Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)nc2)CC1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 48.2 %

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (1.2 g, 4.3 mmol), diisopropylethylamine (1.1 g, 8 mmol), and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (1 g, 3.5 mmol) in IPA (20 mL) was stirred at 130° C. under microwave irradiation for 1.5 h. The resulting suspension was filtered and the solid was washed with water and dried in vacuum to afford the crude product, which was further purified by silica gel chromatography eluting with CH2Cl2/MeOH (50:1) to afford 106a as a white solid (800 mg, 50%). MS: [M+H]+ 474.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].CCN(C(C)C)C(C)C.[CH:44]1([N:50]=[C:51]=[O:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[C:51]([NH:50][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:52])=[CH:33][CH:34]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)NC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
To a suspension of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate hydrochloride (500 mg, 1.05 mol) in anhydrous DCM (10 ml) was added DIEA (0.2 mL, 1.18 mmol) and cyclohexyl isocyanate (Aldrich, 0.28 mL, 2.20 mmol). The reaction mixture was stirred at rt for 15 hrs. Then PS-trisamine resin (670 mg, Novabiochem, 3.5 mmol/g) was added and the resulting mixture was stirred at rt for 5 additional hrs. The resin was removed by filtration, washed with DCM and the solvent was evaporated off under reduced pressure. Purification by flash chromatography on silicagel (c-Hex/EtOAc (2/1)) gave 500 mg (84%) of the title compound as a pale yellow oil. HPLC, Rt: 5.9 min (purity: 100%). LC/MS, M+(ESI): 567.4. 1H NMR (DMSO-d6) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.18 (d, J=7.6 Hz, 1H), 4.76 (s, 2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.68 (s, 3H), 3.48 (m, 1H), 2.60 (t, J=7.5 Hz, 2H), 1.75-1.01 (m, 14H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([C:42](=[O:44])[CH3:43])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(n1)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O)C[C@H](C)N2C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
Cool to 0° C. a suspension of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol) and pyridine (0.203 mL, 2.52 mmol) in dichloromethane (3 mL) under nitrogen. Add acetic anhydride (0.117 mL, 1. 247 mmol) dropwise. After the addition is complete, remove the cooling bath and warm the reaction to room temperature with stirring for 12 h. Dilute the mixture with dichloromethane (25 mL) and wash with saturated aqueous sodium bicarbonate (25 mL). Dry the organic layer over sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue using silica gel chromatography, eluting with hexanes/ethyl acetate (gradient eluent, 0-30% ethyl acetate in hexane), to afford the title compound (0.196 g, 88%). MS (ES+): 548 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=[O:15])[C:5]2=[CH:4][N:3]=1.CC(=CC)C.Cl([O-])=[O:28].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[C:14]([OH:28])=[O:15])[C:5]2=[CH:4][N:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(C=O)cc1-c1nn(C)c2nc(N)ncc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzaldehyde (Example 75) (0.5 g, 1.77 mmol) is suspended in t-butanol (12 ml) and 2-methyl-2-butene (0.562 ml, 5.31 mmol). To this is added a solution of sodium chlorite (0.367 g, 4.06 mmol) and sodium dihydrogen phosphate (0.848 g, 7.06 mmol) in water (5 ml). The reaction mixture is stirred at room temperature for 48 hours and the resulting precipitate is collected by filtration, dissolved in saturated aqueous NaHCO3 (100 ml) and washed with EtOAc (2×50 ml). The aqueous portion is acidified to pH1 with 2M HCl resulting in an off-white solid which is collected by filtration and dried under vacuum for 72 hours to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[CH3:17][C:18](C)([O-])C.[Na+].C(Br)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Reactant: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 38 °C
Reaction time: 0.08 h

