Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[C:23]3[CH2:25][O:26][C:27]4[CH:52]=[C:51]5[C:30]([CH2:31][CH2:32][C:33]6[N:37]=[C:36]([C@@H:38]7[CH2:42][CH2:41][C@H:40]([CH3:43])[N:39]7[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[NH:35][C:34]=65)=[CH:29][C:28]=4[C:22]3=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:47]([O:46][C:44]([N:39]1[C@@H:40]([CH3:43])[CH2:41][CH2:42][C@H:38]1[C:36]1[NH:35][C:34]2[C:51]3[C:30]([CH:31]=[CH:32][C:33]=2[N:37]=1)=[CH:29][C:28]1[C:22]2[C:23]([CH2:25][O:26][C:27]=1[CH:52]=3)=[CH:24][C:19]([C:16]1[NH:15][C:14]([C@@H:9]3[CH2:10][CH2:11][C@H:12]([CH3:13])[N:8]3[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[N:18][CH:17]=1)=[CH:20][CH:21]=2)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(cc3-4)CCc3nc([C@@H]4CC[C@H](C)N4C(=O)OC(C)(C)C)[nH]c3-5)[nH]2)N1C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)OC(C)(C)C)[nH]c65)cc3-4)[nH]2)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
Tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (393 mg, 0.55 mmol) was suspended in DCM (7 mL) and activated MnO2 (1.45 g, 16.7 mmol) was added in a single portion. The reaction mixture was heated to 40° C. After stirring for 2.5 h, the mixture was cooled to rt and the slurry was filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH and the filtrate was concentrated under reduced pressure. The crude material was taken on to the next step without further purification to afford tert-butyl(2S,5S)-2-(5-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (328 mg, 85%).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C(=O)C>[CH3:27][N:13]([CH2:12][CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5](/[CH:4]=[CH:3]/[CH2:2][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:6][CH2:7]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: C1CCNCC1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(CC[C@H]1CC[C@H](/C=C/CN2CCCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 473 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25]Cl)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[I-].[Na+]>COCCOC>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:27]#[N:28])=[C:4]([F:29])[CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCN1CCOCC1

Procedure:
A mixture of 0.8 g (1.83 mmol) of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile, 2.4 g (27.5 mmol) of morpholine, and 0.11 g of sodium iodide in 15 ml ethylene glycol dimethyl ether refluxed for 7 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was recrystallized from ethyl acetate-carbon tetrachloride giving 0.63 of the title compound as a light tan solid: mass spectrum (electrospray, m/e) M+H 487.0; (M+2H)+2 243.9.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH2:63]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:63][CH2:62][CH2:61][CH2:60][N:59]([CH3:64])[CH3:58])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethyl-1,3-propanediamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.49 (m, 3 H) 1.53-1.87 (m., 9 H) 2.13 (s, 6 H) 2.25 (t, J=6.44 Hz, 2 H) 3.29 (m, 2 H) 3.31 (s, 3 H) 3.93 (s, 3 H) 4.06 (t, J=13.26 Hz, 2 H) 4.46 (m, 1 H) 7.46 (d, J=8.0 Hz, 1 H) 7.51 (s, 1 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.08 Hz, 1 H) 8.48 (br. s., 1 H). [M+H] calculated for C27H37F2N7O3, 546; found 546.
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[N:40]1[CH:41]=[CH:42][CH:43]=[C:44]([C:36]([O-:38])=[O:37])[CH:45]=1
Reactant: O=C(O)c1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Solvent: ClCCl
Product: O=C([O-])c1cccnc1

