Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH2:39][CH2:40][N:41]3[CH:45]=[CH:44][N:43]=[CH:42]3)=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1>CN(C=O)C>[ClH:25].[N:41]1([CH2:40][CH2:39][O:38][C:32]2[CH:31]=[C:30]3[C:35]([C:26]([CH:16]4[C:15]5[C:19](=[CH:20][CH:21]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][N:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)(=[O:12])=[O:11])[CH:14]=5)[NH:18][C:17]4=[O:22])=[N:27][CH:28]=[N:29]3)=[CH:34][C:33]=2[O:36][CH3:37])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Reactant: O=C1Cc2cc(S(=O)(=O)NCCN3CCOCC3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(S(=O)(=O)NCCN5CCOCC5)cc43)ncnc2cc1OCCn1ccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A solution of 5-(2-morpholinoethylaminosulphonyl)oxindole (320 mg, 0.98 mmol), (prepared as described for the starting material in Example 48), in DMF (3.5 ml) was added to a suspension of sodium hydride (39.4 mg, 0.98 mmol, prewashed with THF) in DMF (1.5 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (100 mg, 0.32 mmol), (prepared as described for the starting material in Example 22), was added. The mixture was stirred for 1 hour at 60° C., allowed to cool and partitioned between methylene chloride and saturated aqueous ammonium chloride solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methanoymethylene chloride (5/95 to 15/85). The purified product was triturated with ether, collected by filtration and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 2.2M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-4-(5-(2-morpholinoethylaminosulphonyl)oxindol-3-yl)quinazoline hydrochloride (153 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1.[OH2:41]>>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)(=[O:38])=[O:41])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(Sc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.05 g (2.8 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoate and 30 ml of dichloromethane were introduced into a round-bottomed flask, and 2.45 g (7.12 mmol) of meta-chloroperbenzoic acid were then added. The entire contents were stirred at room temperature for two hours, the reaction medium poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>CC1C=CC(C)=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: c1ccccc1
Reactant: CCCCCC
Solvent: Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CCCCCCCCCCCC

Procedure:
When the dispersion of the solid polymer electrolyte was added to organic solvents having a dielectric constant of less than 3, such as n-hexane, benzene, toluene, p-xylene and dodecane having dielectric constants of 1.89, 2.28, 2.38, 2.27 and 2.02, respectively, the solid polymer electrolyte produced a white precipitate and the polarization characteristics of the cells could hardly be taken out.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH:5](C)[C:4](=[O:10])[O:3]1.C(OC1NC(=O)C1)(=O)C.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][C:2]1([CH3:11])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:10])[O:3]1
Reactant: CC1C(=O)OC(C)(C)OC1=O
Agent: CC(=O)OC1CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.9 %

Procedure:
2,2,5-trimethyl-1,3-dioxan-4,6-dione II (17.4 g, 110 mmol), 4-acetoxy-azetidinone I (28.7 g, 100 mmol) and K2CO3 (15.2 g, 110 mmol) were mixed in dry acetonitrile (150 mL, KF=5.6 mg/mL), and the mixture was aged at 45-50° for 14 hours. Upon completion, the reaction mixture was cooled to room temperature and water (150 mL) was added. The organic layer was separated and the aqueous layer was back extracted with acetonitrile (100 mL). Combined organic extracts were washed with brine (100 mL) and concentrated to ca. 50 mL in volume. The mixture was then diluted with heptane (200 mL) and concentrated to 50 mL. Additional heptane (150 mL) was added and the mixture was aged at room temperature for crystallization. The resulting product was collected by filtration, washed with heptane (50 mL) and dried under vacuum at 40-50 for 15 hours to give an off-white crystalline solid (30.9 g, 80.2 mmol). A second crop was obtained by concentrating the combined filtrate and washed to ca. 50 mL in and aging at room temperature to give a white, fluffy solid (2.07 g, 5.4 mmol). Combined yield was 85.6%. Melting Range (° C.) 78-83 d.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C.C(Cl)Cl.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)=[O:20])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(CBr)N1CCc2ccccc21
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CC#N
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCc2ccccc21

