Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[O:20][C:21]=2[CH3:22])=[C:9]([CH3:29])[CH:8]=1)C.[OH-].[Na+].CCOC(C)=O>C1COCC1.CCO>[CH:23]1([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][O:14][C:10]3[C:9]([CH3:29])=[CH:8][C:7]([CH2:6][CH:5]([O:30][CH:31]([CH3:32])[CH3:33])[C:4]([OH:34])=[O:3])=[CH:12][C:11]=3[CH3:13])[N:18]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)C(Cc1cc(C)c(OCCc2nc(C3CCCCC3)oc2C)c(C)c1)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(CC(OC(C)C)C(=O)O)cc(C)c1OCCc1nc(C2CCCCC2)oc1C
Reaction time: 14 h
Yield: 87.5 %

Procedure:
0.181 g of the above prepared 3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-3,5-dimethyl-phenyl}-2-isopropoxy-propionic acid ethyl ester (0.384 mmol) was dissolved in 6 ml of THF/EtOH=1/1, treated with 0.959 ml of 2N NaOH (5 eq.), and kept at ambient temperature for 14 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water, dried over magnesium sulfate, and evaporated to dryness. Boiling up in hexane, followed by decantation after cooling, yielded 0.149 g of the title compound as pale-yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:24][C:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33].O>C1COCC1>[OH:24][C:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCCCCC(O)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.4 g (23.0 mmol) 3-(3-pyridyl)-acrylic acid and 3.7 g (23.0 mmol) CDI are heated under reflux in 50 ml THF under moisture exclusion. After one hour this is cooled to RT and 6.5 g (21.9 μmmol) 8-hydroxy-8,8-diphenyloctylamine, dissolved in 20 ml THF, is added dropwise. After complete addition, stirring is carried out for a further three hours at RT and this is left to stand overnight. 50 ml water is added to the mixture and extracted three times with acetic acid ethyl ester by shaking. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate, and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and subsequently, crystallized twice from 200-ml and 140 ml acetic acid ethyl ester: Colorless crystals with MP. 139-140° C. in a yield of 3.7 g (39%). C28H32N2O2 (428.6)
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[CH2:5].C([O-])([O-])=O.[Na+].[Na+]>O.C(OC(=O)C)(=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:4][CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: C=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCCc1ccccn1
Temperature: 105 °C

Procedure:
3-(2-Pyridinyl)propionitrile is prepared in this example using the procedure of V. Boekelheide, et al., J. Am. Chem. Soc., 75, 3243 (1953). A solution of potassium cyanide (83.74 g) in water (160 ml) is added to a solution of freshly distilled 2-vinylpyridine (67.59 g) in acetic anhydrid (131.30 g) with the rate of addition adjusted to maintain gentle refluxing. When the addition is complete, the resulting dark red mixture is heated for about 17 hours at 105° C. in an oil bath with vigorous stirring. The cooled reaction mixture is adjusted to pH 8 with a saturated Na2CO3 solution. The mixture is extracted with CHCl3 (4×150 ml), washed with water, dried with Na2SO4, and evaporated to a dark viscous oil. The oil is fractionally distilled in vacuo through a Vigreaux column. After a small forerun containing 2-vinylpyridine (0.35 g), the desired 3-(2-pyridinyl)propionitrile is collected as a clear, fluorescent yellow-green, viscous oil: yield 59.8 g; 70.4%; bp 86° C. at 1.0 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[N:5]=[N:4][N:3]=1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: Cc1nnnn1CCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCn1nnnc1C
Yield: 62.2 %

