Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:16]([Mg]Br)=[CH2:17]>C1COCC1>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH:14]([OH:15])[CH:16]=[CH2:17])=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: C=C[Mg]Br
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CC(O)C(CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
To a stirred 0° C. solution of Boc-leucinal (3.00 g, 13.9 mmol) in dry THF (70 ml) was added vinyl magnesium bromide (35 ml of a 1.0M solution in THF). After 5 hours, the mixture was quenched with 1.0M NH4Cl (50 ml). Most of the THF was evaporated in vacuo and the residue was extracted with ether several times. The combined extracts were washed (brine), dried (Na2SO4), filtered, and evaporated to give the desired product as a 3:2 mixture of hydroxydiastereomers in 65% field.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:14]([CH3:20])[C:15](I)=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:14]([CH3:20])[C:15]([C:26]([OH:28])=[O:27])=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C=O
Reactant: CCCCCCc1cccc(-c2nc(I)c(I)n2C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of 7.27 g (14.7 mmol) of 2-(3-hexyl-phenyl)-4,5-diiodo-1-methyl-1H-imidazole in 150 ml of THF was cooled down to −75° C.; then, 11.95 ml (19.1 mmol) of an n-butyl lithium solution (1.6 molar in n-hexane) was added drop by drop below −70° C. 30 min later, the reaction mixture was treated with an excess of solid carbon dioxide and subsequently warmed up to RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 2.97 g (49%) of the title compound as light red oil. MS: 411.2 ([M-H]−).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:2]2[CH2:7][CH2:6][O:5][C:3]2=[O:4])=[CH:11][CH:10]=1
Reactant: O=C1OCCC1Br
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C1OCCC1Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
α-Bromobutyrolactone (12.4 g, 0.075 mol) is added to a mixture of 4-fluorophenol (5.6 g, 0.05 mol) and caesium carbonate (17.9 g, 0.055 mol) in acetone (100 ml). The reaction medium is refluxed for two hours. After cooling to room temperature, the reaction is filtered through a bed of Celite and the filtrate is evaporated. The oily residue is purified by flash chromatography (1/2 EtOAc/heptane) to give the expected product in the form of an oil (9.8 g, 87%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CCCCCC>[Si:20]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=C1CCCCC1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.3 %

Procedure:
In dry DMF (200 ml) was dissolved 2-(2-hydroxyethyl)cyclohexanone (7.86 g) followed by addition of imidazole (9.53 g) and tert-butyldimethylchlorosilane (10 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with hexane (500 ml), washed successively with aqueous sodium hydrogen carbonate, diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was further subjected to vacuum distillation to give 7.55 g of 2-[2-(tert-butyldimethylsilyloxy)ethyl]cyclohexanone as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:11]([OH:13])[CH3:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.O=[Mn]=O>[F:1][C:2]1[C:3]([C:11](=[O:13])[CH3:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)c1ccnc(C(C)O)c1F
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CC(=O)c1nccc(C(C)C)c1F
Temperature: 140 °C
Reaction time: 8 h

Procedure:
1-(3-Fluoro-4-isopropyl-pyridin-2-yl)-ethanol (prepared in the previous step, 3.00 g, 16.39 mmol) was dissolved in 60 mL of anhydrous toluene. MnO2 (4.05 g, 46.55 mmol) was added and the resulting mixture was stirred at 140° C. overnight. The mixture was then cooled to room temperature and filtered thought a pad of celite. The filtrate was concentrated and purified via MPLC (80 g, 0 to 20% ethyl acetate in hexane) to afford the title compound. Spectroscopic data: 1H-NMR (300 MHz, CDCl3): δ ppm 1.28 (d, J=6.73 Hz, 6 H), 2.70 (s, 3 H), 3.35 (hept, J=6.73 Hz, 1 H), 7.38 (dd, J=5.13 Hz, 1 H), 8.39 (d, J=4.69 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[C:16]([C:21]4[N:22]=[C:23]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)[C:24]5[N:29]=[C:28]([CH2:30][N:31]6[CH2:36][CH2:35][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:33][CH2:32]6)[S:27][C:25]=5[N:26]=4)[C:15]=3[CH:14]=[CH:13]2)(=O)=O)C=CC=CC=1>O1CCOCC1>[CH3:42][C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:28]2[S:27][C:25]3[N:26]=[C:21]([C:16]4[C:15]5[CH:14]=[CH:13][NH:12][C:20]=5[CH:19]=[CH:18][N:17]=4)[N:22]=[C:23]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[C:24]=3[N:29]=2)[CH2:36][CH2:35]1)([CH3:41])[C:38]([NH2:40])=[O:39]
Reactant: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4nccc5c4ccn5S(=O)(=O)c4ccccc4)nc3s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4nccc5[nH]ccc45)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