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g, 45.4 mmol), K2CO 3 (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12 g, 50 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The mixture was cooled and filtered. The solution was concentrated down until solid appeared. The crystals were collected: weight 12.68 g. The mother liquor was concentrated to dryness. The residues were purified further by flash chromatography to yield an additional 1.35 g. Total yield was 14.03 g. A 2 g sample was dissolved in ethanol/methylene chloride and was treated with a solution of fumaric acid (612 mg) in ethanol to yield 2.58 g, m.p. 226°-227° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.BrN1C(=[O:20])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2[CH:13]=[O:20])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1snnc1-c1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1snnc1-c1ccc(F)cc1
Reaction time: 6 h
Yield: 5.4 %

Procedure:
A mixture of 4-(4-fluorophenyl)-5-methyl-1,2,3-thiadiazole (6.19 g), N-bromosuccinimide (12.4 g), 2,2′-azobis(isobutyronitrile) (100 mg) and carbon tetrachloride (100 ml) was stirred for 6 hrs. with heating under reflux. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. Sodium acetate (30 g) and acetic acid (100 ml) were added to the residue and the mixture was stirred for 12 hrs. with heating under reflux. 6N Hydrochloric acid (50 ml) was added and the mixture was further stirred for 1 hr. with heating under reflux. The reaction mixture was concentrated, poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-(4-fluorophenyl)-1,2,3-thiadiazole-5-carbaldehyde (360 mg, yield 5.4%) as pale-yellow crystals from a fraction eluted with hexane-ethyl acetate (2:1, v/v).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].CO[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH:8]2[NH:5][CH2:4][CH:3]=[CH:2][NH:1]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccccc1
Reactant: NCCCN
Product: C1=CNC(c2ccccc2)NC1
Reaction time: 3 h
Yield: 79 %

Procedure:
With 185 g 1,3-diaminopropane, 136 g benzoic acid methyl ester were reacted under pressure at 200° C. in the reactor. After 3 hours, the excess of diamine was distilled off, and the 2-phenyl-tetrahydropyrimidine was isolated in a 79% yield. Boiling point 165° C./1 mm; melting point=86°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].Br[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[Cl:9]
Reactant: BrCCOCCBr
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(N2CCOCC2)ccc1Br
Temperature: 80 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
4-Bromo-3-chloroaniline (500 mg) was dissolved in DMF (10 ml), and bis(2-bromoethyl)ether (1.12 g), K2CO3 (1.34 g), and potassium iodide (80 mg) were added thereto, followed by stirring at 80° C. for 2 days. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 20% EtOAc/hexane) to obtain 4-(4-bromo-3-chlorophenyl)morpholine (263 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)C.C(O)(=O)C>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 19 h
Yield: 50 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (3.43 g, 0.0171 mol, 1.15 eq) and 4-hydroxypiperidine (1.51 g, 0.0149 mol, 1 eq) were stirred at room temperature in THF (20 ml), ethanol (3 ml) and acetic acid (0.4 ml) for 4 hours. To the solution was added 0.4 g of 5% palladium on carbon type 87L Johnson Matthey catalyst The reaction was then hydrogenated under a pressure of 2.5 bar at room temperature for 19 hours. The catalyst was filtered off through CELITE™ and washed with ethanol (20 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (50% purity by HPLC area %) was not isolated.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=[O:40])[CH3:39].O>CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH2:37][C:38](=[O:40])[CH3:39])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1
Reactant: CC(=O)CCl
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CC(C)=O)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
(S)-5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (140 mg, 0.34 mmol) obtained in Step 1 of Example 89 was dissolved in DMF (3.0 mL), and the mixture was stirred at room temperature for 1 hour after adding potassium carbonate (94 mg, 0.68 mmol) and chloroacetone (0.030 mL, 0.38 mmol). Thereafter, water was added to the mixture, and the precipitated pale yellow solid was filtered off to obtain (S)-5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-(2-oxopropyl)-1,3,4-oxadiazol-2(3H)-one (144 mg, 91%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[S-:12][C:13]#[N:14].[Na+].[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17]>C(O)C>[C:16]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:13]1[S:12][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2 g (9.2 mmol) of 2-bromo-1-(4-fluoro-phenyl)-ethanone and 801.7 mg (9.89 mmol) of sodium thiocyanate in 25 ml of ethanol were stirred at 50° C. for 4 h. 1.2 g (9.2 mmol) of aminoacetic acid tert-butyl ester in 2.5 ml of ethanol were added, and the reaction mixture was stirred at room temperature for 2.5 h and allowed to stand overnight. After evaporation, water and ethyl acetate were added, the organic phase was separated, washed with water, dried and evaporated. Yield: 787 mg.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Cl[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1>>[F:22][C:21]1[C:16]([C:5]#[C:4][CH2:3][CH2:2][C:1]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[O:6])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: C#CCCC(=O)Oc1cccc(Cl)c1
Reactant: Fc1cccnc1Cl
Product: O=C(CCC#Cc1ncccc1F)Oc1cccc(Cl)c1
Yield: 13.1 %