Procedure:
As in Example 8, maytansinol (109.0 mg, 0.193 mmol), picolic acid (144.2 mg, 1.171 mmols), DCC (278.5 mg, 1.352 mmols) and DMAP (50.2 mg, 0.411 mmol) are reacted in 10 ml of dry dichloromethane at room temperature for 6 hours. After the insolubles are filtered off, the filtrate is concentrated to dryness and the residue is dissolved in ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent is then distilled off. The residue is chromatographed on a column of silica gel (80 g) and elution is carried out with H2O-saturated ethyl acetate, the eluate being collected in 16-g fractions. Fractions 24 through 49 are pooled and the solvent is distilled off to recover 98 mg of crude product. This crude product is chromatographed again on a column of silica gel (50 g), elution being carried out with chloroform-methanol (40:1, V/V). Fraction 18 through 33 (16 g each) are pooled, the solvent distilled off and the residue dissolved in ethyl acetate, followed by addition of ether. The resultant crystals are collected by filtration. By the above procedure is obtained 45.4 mg of maytansinol 3-picolinate. m.p. 190°-193° C. (decompn.)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:23])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[OH:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:13]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH:10]([CH3:12])[CH3:11])[CH:8]=1)=[O:23]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 5-(3-Hydroxy-benzylcarbamoyl)-3-isopropyl-thiophene-2-carboxylic acid methyl ester (70 mg, 0.21 mmol), lithium hydroxide monohydrate (89 mg, 2.10 mmol), THF (5 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 71.8 mg (100%). MS m/e 319.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20]([NH:22]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([O:12][NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NO
Product: C[C@@H](C(=O)ONC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-propanoate is prepared from (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid and N-tert-butoxycarbonyl hydroxylamine according to Scheme 6. (0.96 g, 61%), The compound exists as rotomers and is reported as such. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.73-7.89 (1H, m), 4.61-5.04 (1H, m), 2.86-2.96 (3H, m), 1.41-1.53 (21H, m).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[H-].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38]Cl)[CH2:33][CH2:32]1)=[O:30].[Cl-].[NH4+]>CS(C)=O>[CH3:1][N:2]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)[C:3]([C:5]1[N:6]([CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][N:31]([C:29](=[O:30])[C:28]3[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:26]([O:25][CH3:24])[CH:27]=3)[CH2:32][CH2:33]2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4]
Reactant: Cc1cc(C)nc(N(C)C(=O)c2nc3ccccc3[nH]2)c1
Reactant: COc1ccc(C(=O)N2CCN(CCCl)CC2)cc1OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)N2CCN(CCn3c(C(=O)N(C)c4cc(C)cc(C)n4)nc4ccccc43)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
In an argon atmosphere, N-methyl-N-(4,6-dimethyl-2-pyridyl)benzimidazole-2-carboxamide (2.00 g) was dissolved in DMSO (15 ml), and 60% sodium hydride (0.33 g) was added and stirred at room temperature for 1 hr. A solution (7 ml) of 2-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]ethyl chloride (2.20 g) in DMSO was added dropwise and allowed to react overnight at room temperature under agitation. The reaction solution was added to an aqueous solution of ammonium chloride and extracted with chloroform, the chloroform layer was dried over Na2SO4, and the solvent was distilled off. Purification of the residue by column chromatography gave the title compound (3.10 g) as amorphous solid.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13](=[O:30])[N:12]2[CH2:31][C:32]([O:34]C)=[O:33])[CH:7]=[C:8]([F:10])[CH:9]=1>C1COCC1.O>[C:20]([O:19][C:17]([N:15]1[CH2:16][CH:11]([C:6]2[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=2)[N:12]([CH2:31][C:32]([OH:34])=[O:33])[C:13](=[O:30])[CH:14]1[CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)CN1C(=O)C(C2CCOCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 mg (0.48 mmol) lithium hydroxide were added to 0.20 g (0.43 mmol) tert-butyl 5-(3,5-difluorophenyl)-4-(2-methoxy-2-oxoethyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (isomer mixture 1.1) in 5 ml THF and 1 ml of water. The mixture was stirred for 2 h at RT and then evaporated to dryness.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[O:20][CH3:21])[NH:16][C:15](=[O:22])[CH2:14][CH2:13]3)=[CH:6][CH:5]=1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[O:20][CH3:21])[N:16]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15](=[O:22])[CH2:14][CH2:13]3)=[CH:8][CH:9]=1
Reactant: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccc(Cl)cc1)CCC(=O)N2CC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a mixture of 95% dry sodium hydride (24 mg, 1.00 mmol) in anhydrous N,N-dimethylformamide (8 mL) at room temperature was added a solution of 6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (7) (110 mg, 0.38 mmol) in N,N-dimethylformamide. The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl bromoacetate (390 mg, 2.00 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature until majority of the starting material was converted (as shown by LCMS), then it was quenched by addition of methanol (10 mL). The mixture was concentrated under reduced pressure, anhydrous toluene (10 mL) was added to the residue, and the solvent removed under reduced pressure, to afford crude (tert-butyl 2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetate).
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH:10]([CH3:12])C)=[CH:7][CH:6]=[CH:5][C:4]=1O.[Na].[CH2:15](Cl)C=C(C)C>CCOCC>[O:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:12][CH2:10]1
Reactant: COc1c(O)cccc1OC(C)C
Reactant: CC(C)=CCCl
Agent: [Na]
Solvent: CCOCC
Product: c1ccc2c(c1)CCCO2
Reaction time: 8 h

