4.0 (s, 3 H), 3.96 (s, 3 H)m 3.65 (t, 2 H), 3.28 (m, 2 H), 2.96 (t, 2 H), 2.0-1.2 (m).
Reaction SMILES: C(O[C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[N:20](C(OC(C)(C)C)=O)[CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]3[CH2:31][CH2:32][CH2:33][C:14]=23)=[CH:8][CH:7]=1)C.[NH3:35]>CO>[NH:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[N:16]=[C:15]2[CH2:31][CH2:32][CH2:33][C:14]2=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([NH2:35])=[O:34])=[CH:11][CH:10]=2)[CH:18]=1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cccn3C(=O)OC(C)(C)C)nc3c2CCC3)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3ccc[nH]3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 65 h
Yield: 37.6 %

Procedure:
A 20-mL vial was charged with tert-butyl 2-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylate (0.110 g, 0.24 mmol, 1.0) and methanol (3 mL). To this solution was added NH3 (6.8 mL, 7N in methanol, 476 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 65 h. After this time, the crude reaction solution was concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using dichloromethane/(90:10:0.25 dichloromethane/methanol/aq. NH4OH) (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford 2-(4-((2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (0.030 g, 38%) as a brown solid. MW=332.40. 1H NMR (DMSO-d6, 500 MHz) δ 11.16 (br s, 1H), 7.93 (br s, 1H), 7.42 (br s, 1H), 7.26-7.22 (m, 2H), 7.17-7.13 (m, 2H), 7.03 (s, 1H), 6.85 (s, 1H), 6.74-6.71 (m, 1H), 6.39 (s, 1H), 6.05-6.20 (m, 1H), 3.34 (s, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.05 (quin, J=7.5 Hz, 2H). MS: ESI, m/z 333 [M+H]+. Treatment with 1.25M HCl in methanol afforded the title compound (0.035 g, 100%) as an off-white solid. MW=368.86. M.p. 163-165° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.43 (br s, 1H), 12.06 (br s, 1H), 9.46 (br s, 1H), 7.52 (br s, 1H), 7.40-7.36 (m, 2H), 7.32-7.28 (m, 2H), 7.12-7.09 (m, 1H), 7.08 (s, 1H), 7.06-7.03 (m, 1H), 6.92 (br s, 1H), 6.29-6.25 (m, 1H), 3.43 (s, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); APCI MS m/z 333 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.CO.[C:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])(=[O:10])[CH3:9].[C:20]([O-])(O)=O.[Na+]>O>[CH3:20][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([C:8](=[O:10])[CH3:9])[CH:12]=1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(C(C)=O)c1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Sulfuric acid (23.4 μl, 0.430 mmol) was added into the MeOH (15 ml) solution of 3-acetylbenzoic acid (720 mg, 4.30 mmol). The mixture was stirred at 70° C. for 20 h. After that time, the mixture was cooled and was treated with saturated NaHCO3 till pH>9, followed by adding water to dissolve the solid which was formed, extracted with EtOAc (2×50 ml). The extracts were washed with water (50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo, giving the title compound as brown oil. 1H NMR (400 MHz, CDCl3): δ=2.66 (s, 3H), 3.96 (s, 3H), 7.54-7.59 (m, 1H), 8.14-8.19 (m, 1H), 8.22-8.26 (m, 1H), 8.59-8.61 (m, 1H). MS (ES+): m/z 179.17 [MH+]. HPLC: tR=2.82 min (polar—5 min, ZQ3).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([C:19]1[CH:47]=[CH:46][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=3)[C:25]2=O)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+].[Na+].[Cl-]>C1(C)C=CC(C)=CC=1.O>[C:15]([C:19]1[CH:47]=[CH:46][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=3)[C:25]2=[S:2])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc(NS(C)(=O)=O)cc3)c3ccccc32)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)c1ccc(Cn2c(=S)n(Cc3ccc(NS(C)(=O)=O)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
Phosphorus pentasulfide (300 mg, 0.67 mmol) was added to a suspension of N-{4-[3-(4-tert-butylbenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (6) (235 mg, 0.51 mmol) in para-xylene (20 mL) under a blanket of argon. The reaction mixture was heated to the boil over a period of 5 h. Following cooling, there was added to the reaction mixture water (1 mL) followed by 2N NaOH solution in water (10 mL), and the mixture was stirred at RT for 30 min. To the reaction mixture there was added aqueous NaCl solution, and the resulting mixture was extracted with ethyl acetate (4×20 mL). The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo. After purifying the residue by means of column chromatography (SiO2; cyclohexane/EtOAc 7:3), the desired product N-{4-[3-(4-tert-butylbenzyl)-2-thioxo-2,3-dihydrobenzoimidazol-1-ylmethyl]phenyl}methanesulfonamide (2) (99 mg, 40% of theory, mp: 176-178° C.) was obtained.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH3:32])[C:16]=2[CH:33]=1.[CH2:40]=[O:41].O>C1COCC1>[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:37])[CH3:38])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH2:32][CH2:40][OH:41])[C:16]=2[CH:33]=1
Reactant: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Reactant: C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Oc1cc2oc(=O)c(Cc3cccc([N+](=O)[O-])c3)c(CCO)c2cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
LiHMDS (57.5 mL, 1.0 M in THF) was added under nitrogen atmosphere at −78° C. to a suspension of dimethylcarbamic acid 6-chloro-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-3) (20.0 g, 48.0 mmol) in anhydrous THF (250 mL), and the reaction mixture was stirred at −78° C. for 30 minutes and at 0° C. for 30 minutes. Paraformaldehyde (2.88 g, 96.0 mmol) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was obtained by vacuum concentration, and it was washed with ethyl acetate to yield the title compound (18.5 g, 86%) as a white powder.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:28][C:29](=[O:44])[O:30][CH2:31][C:32]1([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33]1)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].OC([C@@H](NC(=O)OCC1(CC2C=CC=CC=2)CCCCC1)CCCCNC(N1CCOCC1)=O)C(=O)N[C@@H](C1C=CC=CC=1)C>>[N:22]1([C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]([NH:28][C:29](=[O:44])[O:30][CH2:31][C:32]2([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[CH2:33][CH2:34][CH2:35]2)[C:2](=[O:1])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:6])=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)c1ccccc1
Agent: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Product: C[C@@H](NC(=O)C(=O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)c1ccccc1