Procedure:
According to the protocol described in Example 237(B), the reaction between 3-chlorophenyl pent-4-ynoate (580 mg, 2.80 mmol) and 2-chloro-3-fluoropyridine (370 mg, 2.80 mmol) afforded 111 mg of 3-chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate (Yield: 13%) as yellow-oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[N:6]([C:13]1[C:14]([CH3:33])=[C:15]([CH3:32])[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:17]=3[C:30]=1[CH3:31])[C:5]2=O>C(OCC)(=O)C>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[CH2:5][N:6]([C:13]1[C:14]([CH3:33])=[C:15]([CH3:32])[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:17]=3[C:30]=1[CH3:31])[CH2:7]2
Reactant: Cc1c(C)c(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2Cc3cc(Cl)c(Cl)cc3C2)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Yield: 25 %

Procedure:
By using 5,6-dichloro-2-[3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 25%. Melting point: 233-238° C. (Ethyl acetate).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C.O>[ClH:32].[CH:22](=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]1=[N:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (2.5 g, 6.5 mmol) was dissolved in ethanol (20 ml) and 4N sodium hydroxide (4.9 ml) was added. The mixture was stirred at ambient temperature for 3 h and excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml) and water (15 ml). The phases were separated and the organic phase was dried (MgSO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone and recrystallised from acetone (180 ml) to give 1.5 g of the title compound as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[CH2:11]([O:13][C:14]([C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[NH:19][CH:20]=1)=[O:15])[CH3:12].CN(C=O)C>CCOC(C)=O>[CH2:11]([O:13][C:14]([C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)[N:19]([CH2:8][CH2:9][CH3:10])[CH:20]=1)=[O:15])[CH3:12].[CH2:11]([O:13][C:14]([C:16]1[N:17]([CH2:8][CH2:9][CH3:10])[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=2)=[N:19][CH:20]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1c[nH]c(Cc2ccc(Br)cc2)n1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1c(C(=O)OCC)cnc1Cc1ccc(Br)cc1
Product: CCCn1cc(C(=O)OCC)nc1Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 33.6 %
Yield: 20 %

Procedure:
Potassium carbonate (2.6 g, 18.7 mmol) and 1-iodopropane (669.7 μL, 6.9 mmol) were added to 2-(4-Bromobenzyl)-1H-imidazole-4-carboxylic acid ethyl ester (1.9 g, 6.2 mmol) dissolved in DMF (40 mL, 500 mmol). The mixture was heated at 60° C. for 5 hours. The mixture was cooled and then diluted with EtOAc (100 mL), washed with water and saturated aqueous NaCl (100 mL each), dried over MgSO4, filtered and concentrated. The mixture was purified by column chromatography (20-60% EtOAc in Hexanes) to yield the desired product, 2-(4-bromobenzyl)-1-propyl-1H-imidazole-4-carboxylic acid ethyl ester (736 mg, 33.6% yield), and its regioisomer, 2-(4-bromobenzyl)-3-propyl-3H-imidazole-4-carboxylic acid ethyl ester (500 mg, 20% yield). The structures were confirmed by NMR.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:22]I>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:22])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1ccc2[nH]c(C(=O)OCC)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)cc(C(=O)OCC)n2C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
Sodium hydride (60%-suspension, 144 mg, 3.6 mmole) was added to a stirred solution of 1H-indole-2,5-dicarboxylic acid diethyl ester 16 (784 mg, 3.0 mmole) in dry DMF (15.0 ml) and kept at ambient temperature for 30 min. To a resulted reaction mixture MeI (280 μl, 4.5 mmol) was added and kept at ambient temperature for 16 hours and evaporated. The residue was suspended in AcOEt (100 ml) and washed with water (2×20 ml), 0.01 M HCl (3×20 ml) and brine (2×100 ml). The organic layer was dried over sodium sulfate and evaporated to give 800 mg (97%) of 1-methyl-indole-2,5-dicarboxylic acid diethyl ester 17 as a yellow oil. 1H-NMR (DMSO-d6): 8.45 (m, 1H, H-4, indole); 8.03 (m, 1H, H-6, indole); 7.40 (m, 11H, H-7, indole); 7.38 (s, 1H, H-3, indole); 4.40 (m, 4H, —OCH2CH3); 4.10 (s, 3H, NCH3, indole); 1.42 (m, 4H, —OCH2CH3).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH:21][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:20]=2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(Cl)cc2)c1
Reaction time: 0.67 h
Yield: 33.3 %

