Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[NH:23]C(OC(C)(C)C)=O)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[NH2:23])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(C)(C)OC(=O)NC1CCCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (6-chloro-9H-β-carbolin-8-yl) amide (736 mg, 1.72 mmol) in trifluoroacetic acid (5 ml) was stirred at RT for 20 min, then concentrated to an orange oil. The oil was dissolved in MeOH (5 ml) and neutralized with a saturated aqueous sodium bicarbonate solution (25 ml). The resulting mixture was further diluted with H2O (25 ml) and EtOAc (100 ml). The aqueous layer was removed and extracted with EtOAc (100 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to yellow solids (507 mg). These solids were dissolved in MeOH (5 ml) and a solution of HCl in dioxane (4 M, 1.5 ml) was added. The bright yellow solution was stirred 30 min, then concentrated to yield cis-2-amino-cyclopentanecarboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide as a yellow powder (600 mg). 1H-NMR (300 MHz, DMSO-d6): δ 9.29 (s, 1); 8.75 (d, 1); 8.53 (d, 1); 8.37 (s, 1); 8.02 (s, 1); 4.05-3.95 (m, 1); 3.42-3.34 (m, 1); 2.46-1.80 (m, 6). NH4OAc standard conditions. DAD Rf=1.65 min. M+H=329.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:34])[C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20](C(OC(C)(C)C)=O)[CH:21]=[C:22]([C:23]([O:25]C)=[O:24])[C:15]=23)[CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:6][C:7](=[O:34])[C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]=23)[CH:9]([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)NC1CCCC1

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-1-tert-butyl 3-methyl 4-((1-(cyclopentylamino)-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (105 mg, 0.222 mmol) under nitrogen. Aqueous NaOH (12N, 2 mL) and MeOH (1 mL) were added and the solution was stirred at 53° C. for 48 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[F:19][C:20]([F:34])([F:33])[CH2:21][C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([CH2:21][C:20]([F:34])([F:19])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1
Yield: 36 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69(e)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 36%). MS (m/e): 492.4 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[OH-:14].[Na+].Cl>O>[OH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 101.3 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid (20 g, 1.0 eq) and NaOH (20.5 g, 2.0 eq) in 100 mL H2O was reflux at 100° C. overnight. After cooling to rt, con. HCl was added to pH=7. The precipitate thus formed was isolated by filtration, washed with cold water, and dried, to give the desired product as a white solid (18.4 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15](SC)[N:14]([CH2:20][CH2:21][CH2:22][OH:23])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]3[O:23][CH2:22][CH2:21][CH2:20][N:14]3[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc2c(OCc3ccccc3)cccc2n1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2cccc3c2nc2n3CCCO2)cc1
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a solution of 4-benzyloxy-1-(3-hydroxypropyl)-2-methylthio-1H-benzimidazole (59 mg) in dimethylformamide (1 ml) was added sodium hydride at ambient temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, v/v) and pulverized with diisopropyl ether to give 9-benzyloxy-3,4-dihydro-2H-[1,3]oxazino-[3,2-a]benzimidazole (43 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[CH:17]([N-]C(C)C)(C)[CH3:18].[Li+].C(Br)C.Cl>O1CCCC1>[CH2:17]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]1=[O:16])[CH3:18]
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cccc(C2CCCCNC2=O)c1
Agent: Cl
Agent: [Li+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC1(c2cccc(OC)c2)CCCCNC1=O
Temperature: 25 °C

Procedure:
Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one (2.19 g) in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (from butyllithium 1.4 molar 15.7 ml, and diisopropylamine 3.15 ml) under nitrogen at 0° C. Ethyl bromide (1 ml) was added in one portion and the reaction allowed to warm up to room temperature. After two hours the reaction was poured into 2 M HCl, the organic layer separated and the aqueous layer extracted with chloroform. The combined organic layers were dried over magnesium sulphate, filtered and evaporated to an oil which was crystallised from ethyl acetate giving 1.68 g of the title compound m.p. 85°-7° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][N:5]3[CH:4]=[C:3]1[C:14]([OH:16])=O)[CH:8]=[CH:9][CH:10]=2.ClC(OCC(C)C)=O.[CH3:25][C:26]([O:28][CH2:29][C:30]1[CH2:49][S:48][C@@H:33]2[C@H:34]([NH:37][C:38]([C@H:40]([NH2:47])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:39])[C:35](=[O:36])[N:32]2[C:31]=1[C:50]([OH:52])=[O:51])=[O:27].S([O-])([O-])(=O)=O>CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][N:5]3[CH:4]=[C:3]1[C:14]([NH:47][CH:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]([NH:37][CH:34]1[C:35](=[O:36])[N:32]3[CH:33]1[S:48][CH2:49][C:30]([CH2:29][O:28][C:26](=[O:27])[CH3:25])=[C:31]3[C:50]([OH:52])=[O:51])=[O:39])=[O:16])[CH:8]=[CH:9][CH:10]=2
Reactant: O=C(O)c1cn2c3c(cccc3c1=O)CC2
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)c3cn4c5c(cccc5c3=O)CC4)c3ccccc3)C2SC1
Reaction time: 0.25 h
Yield: 68 %

Procedure:
2.1 g of 6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid was added to 50 ml of anhydrous dimethylformamide and 1.66 ml of triethylamine was added to the mixture while ice-cooling and stirred for 15 minutes. Then, 1.6 ml of isobutyl chloroformate was added thereto dropwise and stirred for 45 minutes while ice-cooling. On the other hand, 4.5 g of cephaloglycine was suspended in 60 ml of anhydrous dimethylformamide and 2.8 ml of triethylamine and 1 g of anhydrous sulfate were added to the resulting mixture while ice-cooling followed by stirring the mixture for 30 minutes. Insoluble materials were removed by filtration and the filtrate was added at one time to the former reaction mixture and allowed to react for 2 hours while ice-cooling. After completion of the reaction, insoluble materials were removed by filtration and the filtrate was mixed with 10 ml of a 20% butanol solution of sodium 2-ethylhexanoate followed by the addition of 500 ml of diethyl ether to precipitate crystals. The crystals were collected by filtration and dissolved in 300 ml of water. The resulting solution was rendered acidic (pH=3) with dilute hydrochloric acid to precipitate solid materials, which were washed with water and dried under reduced pressure to obtain 4.0 g of 7-[2-(1,2-dihydro- 6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamido)-2-phenylacetamido]-3-(acetyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid as white amorphous crystals having a melting point of 245° to 248° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:13]([F:16])([F:15])[F:14])([OH:12])[CH2:4][C:5]1[CH:6]2[CH2:11][CH:9]([CH:10]=1)[CH2:8][CH2:7]2.[C:19](Cl)(=[O:21])[CH3:20]>C(N(CC)CC)C>[F:1][C:2]([F:17])([F:18])[C:3]([C:13]([F:15])([F:14])[F:16])([O:12][C:19](=[O:21])[CH3:20])[CH2:4][C:5]1[CH:6]2[CH2:11][CH:9]([CH:10]=1)[CH2:8][CH2:7]2
Reactant: OC(CC1=CC2CCC1C2)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OC(CC1=CC2CCC1C2)(C(F)(F)F)C(F)(F)F

Procedure:
Notes: 2-(1′,1′-bis(trifluoromethyl)-1′-acetoxyethyl)norbornene was prepared from 2-(1′,1′-bis(trifluoromethyl)-1′-hydroxyethyl)norbornene (Central Glass, Japan), using a standard procedure (acetylchloride and triethyl amine).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83(t, J=7.2 Hz, 3 H), 1.20–1.70 (m, 6 H), 1.95–2.10 (m, 2 H), 2.67 (brt, J=11.7 Hz, 2 H), 2.70–3.20 (m, 7 H), 3.62–3.75 (m, 2 H), 3.95–4.10 (m, 3 H), 6.59 (d, J=7.5 Hz, 1 H), 6.63 (d, J=8.0 Hz, 1 H), 6.80–7.00 (m, 3 H), 7.06 (d, J=9.0 Hz, 2 H), 9.32 (brs, 1 H), 10.61 (brs, 1 H), 10.73 (brs, 1 H); MS (ES) m/z: 518.1 (MH+); HRMS Calcd. for C25H36N5O5S (MH+): 518.2437. Found: 518.2452.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[C:36]([O:40][C:41](=[O:44])[CH2:42]Br)([CH3:39])([CH3:38])[CH3:37].[Cl-].