Procedure:
4-(5-Methyl-1,2,3,4-tetrazol-1-yl)butyric acid (1.7 g) is dissolved in dimethylformamide (50 ml) and triethylamine (1.1 g) is added to the solution. Isobutyl chloroformate (1.5 g) is added dropwise to the mixture with stirring and ice-cooling and the mixture is stirred at room temperature for 30 minutes. Diethylamine (0.9 g) is added dropwise to the mixture with stirring at room temperature. The mixture is stirred for 3 hours. Dimethylformamide is distilled off and the residue is purified by silica gel column chromatography (silica gel made of Merck & Co.). The column is eluted with chloroform-methanol (50:1) to obtain N,N-diethyl-4-(5-methyl-1,2,3,4-tetrazol-1-yl)butyric acid amide (1.4 g), b.p. 190°-200° C. (bath temperature)/0.04 mmHg, nD25 =1.4908.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[CH3:14][CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([C:32]3[O:33][C:34]4[CH:40]=[CH:39][C:38]([CH2:41]Cl)=[CH:37][C:35]=4[CH:36]=3)=[N:29]2)=[CH:24][CH:23]=1>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([C:32]3[O:33][C:34]4[CH:40]=[CH:39][C:38]([CH2:41][C:15]([C:16]([O:18][CH3:19])=[O:17])([CH3:20])[CH3:14])=[CH:37][C:35]=4[CH:36]=3)=[N:29]2)=[CH:24][CH:23]=1
Reactant: COC(=O)C(C)C
Reactant: ClCc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
To a cooled suspension of lithium diisopropylamide {(1.45 mM tetrahydrofuran and n-hexane solution), 3.1 ml} and methyl 2-methylpropionate (0.5 g), dried hexamethylphosphoric triamide (0.5 ml) was added at -78° C. and the mixture was stirred for 10 minutes at the same temperature. Subsequently, 7-chloro-2-(5-chloromethylbenzofuran-2-yl)quinoline (6.43 g) was added to the mixture. After being stirred for 30 minutes at the same temperature, additive hexamethylphosphoric triamide (1.36 ml) was added to the mixture. The reaction temperature was gradually elevated to -10° C. for 1 hour. The resulting mixture was poured into ice-water and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (100 g) and eluted with n-hexane, successively 10% ethyl acetate in n-hexane and toluene. The fractions containing object compound were combined and concentrated under reduced pressure. The residue was dissolved in chloroform and n-hexane was added to the solution. The resulting precipitates were collected by filtration and dried to give 7-chloro-2-[5-(2-methoxycarbonyl-2-methylpropyl)benzofuran-2-yl]-quinoline (0.18 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][N:24]=[C:25]=[S:26]>C1(C)C=CC=CC=1>[CH3:23][NH:24][C:25]([N:20]1[CH2:21][CH2:22][CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:18][CH2:19]1)=[S:26]
Reactant: Fc1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Reactant: CN=C=S
Solvent: Cc1ccccc1
Product: CNC(=S)N1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 55.1 %

Procedure:
A stirred mixture of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 102 (30 g, 0.094 moles) and 25% H2SO4 (225 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 21 g (76%) of 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.0135 moles) in toluene (70 ml) was added dropwise methyl isothiocyanate (1.5 ml, 0.022 moles). The mixture was stirred for 23 hours at ambient temperature during which time the product precipitated from the solution. The product was collected and recrystallized twice from isopropyl alcohol to yield 2.74 g (55%) of N-methyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbothioamide, m.p. 179°-181° C.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4cccc(F)c4)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4cccc(F)c4)cc3OCC)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-3′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (300 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with 2 M hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (173 mg).
Reaction SMILES: [C:1]12([N:11]3[C:15](=[O:16])[C:14]([CH2:23][C:24]4[CH:28]=[CH:27][O:26][CH:25]=4)([CH2:17][C:18]4[CH:22]=[CH:21][O:20][CH:19]=4)[NH:13][C:12]3=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:32]I>C1COCC1>[C:1]12([N:11]3[C:15](=[O:16])[C:14]([CH2:23][C:24]4[CH:28]=[CH:27][O:26][CH:25]=4)([CH2:17][C:18]4[CH:22]=[CH:21][O:20][CH:19]=4)[N:13]([CH3:32])[C:12]3=[O:29])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CI
Reactant: O=C1NC(Cc2ccoc2)(Cc2ccoc2)C(=O)N1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)N(C23CC4CC(CC(C4)C2)C3)C(=O)C1(Cc1ccoc1)Cc1ccoc1
Reaction time: 1.5 h
Yield: 100.9 %

Procedure:
Under a N2 atmosphere was combined 3-adamantan-1-yl 5,5-bis-furan-3-ylmethyl-imidazolidine-2,4-dione (0.100 g, 0.25 mmol) in 2 ml of dry THF. To this solution was added a 60% dispersion of sodium hydride (11.1 mg, 0.28 mmol) and the suspension was allowed to stir for 1.5 hours. To this reaction mixture was then added methyl iodide (32 μl, 0.508 mmol) and the reaction mixture was allowed to stir for 30 minutes and quenched with water and extracted with 2×30 ml of methylene chloride (CH2Cl2). The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to yield 0.103 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([O:14][CH3:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:17][CH:18]=1
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
4-(4-Chloro-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.108 g, 0.331 mmol) was dissolved in methylene chloride (6 mL) and cooled in an ice bath. Trifluoroacetic acid (2 mL) was added slowly dropwise. The mixture was stirred for 2 hr as it warmed to room temperature. The reaction mixture was concentrated in vacuo and then redissolved in methylene chloride and washed with saturated sodium bicarbonate (2×10 mL). The pooled aqueous layers were extracted with methylene chloride (2×10 mL). The methylene chloride extracts were pooled, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4-(4-Chloro-phenyl)-4-methoxy-piperidine as a clear oil (72 mg, 97%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[C:6]=2[N:7]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH:35][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[C:17]([F:20])([F:19])[F:18])[C:6]=4[N:7]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)[CH3:22]
Reactant: FC(F)(F)c1ccccc1-c1csc2cnc(Cl)nc12
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5ccccc5C(F)(F)F)c4n3)cn2)CC1
Yield: 61.3 %