Procedure:
To a mixture of 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt (90 mg, 0.25 mmol), 4-chloro-phenylboronic acid (45 mg, 0.29 mmol), copper (II) acetate (218 mg, 1.2 mmol), 4A molecular sieves (5 g) in dichloromethane (20 ml) was added triethylamine (0.3 ml). The mixture was stirred under an oxygen atmosphere for 40 minutes and filtered through a pad of celite under suction. After evaporation of volatiles under reduced pressure, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (3:5 followed by 1:1 followed by 5:3) to provide the title compound (30 mg, 33% yield). 1H NMR (acetone-d6) δ 3.84 (s, 3H, CH3), 5.33 (d, 2H, J=8.8 Hz, NH2), 6.16 (d, 1H, J=1.1 Hz, Ar), 6.27 (t, 1H, J=1.1 Hz, Ar), 7.12 (d, 1H, J=8.8 Hz, Ar), 7.23 (d, 2H, J=8.9 Hz, Ar), 7.30 (d, 1H, J=2.7 Hz, Ar), 7.36 (dd, 1H, J=8.8 Hz, J=2.7 Hz, Ar), 7.76–7.79 (m, 2H, Ar), 8.05 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][NH:44][CH3:45].[C:46](=[O:48])=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:43][N:44]([CH3:45])[C:46]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[C:13]=2[CH:12]=1)=[O:48]
Reactant: O=C=O
Reactant: CNC
Reactant: Cn1c(C(F)(F)F)nc2c(OCc3ccccc3)cc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c2nc(C(F)(F)F)n(C)c2c1
Yield: 62 %

Procedure:
15.8 g (41.0 mmol) 4-Benzyloxy-6-bromo-1-methyl-2-trifluoromethyl-1H-benzimidazole, 6.4 g (24.6 mmol) triphenylphosphine, 1.4 g (6.2 mmol) palladium(II) acetate and 205 ml (410 mmol) dimethylamine (2 M in THF) were transferred to an autoclave and carbonylated (6 bar CO2) at 120° C. for 16 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel (dichloromethane/methanol=50:1) afforded 9.3 g (62%) of the title compound as a white solid. m.p. 144°-146° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH2:8][S:9]([O-:12])(=[O:11])=[O:10])[CH3:7].P(Cl)(O[CH2:19][CH3:20])(OCC)=O.[Br:22][C:23]1[CH:30]=[CH:29]C(C=O)=[CH:25][CH:24]=1>C1COCC1.O>[Br:22][C:23]1[CH:30]=[CH:29][C:7](/[CH:6]=[CH:8]/[S:9]([O:12][CH2:19][CH3:20])(=[O:11])=[O:10])=[CH:25][CH:24]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCS(=O)(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOS(=O)(=O)/C=C/c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
n-Butyllithium (59.0 mL, 1.6M solution in hexanes) was added dropwise during 25 min to a solution of ethylmethanesulfonate (9.1 mL, 86 mmol) in THF (200 mL) at −78° C. The reaction mixture was stirred for 15 min then diethyl chlorophosphate (7.2 ml, 50 mmol) was added dropwise. The solution was stirred at −78° C. for 30 min, allowed to warm to 0° C. and then cooled to −78° C. again. 4-Bromobenzaldehyde (9.2 g, 50 mmol) in THF (50 mL) was then added dropwise during 15 minutes and the resulting mixture was then allowed to slowly reach RT and stirred overnight. Water (20 mL) was added to the mixture and the reaction was concentrated in vacuo. The residue was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. Purification by column chromatography, using 15% ethyl acetate/hexanes as the eluent, afforded the title compound (9.3 g, 64%).