A degassed solution of 2-[4-(7-morpholin-4-yl-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]isobutyramide (250 mg, 0.36 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (130 mg, 0.39 mmol), PdCl2{PtBu2(Ph-p-Nme2)}2 (26 mg, 0.036 mmol) and copper(I) thiophene-2-carboxylate (14 mg, 0.07 mmol) in 1,4-dioxane (4 mL) was subjected to microwave irradiation at 140° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to give 2-{4-[5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-ylthiazolo[5,4-c]pyrimidin-2-ylmethyl]piperazin-1-yl}isobutyramide as a crude oil. Aqueous NaOH (12.5 M, 0.4 mL) was added to a solution of 2-{4-[5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-piperazin-1-yl}isobutyramide in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 45 min, then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to afford a solid. The solid was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 96:4) followed by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 169 as a yellow solid (43 mg, 23%). LCMS (method E): RT=5.03 min, [M+H]+=522.2. 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J=5.6 Hz, 1 H), 7.45-7.40 (m, 2 H), 7.38 (d, J=3.3 Hz, 1 H), 7.11 (d, J=5.3 Hz, 1 H), 5.25 (d, J=5.3 Hz, 1 H), 4.53-4.42 (m, 4 H), 3.90 (m, 6 H), 2.68 (m, 4 H), 2.62 (m, 4 H), 1.25 (s, 6 H)
Reaction SMILES: C([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH:25][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][NH:30]3)[CH3:24])[CH2:10]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:15]=[C:14]([C@@H:23]([NH:25][C:26]3[N:34]=[CH:33][N:32]=[C:31]4[C:27]=3[N:28]=[CH:29][NH:30]4)[CH3:24])[N:13]([CH:11]3[CH2:12][CH:9]([OH:8])[CH2:10]3)[C:17]=2[CH:18]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC(O)C1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
A mixture of [(S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl]-(9H-purin-6-yl)amine (0.12 g, 0.26 mmol) in DCM (5 mL) cooled to 0° C. To this mixture was added boron tribromide (1M in DCM, 0.53 mL, 0.53 mmol) dropwise and the resultant mixture stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2 mL) and concentrated in vacuo. The resulting yellow was solid purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 391 as an off-white glassy solid (50 mg, 50%). LCMS (Method K): RT 2.21 min [M+H]+ 368.3. 1H NMR (DMSO-d6): δ 12.8 (1H, br s), 8.21 (1H, s), 8.09 (1H, s), 7.78-7.89 (1H, m), 7.47-7.61 (2H, m), 6.95-7.04 (1H, m), 5.78 (1H, br s), 5.43 (1H, qn, J=8.82 Hz), 5.11 1H, d, J=4.2 Hz), 4.41-4.50 (1H, m), 2.86-3.04 (2H, m), 2.26-2.38 (1H, m), 2.08-2.20 (1H, m), 1.59 (1H, d, J=6.7 Hz)
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.CS([C:18]1[N:23]=[C:22]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)(=O)=O>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([NH:3][C:18]2[N:23]=[C:22]([C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccnn2-c2ccccc2)n1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2nccc(-c3ccnn3-c3ccccc3)n2)cc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (22 mg, 0.93 mmol, 2.0 equiv) was added to a solution of methyl 4-aminobenzoate (140 mg, 0.93 mmol, 2.0 equiv) in DMF (5 mL) at 23° C. The resulting yellow solution was stirred for 15 minutes before 2-(methylsulfonyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidine (1-7, 140 mg, 0.47 mmol, 1 equiv) was added. The resulting red mixture was stirred for 30 minutes, then partitioned between brine (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes, initially, grading to 40% hexanes in ethyl acetate) to give methyl 4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino}benzoate (2-1) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.41 (d, 1H, J=4.9 Hz), 7.86 (d, 2H, J=8.8 Hz), 7.78 (d, 1H, J=1.8 Hz), 7.52–7.33 (m, 5H), 7.28 (d, 2H, J=8.6 Hz), 6.90 (d, 1H, J=1.8 Hz), 6.78 (d, 1H, J=4.9 Hz), 3.90 (s, 3H)
Reaction SMILES: [Li+].[Br-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[CH3:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH2:22][CH:23]3[CH2:25][O:24]3)[C:17]3[CH2:26][CH2:27][N:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][C:16]=3[C:15]=2[CH:14]=1>>[OH:24][CH:23]([CH2:25][NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=1)[CH2:22][N:18]1[C:19]2[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][C:15]=2[C:16]2[CH2:29][N:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26][C:17]1=2
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC2CO2)C1
Agent: [Br-]
Agent: [Li+]
Product: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC(O)CNc2cccc(OC)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following a literature procedure (Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem. 2004, 3597-3600) LiBr (0.001 g, 0.010 mmol) and m-anisidine (0.011 mL, 0.102 mmol) were added to ethyl 8-Methyl-5-(oxiran-2-ylmethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.032 g, 0.102 mmol) and stirred vigorously at ambient temperature overnight. Upon completion the reaction was partitioned between EtOAc/H2O, and the organic layer was concentrated to an orange oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[NH:8])[O:4][N+:5]([O-:7])=[O:6].Cl.[CH3:10]N.[OH-].[Na+].Cl>O>[CH3:1][NH:2][C:3](=[N:8][CH3:10])[O:4][N+:5]([O-:7])=[O:6]