Procedure:
N-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)-7-(2-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine (19 mg, 61% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-7-(2-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidine (20 mg, 0.64 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (13 mg, 0.064 mmol).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].S(Cl)(Cl)=O.[CH2:20](O)[CH3:21]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH2:20][CH3:21])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Yield: 85 %

Procedure:
3.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III) from Example 4, 30 ml of ethanol, and 3.36 grams of thionyl chloride were added into 100 ml three-necked flask, and refluxed until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with 10 ml×3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 2.9 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][CH2:11][C:12](Cl)=[O:13].O>ClCCl>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1C=O
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2-Aminobenzaldehyde (650 mg) was dissolved in dichloromethane (20 ml) to prepare a solution. Chloroacetyl chloride (728 mg) was added to the solution, and the mixture was stirred at room temperature overnight. Water was added thereto, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 2-chloro-N-(2-formylphenyl)-acetamide (1.05 g, yield 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Br:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:15][C:12]1[CH:11]=[C:4]([CH:3]=[C:2](/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: Cc1c(Br)cc(C(=O)NC2CC2)cc1Br
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1cc(C(=O)NC2CC2)cc(Br)c1C
Temperature: 100 °C

Procedure:
To a solution of 3,5-dibromo-N-cyclopropyl-4-methylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow-orange oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Cl.[Cl-].[K+]>O1CCCC1.ClCCl>[CH2:9]1[O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:15][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:14][CH2:13][CH2:12][O:11][CH2:10]1
Reactant: ClCCOCCCl
Reactant: OCCOCCOCCOCCO
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C1COCCOCCOCCOCCOCCO1
Reaction time: 18 h
Yield: 119.9 %

Procedure:
A 3 l three-necked round-bottomed flask, fitted with a mechanical stirrer, a reflux condenser and a 250-ml dropping funnel was charged with potassium hydroxide pellets (416 g. containing 6.3 mol KOH), tetraethylene glycol (1.25 mol) and tetrahydrofuran (1000 ml). The reaction vessel was placed in a heating mantle and gently heated. After 15 minutes a solution of bis(2-chloroethyl) ether (3.125 mol) in tetrahydrofuran (150 ml) was added in one stream from the dropping funnel to the vigorously stirred reactants. The reaction mixture was then heated under reflux, with stirring for 18 hours. Subsequently, the reaction mixture was cooled and boiled down under a pressure of 1.9 kPa to give a brown slurry to which dichloromethane (750 ml) was added. The resulting suspension of potassium chloride was filtered and the potassium chloride filtered off was washed with dichloromethane (100 ml). The combined filtrate and washings were dried over anhydrous magnesium sulphate and the solvent was evaporated at a pressure of 1.9 kPa to give a residue of crude 18 -crown-6 (396 g) containing 0.531 mol of 18-crown-6 (yield 42.5%, calculated on starting tetraethylene glycol), potassium chloride and at least eight other compounds among which 1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxacyclohexatriacontane, hexaethylene glycol and unreacted tetraethylene glycol. The crude 18-crown-6 was used as described hereinafter.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: NC(c1cccnc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(c2cccnc2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine with TBTU and DIPEA in THF.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]([CH3:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:4]([CH3:13])[C:3]([O:2][CH3:1])=[O:14])(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-benzyl-D-alanine methyl ester (~2 g) in methylene chloride (40 mL) containing triethylamine (2.47 mL, 17.7 mmol) is added 4-methoxybenzenesulfonyl chloride (2.44 g, 11.8 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is acidified with 1N HCl and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (10%→20% ethyl acetate/hexanes) to provide methyl 2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]propionate.
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[Mg].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>C1COCC1.O>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][C:8]([Br:7])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH2:4][CH3:5]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCC(C)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
Add slowly a solution of 2-bromo-butane (4.8 g, 35 mmol) in anhydrous THF (20 mL) to a stirring mixture of magnesium (980 mg, 37 mmol) and anhydrous THF (10 mL) under a nitrogen atmosphere. Heat the mixture at reflux for 30 min. Cool the mixture to room temperature and add 4-bromo-benzaldehyde (5.36 g, 29 mmol). After stirring for 5 min, cool the mixture in an ice-bath and acidify with 3N aqueous HCl (50 mL). Dilute the mixture with water and extract twice with diethyl ether. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 20:1 and 1:1) to provide the desired intermediate as a clear oil (2 g, 28%). MS (APCI) m/z: 243 (M+H)+.