[NH4+]>C1COCC1>[Si:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:21][CH:20]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C(=O)OCc1ccccc1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.06 M in THF; 12.6 mL, 13.3 mmol) was added dropwise over 10 min to a stirred solution of benzyl (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetate (4.32 g, 12.1 mmol) in THF (40 mL) at −78° C. under nitrogen. On completion of addition stirring was continued at −78° C. for 30 min then t-butylbromoacteate (2.82 g, 2.14 mL, 14.5 mmol) was added dropwise over 5 min. The reaction was allowed to warm slowly to room temperature over 4 h then saturated ammonium chloride solution (40 mL) was added and the resulting suspension extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (5% diethyl ether: cyclohexane) to give the title compound as a colourless oil (5.35 g, 94%). LC/MS: 4.35 min; z/e 488, calcd (M+18) 488. 1H NMR (400 MHz: CDCl3): 7.10 (3H), 7.05 (2H), 6.95 (2H), 6.60 (2H), 4.95 (2H), 3.85 (1H), 2.90 (1H), 2.40 (1H) 1.20 (9H), 0.8 (9H), 0.05 (6H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:39][NH2:40]>CC(O)C>[CH3:39][NH:40][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Solvent: CC(C)O
Product: CNc1nc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)cc1C#N
Temperature: 150 °C

Procedure:
A mixture of 2-Chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (2-6, 0.040 g, 0.077 mmol) and methylamine (2M in THF, 0.192 mL, 0.385 mmol) in i-PrOH (1 mL) were heated@150° C. for 15 min. in the microwave. The mixture was concentrated, taken up in DMF and purified by reverse phase HPLC (6-1; 5% CH3CN: 95% H2O+0.01% TFA to 95% CH3CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 10.93 (s, 1H), 9.59 (bs, 1H), 8.00 (s, 1H), 7.37-7.47 (m, 4H), 7.18-7.37 (m, 5H), 7.12 (dd, J=1.96, 8.06, 2H), 6.95-7.05 (m, 3H), 4.43-4.53 (m, 1H), 4.32 (d, J=5.00, 2H), 3.47 (d, J=10.99, 2H), 3.10-3.25 (m, 2H), 2.94 (d, J=4.39, 3H), 255-2.69 (m, 2H), 1.92 (d, J=11.48, 2H). HRMS m/z (M+H) Calcd: 515.2554, found: 515.2552.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:22]>CN(C)C=O.C(N(CC)CC)C.C(OCC)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([CH2:20][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][N:8]4[CH:16]=[CH:17][CH:18]=[C:7]4[CH:6]3[CH2:1]2)=[O:22])=[CH:24][CH:25]=1
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1CCN2c3ccccc3Cn3cccc3C2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 500 mg of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 7.5 ml of dimethylformamide and 350 mg of triethylamine, 470 mg of α-bromo-p-chloroacetophenone are added and the mixture is stirred at room temperature for 2 hours. It is diluted with 60 ml of diethyl ether, washed with water, dried and evaporated. The residue is taken up in 15 ml of chloroform and the solution again evaporated, to yield the 2-(p-chlorobenzoylmethyl)-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine melting at 71°-74°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1Br.[CH3:12][C:13]1([CH3:28])[CH2:18][CH2:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH2:14]1>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13]([CH3:28])([CH3:12])[CH2:14][CH:15]=1
Reactant: NC(=O)c1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2N)CC1
Yield: 77.9 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 4-amino-3-bromo-benzamide (as prepared in Example 16, step (a), 62.4 mg, 0.289 mmol), and 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (75.0 mg, 0.318 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (55 mg, 78%) as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C15H20N2O, 245.2 (M+H), found 245.2.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.Cl>[Ti](Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]([C:9]1[CH:19]=[C:18]([OH:20])[C:17]([O:28][CH3:29])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1C(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c(O)cc1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a mixture of ethyl 2-benzoyl-4-benzyloxy-5-methoxy-benzoate (reference example 11-1) (848 mg) and dichloromethane (30 mL) was added titanium tetrachloride (0.31 mL) under room temperature. After stirring for 30 minutes, 2 mol/L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10%-100% ethyl acetate/hexane, gradient elution) to give the title compound (550 mg).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH2:9]>C(N(CC)CC)C.N12CCCN=C1CCCCC2.C(O)C>[C:4]([C:3]([C:2](=[O:7])[CH3:1])([CH2:9][CH2:8][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][CH2:8][S:10]([CH3:13])(=[O:12])=[O:11])(=[O:6])[CH3:5]