Procedure:
In a 125 mL 3-neck round-bottom flask was added N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2.57 g, 9.44 mmol), tetrahydrofuran (55 mL), and sodium tert-butoxide (1.81 g, 18.9 mmol). The suspension was stirred for 5 minutes then ethyl bromide (1.41 mL, 18.9 mmol), and tetrabutylammonium iodide (67 mg, 0.2 mmol) were added. The resulting gray colored suspension was then heated to 38° C. The reaction was analyzed after 3 hours and found to have gone to 81% completion, after 24 hours the reaction was found to have gone to completion. The reaction mixture was allowed to cool to ambient temperature and quenched with ammonium hydroxide (NH4OH)/formic acid (HCO2H) buffer (10 mL). The mixture was then diluted with tetrahydrofuran (40 mL), ethyl acetate (120 mL), and saturated sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layers were combined and silica (37 g) was added. The solvent was removed in vacuo to give a solid that was purified using semi-automated silica gel chromatography (RediSep Silica 220 g column; Hexanes (0.2% triethylamine)/ethyl acetate, 40/60 to 0/100 gradient elution system, flow rate 150 mL/minute) to give, after concentration, an orange solid weighing (2.19 g, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([Sn](C)(C)C)=[CH:18][CH:17]=1.[Cl-]>CN(C)C=O>[C:12]([NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
2-Bromo-N-(tert-butyl)benzenesulfonamide (from Step B) (1.00 g, 3.92 mmol), p-tolyltrimethyltin (from Step C) (1.95 g, 6.67 mmol), bis(triphenylphosphinepalladium(II) chloride (Aldrich) (165 mg, 0.235 mmol) and dimethylformamide (25 ml) were heated with stirring under nitrogen at 90° C. for 5 hours. The black suspension was cooled to room temperature, then filtered through a pad of Celite which was washed with tetrahydrofuran. The colorless filtrate was evaporated to dryness, then chromatographed (silica gel, 10% ethyl acetate-hexane) to give the title compound (0.88 g, 74%) as a white solid; 1H NMR (300 MHz, CDCl3) δ8.16 (d, J=7.9 Hz, 1H), 7.60-7.37 (m, 4H), 7.36-7.24 (m, 3H), 3.57 (s, 1H), 2.42 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[O:18][CH2:17][CH2:16][CH2:15][C:13]=2[N:14]=1)=[O:8].CC(C)([O-])C.[K+].Br[CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.O1CCCC1>[CH2:29]([N:14]1[C:13]2[CH2:15][CH2:16][CH2:17][O:18][C:12]=2[S:11]/[C:10]/1=[N:9]\[C:7](=[O:8])[C:6]1[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)OCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)OCCC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 26B (mixture) in 10 mL of N,N-dimethylformamide and tetrahydrofuran (1:4) were added potassium t-butoxide (21 mg, 0.18 mmol) and 1-bromobutane (25 mg, 0.18 mmol). After stirring at 80° C. for 16 h, the reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in methylene chloride) to afford 3 mg of the title compound as a single regioisomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.3 Hz, 3H), 1.28-1.42 (m, 2H), 1.73 (t, 2H), 2.06 (t, 2H), 2.67 (t, J=6.3 Hz, 2H), 3.79 (s, 3H), 4.06-4.13 (m, 2H), 4.18-4.25 (m, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.71 (d, J=3.1 Hz, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].I[C:37]1[C:38](=[O:50])[N:39]=[C:40]2[NH:45][C:44]3[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=3[N:41]2[CH:42]=1.C(O)C.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:37]2[C:38](=[O:50])[N:39]=[C:40]3[NH:45][C:44]4[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=4[N:41]3[CH:42]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Reactant: O=c1nc2[nH]c3ccccc3n2cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3c(nc2=O)[nH]c2ccccc23)cc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 31 %

Procedure:
To a mixture of 2-iodo-3-methoxy-acrylic acid methyl ester (1, 1.21 g, 5 mmol), 1H-benzoimidazol-2-ylamine (2, 0.67 g, 5 mmol) and ethanol (30 mL) was added a solution of sodium methoxide (10 mL, 0.5 M in methanol, 5 mmol). The resulted mixture was refluxed for 3 h and concentrated to afford 3-iodo-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-2-one (3). A mixture of (3-tert-butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]carbamic acid tert-butyl ester (4, 490 mg, 1 mmol), 3 (311 mg, 1 mmol), K2CO2 (414 g, 3 mmol), Pd(PPh3)4 (0) (41 mg, 0.05 mmol), ethanol (6 mL), dioxane (2 mL) and water (2 mL) was degassed and heated at 80° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0%-6% MeOH in methanechloride) to give desired product 5 (170 mg, 31%) as light yellow solid. LCMS (EI) m/z: 570 (M+Na+).
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:50])[C:14]2[CH:19]=[C:18]([S:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[S:32]([CH2:34][C:35]3[C:40]([CH3:41])=[C:39]([O:42][CH2:43][C:44]([F:47])([F:46])[F:45])[CH:38]=[CH:37][N:36]=3)=[O:33])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=2[O:48][CH3:49])(=O)=O)=CC=1.C([O-])(O)=O.[Na+:56].O.CC(O)C>CC#N>[Na+:56].[CH3:49][O:48][C:15]1[CH:16]=[CH:17][C:18]([S:20]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[S:32]([CH2:34][C:35]2[C:40]([CH3:41])=[C:39]([O:42][CH2:43][C:44]([F:46])([F:47])[F:45])[CH:38]=[CH:37][N:36]=2)=[O:33])(=[O:22])=[O:21])=[CH:19][C:14]=1[C:13]([O-:50])=[O:12]
Reactant: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1C(=O)[O-]
Temperature: 70 °C
Yield: 63.5 %