Procedure:
[1-(4-Fluorobenzyl)cyclobutyl]methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate was prepared as in example 9j except that [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate was substituted for (1-benzylcyclohexyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 8.90 (d, J=7 Hz, 1H), 7.07-7.38 (m, 10H), 6.28 (m, 1H), 5.01 (qnt, J=7 Hz, 1H), 4.83 (m, 1H), 3.81 (s, 2H), 3.54 (m, 4H), 3.26 (m, 4H), 3.04 (m, 2H), 2.77 (s, 2H), 1.80-1.90 (m, 6H), 1.19-1.48 (m, 9H). ES-LCMS m/z 633 (M+Na). HRMS C33H43N4O6F1 m/z 633.3064 (M+Na)Cal; 633.3072 (M+Na)Obs.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=O.[CH:20]([NH2:22])=O>>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]3=[N:1][CH:20]=[N:22][C:15](=[O:17])[CH:3]3[CH:4]=[N:5]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1N
Reactant: NC=O
Product: COc1ccc(N2N=CC3C(=O)N=CN=C32)cc1
Temperature: 180 °C

Procedure:
A mixture of compound 44A (7 g, 26.8 mmol) and formamide (64.1 mL, 1607 mmol) was heated at 180° C. overnight and cooled. The precipitate was collected, washed with water and dried to provide the desired product: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.35 (1H, s), 8.28 (1H, s), 8.15 (1H, s), 7.85-7.93 (2H, m), 7.09-7.14 (2H, m), 3.82 (3H, s).