Reactant: C=CS(C)(=O)=O
Reactant: CC(=O)CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(CCS(C)(=O)=O)(CCS(C)(=O)=O)C(C)=O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
6 g of 2,4-pentandione and 3 drops of triethyl amine were mixed and 7 g of methyl vinyl sulfone was added dropwise at room temperature. After stirring at 60° C. for 7 hours, 5 drops of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were added and the mixture was stirred at room temperature for 12 hours. The mixture was stirred with 25 ml of ethanol and neutralized after a white solid was precipitated. The mixture was poured into 200 ml of water and ice, and was kept in the refrigerator overnight. The solvent was filtered off, dried and recrystallized from 500 ml of ethanol. 2.9 g of white, long needles of the subject compound was obtained (melting point: 162° C.; purity: >99%; colorless).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:16][C:15]=2[N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(OCCNS(C)(=O)=O)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.450 g, 0.97 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.418 mL, 3.00 mmol) were combined and then stirred for 10 minutes. Methanesulfonyl chloride (0.075 mL, 0.97 mmol) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.173 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)methanesulfonamide as white needles.
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]([NH:21][C:22]([C:24]3[NH:28][N:27]=[C:26]([C:29]4[N:30]=[CH:31][N:32](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:33]=4)[CH:25]=3)=[O:23])[CH3:20])[N:14]=2)[CH:8]=[CH:9][C:10]=1[C:11]#[N:12]>O.C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]([NH:21][C:22]([C:24]3[NH:28][N:27]=[C:26]([C:29]4[N:30]=[CH:31][NH:32][CH:33]=4)[CH:25]=3)=[O:23])[CH3:20])[N:14]=2)[CH:8]=[CH:9][C:10]=1[C:11]#[N:12]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Temperature: 50 °C
Reaction time: 48 h
Yield: 58.5 %

Procedure:
Formic acid (452 mmol, 20.82 g) was dissolved in a mixture of water (2 ml) and THF (40 ml). (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide (1.508 mmol, 1 g) was added and the resulting mixture was heated to 50° C. for 3 h. The stirring continued for 2 days at RT. The mixture was concentrated. ACN was added and evaporated. This was repeated once more. The crude product was purified by flash chromatography. 0.371 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.14 (d, 3H), 4.23-4.56 (m, 3H), 6.76 (bs, 1H), 6.94 (d, 1H), 7.53 (bs, 1H), 7.76 (s, 1H), 7.83 (d, 1H), 7.95-8.04 (m, 2H), 8.07-8.10 (m, 1H), 8.27 (d, 1H), 12.30 (bs, 1H), 13.40 (bs, 1H).
Reaction SMILES: CS([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[N:5]=1)=O.[N:19]1(C(OC(C)(C)C)=O)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[N:19]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][N:11]=3)[N:5]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)c1ccnc(-c2n[nH]c3ncccc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: c1cnc2[nH]nc(-c3nccc(N4CCNCC4)n3)c2c1
Temperature: 125 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
A mixture of 3-(4-methylsulfinylpyrimidin-2-yl)-1H-pyrazolo[5,4-b]pyridine (45 mg, 0.17 mmol), tert-butyl piperazine-1-carboxylate (100 mg, 0.53 mmol) and potassium carbonate (100 mg, 0.72 mmol) in NMP (0.5 ml) were stirred at 125° C. for 60 minutes in the microwave. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. After drying over MgSO4 and concentration the residue was taken up in DCM (2 ml) and treated with TFA (1 ml). The reaction was allowed to stir at RT for 3 hours and concentrated in vacuo. and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a pink solid (10 mg, 11% Yield).