Procedure:
A mixture of 2-methoxy-5-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 8, 400 mg, 0.52 mmol) and NaHCO3 (52 mg, 0.62 mmol, 1.2 eq) in CH3CN (3 mL)-H2O (2 mL)-i-PrOH (1 mL) was heated to 70° C. for 1.5 h. Then volatile materials were removed by evaporation and the residual oil was dissolved in CH2Cl2-MeOH, the mixture was filtered to remove insoluble solids. The filtrate was concentrated by evaporation. The residual syrup was dissolved in H2O, and the mixture was extracted with CH2Cl2 (2 times) to remove the starting material, lansoprazole and tolyl vinyl sulfone. The water solution was freeze-dried to yield 200 mg (65%) Compound 3 sodium salt as a light yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[OH-].[Li+]>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(CN)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CN)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30C) (300 mg) in THF/H2O (v/v=1/1, 6 mL) was added lithium hydroxide monohydrate (50.4 mg, 2.10 mmol). The solution was stirred at room temperature overnight. THF was removed under reduced pressure and the resulting solution was acidified with 10% hydrochloric acid to pH=6.0. The resulting precipitate was isolated by centrifuge, rinsed with water, dried under reduced pressure and purified by prep-HPLC to afford 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid (30D) (170 mg, 74%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:15]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:16]=2[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][S:2]([N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[C:15]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][C:16]=2[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N(S(C)(=O)=O)S(C)(=O)=O
Reaction time: 20 h
Yield: 78.3 %

Procedure:
Methanesulfonyl chloride (0.86 ml, 1.1 mmol) was added to a stirred solution of ethyl 3-[(2-aminophenyl)sulfanyl]-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 12 220 mg, 0.5 mmol) and N,N-diisopropylethylamine (0.2 ml, 1.1 mmol) in dichloromethane (3 ml). The mixture was left at ambient temperature for 20 hours and then diluted with dichloromethane and washed with water. The organics were dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether, and then ethyl acetate, as eluant. The title product was crystallised from diethyl ether to give a colourless solid (232 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)OC(C)(C)C)=[C:17]([F:29])[CH:16]=3)=[CH:13][N:14]=2)([OH:9])[CH2:5][CH2:4]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[S:11][C:10]([C:6]3([OH:9])[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)=[N:14][CH:13]=2)=[CH:16][C:17]=1[F:29]
Reactant: CCN1CCC(O)(c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(O)(c2ncc(-c3ccc(N)c(F)c3)s2)CC1
Reaction time: 2 h

Procedure:
To an ambient solution of Example 8A (0.20 g, 0.48 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 2 h, and was then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound, which was used without further purification. MS (ESI) m/z 322 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:26](O)[CH3:27]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([O:19][CH2:26][CH3:27])=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)OCc1oc(-c2ccc(Cl)cc2)nc1C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
4.44 g (14.5 mmol) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid were dissolved in 40 ml of dry dichloromethane and 1 drop of dimethylformamide was added. 1.9 g (16 mmol) of thionyl chloride were added and the mixture was heated to reflux for 4 hours. 70 ml of ethanol were added slowly to a stirred solution of the thus-obtained acid chloride at 0° C. and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using 17% by volume ethyl acetate in hexane for the elution. After evaporation of the eluate there were obtained 2.8 g (57.2%) of ethyl 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionate of melting point 75°-76° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1
Reactant: OCc1ccc(CNc2ccccn2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(CNc2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.8 %

Procedure:
To a solution of oxalyl chloride (0.9 ml, 10.32 mmol) in CH2Cl2 (15 ml) at −78° C. was added a solution of DMSO (1.5 ml, 21.11 mmol) in CH2Cl2 (10 ml) and the mixture allowed to stir for 20 min. at −78° C., after which [4-(Pyridin-2-ylaminomethyl)-phenyl]-methanol (1.1 g, 5.13 mmol) in CH2Cl2 (10 ml) was added dropwise. Stirring was continued for 2 hours and then Et3N (2.9 ml, 21.30 mmol) was added dropwise. The cooling bath was removed, stirring was continued for 3 h, and the mixture was diluted with 300 mL ethyl acetate, washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 30% ethyl acetate in CH2Cl2, gave the title compound (335 mg, 31%) as a pure white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of 1-[4-(4-formylbenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.3 g) in methanol (10 ml) is added gradually sodium borohydride (59 mg) under ice-cooling and the mixture is stirred at room temperature for 2 hours. Water is added to the mixture and the solvent is distilled off under reduced pressure. The resulting residue is extracted with dichloromenhane, washed with water, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane methanol=50: 1), and recrystallized from methanol to give 1-[4-(4-hydroxymethylbenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (165 mg) as white powder, m.p. 224.5°-225.5° C.