Reactant: CNC(=N)O[N+](=O)[O-]
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN=C(NC)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a suspension of 1-methyl-2-nitroisourea (1.5 g) in water (15 ml), methylamine hydrochloride (0.9 g) was added (pH: 3.3). An aqueous sodium hydroxide (1%) was gradually added to maintain the pH of the suspension at 8 at room temperature. After the suspension was stirred for 3 hours at room temperature while maintaining the pH thereof to 8, an aqueous hydrochloric acid (4 M) was added, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and it was then concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate: 2/1) and then recrystallized (ethyl acetate-hexane), to obtain the desired compound (1.0 g) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([CH:15]([C:17](=[O:22])[NH:18][CH:19]1[CH2:21][CH2:20]1)[OH:16])[CH2:12][CH2:13][CH3:14])C1C=CC=CC=1>CO>[CH:19]1([NH:18][C:17](=[O:22])[CH:15]([OH:16])[CH:11]([NH2:10])[CH2:12][CH2:13][CH3:14])[CH2:21][CH2:20]1
Reactant: CCCC(NC(=O)OCc1ccccc1)C(O)C(=O)NC1CC1
Solvent: CO
Product: CCCC(N)C(O)C(=O)NC1CC1
Yield: 96.4 %

Procedure:
[1-(Cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-carbamic acid benzyl ester (48 g, 149.82 mmol) was dissolved in Methanol (1 L) and degassed with nitrogen for five minutes, palladium, 10 wt. % on activated carbon (2.5 g) was added, hydrogen was then added for 18 h. After 18 h the hydrogen was removed and the reaction was degassed with nitrogen and filtered the resulting filtrate was evaporated and dried under high vacuum to give a white solid 26.9 g, 144.42 mmol 97%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][CH2:20][S:21][CH3:22])[C:16]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:26][C:15]=2[S:14]1.O>O1CCOCC1>[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][CH2:20][S:21]([CH3:22])=[O:9])[C:16]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:26][C:15]=2[S:14]1
Reactant: CSCCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)CCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reaction time: 72 h
Yield: 27.2 %

Procedure:
90% m-chloroperbenzoic acid (2.5 g) is added in the course of about 15 minutes, at a temperature close to 20° C., to 2-imino-3-(3-methylthiopropyl)-6-trifluoromethoxybenzothiazoline (4.2 g) in solution in a mixture (100 cc) of water and dioxane (40/60 by volume). The reaction mixture is stirred at the same temperature for 72 hours. After adding to distilled water (500 cc) and neutralising with 1N sodium hydroxide solution, the reaction mixture is extracted with dichloromethane. After drying over magnesium sulphate and concentrating to dryness under reduced pressure and then purifying by chromatography on a silica column using a mixture of ethyl acetate and methanol (80/20 by volume) as eluent, (RS)-2-imino-3-(3-methylsulphinylpropyl)-6-trifluoromethoxybenzothiazoline (1.2 g) melting at 114° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=1)=[O:29]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:23][CH2:24]4)[CH2:20][CH2:21]3)[N:10]([CH2:27][C:28](=[O:29])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc12
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Product: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C3CC3)CC1)n2CC(=O)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 15 starting from 1.40 g (4.09 mmol) 2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 1.02 g (4.09 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[OH:7][C:8]1[C:9]([CH3:43])=[C:10]([CH:36]=[CH:37][C:38]=1[C:39](=[O:42])[CH2:40][CH3:41])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)C(O)=O)=[CH:15][CH:14]=1.[N+](=C)=[N-]>O1CCCC1.CN(C)C=O>[Cl:6][CH2:1][C:2]([C:22]1[CH:21]=[C:20]([CH:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]3[CH:36]=[CH:37][C:38]([C:39](=[O:42])[CH2:40][CH3:41])=[C:8]([OH:7])[C:9]=3[CH3:43])=[CH:18][CH:17]=2)[CH:28]=[CH:27][CH:26]=1)=[O:3]
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)CCl)c3)cc2)c(C)c1O
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Add oxalyl chloride (0.660 mg, 5.20 mmol) to a solution of 3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoic acid (2.50 g, 5.00 mmol) in tetrahydrofuran (0.20M). Add dimethylformamide (5 drops). Add ethereal solution of diazomethane (15.0 mmol) and stir for 2 hours. Add hydrochloric acid (4N in dioxane) to quench unreacted diazomethane and evaporate solvents to afford the title compound (2.25 g, 4.19 mmol, 85%): MS (m/z): 536 (M−H).
