Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39].C(O)C.[ClH:50]>O1CCCC1>[ClH:50].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH2:24][N:44]1[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2cc(C(C)(C)C)cc(-c3ccc(C(F)(F)F)nc3)c2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
Sodium triacetoxyborohydride (0.41 g, 2.0 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and 1-acetylpiperazine (0.24 mL, 1.8 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a colorless oil which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was then concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 1-(4-(5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzyl)piperazin-1-yl)ethanone hydrochloride (0.32 g, 61% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:34])([CH3:33])[C:19](=[O:32])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:24][CH2:23]3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:34])([CH3:33])[C:19](=[O:32])[N:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])[CH2:24][CH2:23]3)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OCc1ccccc1
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
Prepared analogously as described for example 1 using 5-[3-(benzyloxy)-4-methoxyphenyl]-2-[1-(chloroacetyl)piperidin-4-yl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (see below) and succinimide as starting compounds.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@:14]([F:26])([CH3:25])[CH:13]([O:27][CH3:28])[O:12]1)(=O)C1C=CC=CC=1.CO>N>[F:26][C@@:14]1([CH3:25])[CH:13]([O:27][CH3:28])[O:12][C@H:11]([CH2:10][OH:9])[C@H:15]1[OH:16]
Reactant: COC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@]1(C)F
Agent: N
Solvent: CO
Product: COC1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Yield: 99 %

Procedure:
((2R,3R,4R)-3-benzoyloxy-4-fluoro-5-methoxy-4-methyl-tetrahydrofuran-2-yl)methyl benzoate (17 g, 43.8 mmol) in methanolic ammonia solution (25% w/w, 340 ml) was stirred at room temperature for about 36 hours, completion of the reaction monitored by thin-layer chromatography, methanol was removed under reduced pressure. Water added to the reaction mixture and extracted with ethyl acetate and the organic layer was dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 20% ethyl acetate in hexane eluded the title compound (8 g) as an off-white solid. Yield: 99%.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:9])[C:7]#[CH:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[C:1]([NH:5][C:6](=[O:9])[C:7]#[C:8][Br:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(=O)NC(C)(C)C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)NC(=O)C#CBr
Temperature: 25 °C
Yield: 67.5 %

Procedure:
0.50 g of N-(tert-butyl)propiolamide was dissolved in 15 ml of methanol, to which 0.17 g of sodium hydroxide was added. 0.64 g of bromine was added dropwise to the mixture while stirring at a room temperature. 50 ml of 5%-aqueous solution of sodium thiosulfate was added to the reaction solution to extract with dichlormethane. The extracted solution was dried and concentrated. The residue was then purified by column chromatography (silica gel, eluent: ethyl acetate/hexane =1/5). Subsequently, 0.55 g of N-(tert-butyl)-3-bromopropiolamide was obtained by means of recrystallization from dichlormethane/hexane.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH3:26]>>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH3:26]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: CCOc1cc(B(O)O)ccc1OC
Product: CCOc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC)nc2C)c(=O)n4C)ccc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 39 mg, 0.100 mmol) and 3-ethoxy-4-methoxyphenylboronic acid (Combi-Blocks, San Diego, USA, 25.5 mg, 0.130 mmol) to give the title compound as an off-white foam. (HPLC: tR 2.86 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.16 (s, 1H), 8.08-8.01 (m, 1H), 7.93-7.87 (m, 1H), 7.52-7.46 (m, 1H), 7.06-6.96 (m, 3H), 4.20-4.03 (m, 4H), 3.77 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H), 1.45-1.33 (m, 6H))
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=O)([O-])=[O:2].Cl.O.O.[Sn](Cl)Cl>C(O)C.O>[OH:2][N:1]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[CH2:13][C:14]1=[O:16]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: O=C1Cc2ccc([N+](=O)[O-])cc2N1O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2.0 g of 2,4-dinitrophenylacetic acid (prepared according to J: Chem. Soc. 1948, 1717) are dissolved in 40 ml ethanol and 6.0 ml of conc. hydrochloric acid and 4.1 g of tin-(II)-chloride-dihydrate are added in batches at ambient temperature. The mixture is stirred for 12 hours at ambient temperature and for 4 hours at 60° C. After cooling another 2.0 g of tin-(II)-chloride-dihydrate are added and the mixture is stirred for another 12 hours at ambient temperature. The reaction mixture is diluted with water, extracted with methylene chloride and the organic phase is dried over sodium sulphate. After elimination of the solvent the residue is triturated with ether and the precipitate is filtered off.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10]1=[O:19])=O)(C)(C)C.Cl.[CH2:21](O)[CH3:22]>>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17])[C:10]1=[O:19]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)O)C1=O
Agent: Cl
Product: CCOC(=O)CN1CCC[C@H](N)C1=O
Reaction time: 1 h