Procedure:
5.5 g (30 millimoles) of 2-methoxy-3-isopropoxy-phenol are dissolved in 30 ml of ether whereupon 2.1 g of metallic sodium are added in small portions and the mixture is heated to boiling for an hour. To the mixture 3.2 g (30 millimoles) of prenyl chloride are added dropwise and the reaction mixture is heated to boiling for 8 hours. The reaction mixture is worked up in the usual manner. Thus 4.4 g of "chromane" are obtained. This product is dissolved in 60 ml of benzene, 1.2 g of dichloro-dicyano-benzoquinone are added and the reaction mixture is purified as described in Example 3. Thus 3.7 g of the desired compound are obtained in the form of a colorless oil, yield 50%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:45]=[CH:44][C:10]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]5[CH:32]=[CH:31][C:30]6[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=6)[N:24]=5)=[CH:20][C:15]=4[N:14]=[C:13]3[CH2:33][C:34]3([C:39]([O:41]CC)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C1COCC1.[Li+].[OH-]>CO>[N:4]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]5[CH:32]=[CH:31][C:30]6[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=6)[N:24]=5)=[CH:20][C:15]=4[N:14]=[C:13]3[CH2:33][C:34]3([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:44][CH:45]=2)[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(N3CCOCC3)cc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(N3CCOCC3)cc2)CCCC1
Temperature: 80 °C

Procedure:
To a 20 mL vial were added ethyl 1-((1-(4-morpholinobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (28 mg, 0.046 mmol), THF (1.1 mL) and MeOH (1.1 mL) followed by LiOH (0.65 mL, 1 M). The reaction mixture was capped and heated to 80° C. for 3 h. The mixture was cooled to RT and the solvent was concentrated to dryness. Water (1 mL) and acetonitrile (1 mL) were added and the pH was adjusted to ˜5-6 using 1 M HCl and then the mixture was concentrated to dryness. The resulting residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C35H36N4O4, 576.27; m/z found, 577.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.5, 1H), 8.11 (d, J=8.4, 1H), 7.83 (d, J=8.1, 1H), 7.77-7.72 (m, 1H), 7.69 (d, J=8.5, 1H), 7.58-7.53 (m, 1H), 7.33-7.31 (m, 1H), 7.22 (d, J=8.9, 1H), 7.10-7.05 (m, 1H), 6.97-6.93 (m, 2H), 6.85-6.80 (m, 2H), 5.43 (s, 2H), 5.22 (s, 2H), 3.86-3.81 (m, 4H), 3.14-3.09 (m, 4H), 3.05 (s, 2H), 2.41-2.33 (m, 2H), 1.75-1.66 (m, 2H), 1.47-1.39 (m, 4H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7](CC1C(OC)=CC(OC)=CC=1OC)[C:8](=[O:27])[CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:6][NH:7][C:8](=[O:27])[CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: COc1ccc(CON(Cc2c(OC)cc(OC)cc2OC)C(=O)CCS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]propionamide (125 mg, 0.19 mmol) in dichloromethane (2 ml) was added triethylsilane (66 μl, 0.42 mmol) and trifluoroacetic acid (150 μl). The mixture was stirred at room temperature for 4 hours. The solvents were evaporated in vacuo. The residue was purified by chromatography on silica (eluant:dichloromethane, then ethyl acetate then dichloromethane −10% MeOH) to give 35 mg of the title compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=O>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:19](=[O:20])[O:21][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Acetic anhydride (40 ml) was added to a mixture of 4-methoxyphthalic acid (30.8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-methoxyphthalic anhydride (27.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 8.02 (1H, d), 7.59 (1H, d), 7.49 (1H, dd), 3.97 (3H, s). MS: [M+H]+ 179.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[Br:13])[CH:2]=[CH2:3].[CH2:15]([CH2:19][C:20](=O)[CH3:21])[C:16]([CH3:18])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)(=O)C>[CH2:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]([CH3:21])=[CH:19][CH:15]=[C:16]2[CH3:18])=[CH:8][C:7]=1[Br:13])[CH:2]=[CH2:3]
Reactant: CC(=O)CCC(C)=O
Reactant: C=CCNC(=O)c1ccc(N)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCNC(=O)c1ccc(-n2c(C)ccc2C)cc1Br