Reaction SMILES: Br[C:2]1[C:6](Br)=[CH:5][O:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:2]2[C:6]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:22]=3)=[CH:5][O:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)c1occ(Br)c1Br
Product: CCOC(=O)c1occ(-c2cccc(OCc3ccccc3)c2)c1-c1cccc(OCc2ccccc2)c1
Yield: 13.1 %

Procedure:
A reaction and treatment was carried out in the same manner as in Reference Example 5(1) using ethyl 3,4-dibromo-2-furancarboxylate (2.00 g) and 3-benzyloxyphenylboronic acid (1.80 g). The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20), thereby giving 1.70 g of a mixture of ethyl 3-(3-benzyloxyphenyl)-4-bromo-2-furancarboxylate and ethyl 4-(3-benzyloxyphenyl)-3-bromo-2-furancarboxylate and 0.26 g of ethyl 3,4-bis(3-benzyloxyphenyl)-2-furancarboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[S:8]([NH2:11])(=[O:10])=[O:9].[BH4-].[Na+].Cl>C1COCC1>[OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)C1COCCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)C1COCCC1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.09 g of 4-oxotetrahydropyran-3-sulfonamide were dissolved in THF, 0.23 g of sodium borohydride was added and the mixture was stirred at room temperature for 18 hours. The mixture was then adjusted to pH=2 with hydrochloric acid and concentrated under reduced pressure. The residue, bound to 8 g of Celite, was purified by means of a silica gel column (50 g): solvent A: dichloromethane, B: methanol, gradient: 0 min 3% B, 3 min 3% B, 5 min 5% B, 35 min 10% B, 44 min 10% B; flow rate 20 ml/min; detection: 220 nm, fraction size: 20 ml. After removal of the solvent under reduced pressure, the product was thus obtained with impurities. The residue (615 mg) was used further without further workup.
Reaction SMILES: C(O[C:9](=[O:46])[CH2:10][CH2:11][CH:12]([N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[C:13]([N:15]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:16]C(OCC1C=CC=CC=1)=O)=[O:14])C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>[Pd].O1CCCC1.CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[CH2:27][N:15]1[C:13](=[O:14])[CH:12]([N:35]2[C:36](=[O:45])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]2=[O:44])[CH2:11][CH2:10][C:9](=[O:46])[NH:16]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)CN(NC(=O)OCc1ccccc1)C(=O)C(CCC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1NC(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Reaction time: 16 h
Yield: 75 %

Procedure:
A suspension of 5-(N′-benzyloxycarbonyl-N-tert-butoxycarbonylmethyl-hydrazino)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-pentanoic acid benzyl ester (3) and 10% palladium on carbon (250 mg) in tetrahydrofuran (THF) (30 mL) and DMF (3 mL) was stirred under hydrogen atmosphere for 16 hours. The mixture was filtered through Celite and the filtrate was evaporated in vacuo. The residue was dissolved in 30 mL of dichloromethane. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (770 mg, 4 mmol) was added and the solution was stirred at room temperature for 3.5 hours. Solvent was removed in vacuo and the residue was dissolved in ethyl acetate (300 mL), then washed with water (100 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered, purified by flash chromatography using hexane/ethyl acetate (85/15 to 50/50) to afford 1.06 g (75% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.30-2.40 (m, 1H), 2.40-2.50 (m, 1H), 3.05-3.12 (m, 1H), 3.38-3.48 (m, 1 H), 3.90-4.00 (d, 1H), 4.60-4.70 (d, 1H), 5.55-5.63 (m, 1H), 7.65 (s, 1H), 7.75-7.7.9 (m, 2H), 7.88-7.92 (m, 2H). Analytical HPLC: 10.36 min. LC-MS (ES+): m/e=388 (M+H+).
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:14]([OH:16])=O)[C@@H:11]([CH3:13])O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2([OH:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>CO.ClCCCl.CN(C=O)C>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2([OH:49])[CH2:44][CH2:45][N:46]([C:14](=[O:16])[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:11][CH3:13])[CH2:47][CH2:48]2)=[CH:39][CH:38]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: C[C@@H](O)[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC=C(NC(=O)c1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A reaction vessel was charged with N-benzoyl-L-threonine (56 mg), HOBt (42 mg), DIEA (130 μL), 4-(4-chlorophenyl)-4-hydroxypiperidine (66 mg), EDC (60 mg), DMF (1 mL) and 1,2-dichloroethane (1 mL). The reaction mixture was stirred for 16 h at rt and then diluted with methanol (0.5 mL). Upon completion of dilution, the reaction mixture was purified by preparative LC-MS to provide Example 226. MS found: (M+H)+=399.