Procedure:
To a solution of compound 21 (5.45 g, 0.020 mol) in 20 mL of dry ethanol at 0° was added ethanolic 12N HCl (50.0 mL, 0.60 mol). The solution was stirred at 0° for one hr and then allowed to stir at ambient temperature for 3 hrs. The solvent was evaporated, the residue was twice redissolved in a mixture of ethanol, acetonitrile: 1,1 and reevaporated. After vacuum pumping at <1 mm Hg for 24 hrs, 4.84 g (~quantitative crude yield) of product 22 was obtained as a sticky light brown foam. TLC (silica; CH2Cl2, methanol, conc NH4OH: 27, 3, 1): Rf=0.35.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[C:28]([CH3:39])[NH:27][N:26]=1>>[CH3:24][C:25]1[C:29]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)=[C:28]([CH3:39])[NH:27][N:26]=1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1n[nH]c(C)c1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)sc2n1
Yield: 25 %

Procedure:
The titled compound (yield=25%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 2.40 (s, 6H) 7.54 (d, J=8.34 Hz, 1H) 7.66 (d, J=8.34 Hz, 2H) 8.04-8.19 (m, 3H) 12.89 (br. s., 1H); ESI-MS: m/z 408.0 (M+H)+.
Reaction SMILES: [F:1]C(F)(N(CC)CC)C(F)C(F)(F)F.O[C@@H:16]1[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:17]1.[F-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C.CCCCCC>[F:1][CH:16]1[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:17]1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CC(F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.11 g of a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise over a period of 10 minutes, and under ice cooling, to a suspension of 5.33 g of 1-benzyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate and 962 mg of sodium fluoride in 53 mL of dichloromethane, after which the reaction mixture was stirred for 16 hours at room temperature. After this, 100 mL of a 5% potassium carbonate aqueous solution was added under ice cooling to the reaction solution, and the reaction mixture was stirred for 30 minutes at the same temperature. After liquid separation, the aqueous layer thus obtained was extracted with chloroform (30 mL×2), and the combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=3/7; v/v) to obtain 1.50 g of the titled compound (colorless oil).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[N:16]=[CH:17][S:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[C:20]1([C:19]2[S:18][CH:17]=[N:16][C:15]=2[CH2:14][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1ncsc1-c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ncsc1-c1ccccc1
Reaction time: 3 h
Yield: 52.7 %

Procedure:
Prepare a cold (0° C.) solution of potassium phthalimide (350 mg, 1.8 mmol) in dimethylformamide (25 mL). Add dropwise 4-bromomethyl-5-phenyl-thiazole (400 mg, 1.6 mmol) in dimethylformamide (10 mL). Warm the reaction to room temperature, stir for 3 hours and then concentrate. Dissolve the residue in ethyl acetate (100 mL), wash with saturated Na2CO3 (50 mL) and brine (50 mL), then dry (Na2SO4), filter and concentrate to a brown residue. Chromatograph (silica gel, 4:1 hexane/ethyl acetate) to afford 2-(5-phenylthiazol-4-ylmethyl)isoindole-1,3-dione (270 mg).
Reaction SMILES: [S:1]([O-])([O-])(=O)=[S:2].[Na+].[Na+].O.Br[CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[CH:13]1>C(O)C>[CH3:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([CH2:11][CH2:10][S:1][S:2][CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13]2)[CH:13]=1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1cn(CCBr)c2ccccc12
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cn(CCSSCCn2cc(C)c3ccccc32)c2ccccc12