Procedure:
11 g of 4-amino-2-bromobenzoic acid-allylamide, 5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid are refluxed for 1.5 hours with a water separator. Then, the solution is diluted with ethyl acetate, washed with 1N hydrochloric acid and then with potassium carbonate solution, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized with hexane. 13.4 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl)-benzamide, melting point 136-138° C., is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5]Cl)[CH3:2].[CH2:10]([O:16][P:17]([O-:25])[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl.[OH-].[Na+]>[CH2:1]([N:3]([CH2:8][CH3:9])[C:4]([CH2:5][P:17](=[O:25])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCCCCCOP([O-])OCCCCCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCOP(=O)(CC(=O)N(CC)CC)OCCCCCC
Reaction time: 1 h
Yield: 93 %

Procedure:
Into a 2-liter, 3-necked, round bottom flask equipped with a mechanical stirrer, thermometer, 250 ml pressure-equalizing dropping funnel, and inert gas fittings was placed a solution of 149.5 g (1.OM) N,N-diethylchloroacetamide and 1.5 g "Adogen 464" in 400 ml CH2Cl2 and 200 ml 50% aqueous sodium hydroxide. The solution was stirred at 200 rpm and cooled to 5°-1020 C. in an ice bath. Dihexylphosphite 250 g (1.09M) diluted with 100 ml CH2Cl2 was added dropwise from the dropping funnel. This addition took about 1 hour. An analytical sample was taken by syringe every hour, and the progress of the reaction was monitored by GC analysis to determine the disappearance of the starting materials and formation of the product. The reaction was allowed to stir another two hours after the addition of dihexylphosphite. The reaction mixture was transferred to a separatory funnel, and 200 ml of distilled water was added to facilitate the separation of the phases. The top organic layer was removed and dried over anhydrous Na2CO3. The filtered organic layer was stripped of the solvent using water suction and a bath temperature of 75° -80° C. to give a light yellow oil weighing 338.9 gms (93% yield). The product was purified by distillation under vacuum, and the fraction boiling at 155° -156° C./0.1MM Hg was collected. The GC purity of this cut was 94.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1C=CC=CC=1.Cl[C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])=[O:20])[CH:3]=2)[NH:7]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Yield: 60.8 %

Procedure:
5-Amino-1,3-dihydro-indol-2-one 30c (500 mg, 3.38 mmol) was dissolved in 10 ml of dichloromethane under stirring at room temperature, and pyridine (470 μl, 5 mmol) was added to the solution at −40° C. in a dry ice-acetone bath. Acetic acid chlorocarbonylmethyl ester (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above reaction solution. Upon completion of the addition, the dry ice-acetone was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water (10 ml×3) and recrystallized to obtain the title compound acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 44a (510 mg, yield 60.7%) as a yellow solid.