Procedure:
A solution of 10.4 g. of sodium thiosulfate in 60 ml. of water and 100 ml. of ethanol is poured onto 8.6 g. of 1-(2-bromoethyl)-3-methylindole. The reactionmixture is stirred and heated at reflux for 3.5 hr., allowed to cool, and evaporated to dryness. The solid residue is dissolved in boiling isopropanol, dried with a hydrated alkali-aluminum silicate ("Molecular Sieves"), and filtered. Chilling of the filtrate causes 6.4 g. of the sodium indolyethyl thiosulfate derivative to precipitate. This material is collected by filtration and washed with ether. The isolated intermediate is heated at reflux with a solution of sodium hydroxide (9 g. of NaOH, 60 ml. of water, 140 ml. of ethanol) for 3 hr. Ethanol is removed under reduced pressure, the aqueous residue diluted with water and extracted with three portions of ether. Combined ether extracts are washed with water, saturated brine solution, and dried over magnesium sulfate. The filtrate is evaporated, to yield bis-[2-(3-methylindole-1-yl)ethyl]disulfide.
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:5].[C:23]([O-:26])(=[O:25])[CH3:24].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:12][C:8]1[N:7]=[C:6]([C:4](=[O:5])[CH:3]([O:26][C:23](=[O:25])[CH3:24])[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Reactant: CC(=O)[O-]
Agent: Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C(=O)c1cccc(C)n1)c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
A solution of of 2-bromo-1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone hydrobromide (94 mg, 0.36 mmol), and potassium acetate (70 mg, 0.72 mmol, 2 equiv) in dimethylformamide (2 mL) is heated to 60° C. for 1 hour. The resulting reaction mixture is cooled to ambient temperature, treated with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organics are washed with brine, dried with magnesium sulfate and concentrated in vacuo to provide acetic acid 2-(6-methyl-pyridin-2-yl)-2-oxo-1-quinolin-6-yl-ethyl ester.
Reaction SMILES: [OH:1][CH:2]([CH3:23])[CH2:3][CH2:4][C:5]1[O:6][C:7]2[C:16]3[CH:15]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:8]=2[N:9]=1.C[N+]1([O-])CCOCC1.O>C(#N)C>[O:1]=[C:2]([CH3:23])[CH2:3][CH2:4][C:5]1[O:6][C:7]2[C:16]3[CH:15]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(CCC(C)O)oc3c21
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CC#N
Product: CC(=O)CCc1nc2ccc3c(c2o1)C(CCNC(C)=O)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A suspension of N-{2-[2-(3-hydroxybutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl}acetamide (72.0 mg, 0.228 mmol), 4 Å molecular sieves (72 mg), 4-methylmorpholine N-oxide (66.8 mg, 0.570 mmol) and tetra-n-propylammonium perruthenate(VII) (8.0 mg, 0.0228 mmol) in acetonitrile (3 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallized (ethyl acetate/hexane) to give the title compound (22.2 mg, yield 31%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(#N)C>[CH2:12]([N:14]([CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: O=Cc1cc(CCl)ccc1O
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)Cc1ccc(O)c(C=O)c1
Yield: 150.8 %

Procedure:
To a solution of 5-(chloromethyl)salicylaldehyde (14)(345 mg, 2 mmol) in acetonitrile (70 mL), diethylamine (0.21 mL, 2 mmol) was added and the mixture refluxed overnight. Then, the solvent was evaporated to give compound 15 (625 mg, 99%) as a yellow oil. □max 3383, 2648 and 1653 cm−1. 1H-NMR δH 1.37 (6H, t, J=7.2 Hz, 2×CH2CH3), 3.43 (4H, q, J=7.2 Hz, 2×CH2CH3), 4.09 (2H, s, CCH2N), 7.05 (1H, d, J=8.6 Hz, HAr), 8.03 (1H, d, J=8.6 Hz, HAr), 8.14 (1H, s, HAr), 9.98 (1H, s, CHO), 12.32 (1H, br s, OH). 13C-NMR δC 11.4, 46.4, 56.0, 118.8, 121.3, 136.7, 139.0, 162.7, 196.5. m/z(ESI) 208 (MH+, 100), 293 (30), 317 (10). HRMS (ESI): Calculated for M+ (C12H17NO2+) 208.1338. Found 208.1355.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[O:12][CH3:13].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:52]([C:54]([OH:87])([CH2:85][CH3:86])/[CH:55]=[CH:56]/[C:57]1[CH:62]=[CH:61][C:60]([C:63]([CH2:82][CH3:83])([C:66]2[CH:71]=[CH:70][C:69](B3OC(C)(C)C(C)(C)O3)=[C:68]([CH3:81])[CH:67]=2)[CH2:64][CH3:65])=[CH:59][C:58]=1[CH3:84])[CH3:53].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([C:69]2[CH:70]=[CH:71][C:66]([C:63]([CH2:64][CH3:65])([C:60]3[CH:61]=[CH:62][C:57](/[CH:56]=[CH:55]/[C:54]([CH2:85][CH3:86])([OH:87])[CH2:52][CH3:53])=[C:58]([CH3:84])[CH:59]=3)[CH2:82][CH3:83])=[CH:67][C:68]=2[CH3:81])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: COC(=O)Cc1cc(Br)ccc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(OC)c(CC(=O)OC)c3)c(C)c2)cc1C)CC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-acetic acid methyl ester (Example 180-(1); 45.1 mg, 0.174 mmol), palladium acetate (2.7 mg, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.5 mg, 0.023 mmol), potassium phosphate (74 mg, 0.348 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 56.7 mg, 0.116 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (54.7 mg, 87%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24]CC5CCNCC5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44](C4C(C)=CN=C(Cl)N=4)S[C:42]=3[CH:41]=CC=2)=O)CC1.C(OC(N1CCC(CCCN)CC1)=O)(C)(C)C>>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:41][CH2:42][CH:46]5[CH2:38][CH2:36][NH:35][CH2:44][CH2:45]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: Cc1cnc(NCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Product: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-[5-methyl-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 450 [M+H].
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18](Cl)[CH:17]=1)([CH3:12])([CH3:11])[CH3:10].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.P>COCCOC.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].C(P([C-]1C=CC=C1)C(C)(C)C)(C)(C)C.C1(C2[C-](C3C=CC=CC=3)C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)C=CC=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:17]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)Cc1ccnc(Cl)c1
Reactant: CN1CCNCC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: COCCOC
Product: CN1CCN(c2cc(CC(=O)OC(C)(C)C)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium phosphate (2.65 g, 12.47 mmol) is dried at 120° C. under high vacuum for 45 minutes. After cooling to RT and venting with dry argon, palladium dibenzylideneacetone (Pd2(dba)3, 25 mg, 0.03 mmol) and di-tert-butylphosphino pentaphenylferrocene (39 mg, 0.06 mmol) are added. (2-Chloro-pyridin-4-yl)-acetic acid tert-butyl ester (631 mg, 2.77 mmol), dissolved in 1,2-dimethoxyethane (14 ml, dried by passing through a column of basic aluminum oxide), and 1-methyl piperazine (830 mg, 8.31 mmol) are added. The reaction mixture is warmed to 40° C. for 1 h. Additional Pd2(dba)3 (25 mg, 0.03 mmol) and phosphine ligand (39 mg, 0.06 mmol) is added, and stirring is continued at 60° C. for 2 h. Additional Pd2(dba)3 (25 mg, 0.03 mmol) and phosphine ligand (39 mg, 0.06 mmol) is added, and stirring is continued at 90° C. for 18 h and at RT for 72 h. TLC and MS analysis indicated the presence of desired product. The reaction mixture is diluted with EtOAc and poured into a saturated solution of NaCl in water. The organic layer is separated, dried over Na2SO4, and the solvent is evaporated. Purification of the residue by FCC (hexane/EtOAc, gradient from 95:5 to 90:10) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H), 2.34 (s, 3H), 2.52 (m, 4H), 3.42 (s, 2H), 3.55 (m, 4H), 6.55 (d, J=4 Hz, 1H), 6.56 (s, 1H), 8.11 (d, J=4 Hz, 1H). ES+−MS: 292.4 [M+H]+.