Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: C1COCCO1
Product: CC(=O)N1CCC(Nc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 112 °C
Yield: 44 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (208 mg, 0.5 mmol), 1-(4-aminopiperidin-1-yl)ethanone (170 mg, 0.6 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), Xphos (14 mg, 0.05 mmol), t-BuONa (115 mg, 1.0 mmol) and dioxane (2.0 ml) was added into a 10 mL of sealed tube, and the mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC (DCM/EtOAc=10:1) to get 353 (115 mg, yield: 44%). 1HNMR (DMSO-d6, 400 MHz): δ8.24 (s, 1H), 7.87-7.83 (m, 1H), 7.70 (t, J=2.8 Hz, 1H), 7.69 (t, J=2.8 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.43 (d, J=11.2 Hz, 1H), 6.37 (d, J=8.8 Hz, 1H), 4.14-4.03 (m, 4H), 3.69-3.66 (m, 2H), 3.06-3.04 (m, 2H), 2.64 (t, J=2.0 Hz, 1H), 2.87 (s, 3H), 1.88-1.78 (m, 2H), 1.23-1.22 (m, 2H). ESI-MS: m/z=523 [M+H+]
Reaction SMILES: Cl.[C:2](=[NH:12])([O:9][CH2:10][CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClC(Cl)C>[Cl:20][CH2:21][C:22](/[N:12]=[C:2](\[O:9][CH2:10][CH3:11])/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:23]
Reactant: CCOC(=N)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCO/C(=N\C(=O)CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To a suspension of ethyl benzimidate hydrochloride (500 mg, 2.69 mmol) in dichloroethane (25 mL) was added under argon atmosphere triethylamine (872 mg, 1.2 mL, 8.62 mmol). The stirred reaction mixture was cooled to 0° C. and chloroacetyl chloride (608 mg, 431 μL, 5.39 mmol) was added. After 30 min the cooling bath was removed and stirring was continued at RT for 4 h. After filtration the organic phase was extracted with KHSO4 (10% aqueous solution), dried and evaporated to yield the product as light brown semi-solid (740 mg with 80% purity, 2.62 mmol, 97%) which was used without further purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[O:17]([CH2:16][CH2:15][CH2:14][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCCOc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCOc2ccccc2)cc1

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 21.5 g of 3-bromopropylphenyl ether and 100 ml of hexamethylphosphoramide is heated at 100°-110° C. in an oil bath for 20 hours. The mixture is chilled, diluted with 50 ml of water, chilled and filtered. The solid is washed with ethanol-water (1:1) and with water to give yellow crystals, mp 73°-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 5-chlorovanilline (505 mg, 2.7 mmol) in acetone (25 mL) was added cesium carbonate (1.16 g, 3.56 mmol), followed by ethyl bromoacetate (0.45 mL, 4.05 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 mL of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 330 mg of an oil (45% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.27 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 4.87 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H), 9.90 (s, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.1, 57.5, 62.1, 70.5, 112.3, 125.8, 128.9, 134.0, 149.7, 154.5, 169.5, 191.2.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]([C:15]([O:17]C(C)(C)C)=[O:16])([CH2:11][CH2:12][CH:13]=[CH2:14])[C:4]([O:6]C(C)(C)C)=[O:5]>FC(F)(F)C(O)=O>[C:15]([C:3]([CH:2]([F:1])[F:22])([CH2:11][CH2:12][CH:13]=[CH2:14])[C:4]([OH:6])=[O:5])([OH:17])=[O:16]
Reactant: C=CCCC(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(C(=O)O)(C(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Difluoromethyl 2(tert-butoxycarbonyl)-5-hexenoic acid, tert-butyl ester prepared as in Step B (5 mM, 1.600 g) is dissolved in trifluoroacetic acid (10 ml) at 0° C. After stirring for 1.5 hours at room temperature, the solvent is evaporated in vacuo yielding a white solid. 1.040 g (quantitative yield). Mp: 80°-81° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[F:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[F:8])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Fc1cnccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccncc2F)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
To a degassed solution of 4-bromo-3-fluoro-pyridine (2.98 g, 16.93 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.07 g, 20.31 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (4.75 g, 42.32 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.16 g, 0.34 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone) dipalladium(0) (1.40 g, 1.35 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:0→9:1) and then recrystallized from diethylether to provide 0.20 g (4%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): δ 1.27-1.38 (m, 2H), 1.40 (s, 9H), 1.82 (d, J=10.9 Hz, 2H), 2.84 (br s, 2H), 3.51-3.53 (m, 1H), 3.96-3.98 (m, 2H), 6.34 (d, J=7.6 Hz, 1H), 6.79 (dd, J=7.9 Hz, J=5.6 Hz, 1H), 7.95 (d, J=5.5 Hz, 1H), 8.08 (d, J=4.0 Hz, 1H). MS (ESI): 296.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:17]#[C:18]/[C:19](/[C:26]([F:29])([F:28])[F:27])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:15])([CH3:14])[CH2:12][C:5]2(OC(C)C(C)[O:6]2)[CH:4]=[C:3]1[CH3:16].Cl.O>CC(C)=O>[OH:1][C:2]1([C:17]#[C:18]/[C:19](/[C:26]([F:27])([F:28])[F:29])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:14])([CH3:15])[CH2:12][C:5](=[O:6])[CH:4]=[C:3]1[CH3:16]
Reactant: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
Ethyl (2E)-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-3-(trifluoromethyl)pent-2-en-4-ynoate (200 mg, 0.48 mmol) was dissolved in acetone (5 ml) under argon in a round-bottom flask, and 10% strength hydrochloric acid was added. The resulting reaction solution was stirred at room temperature for 45 minutes, and water was then added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)pent-2-en-4-ynoate (130 mg, 79% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.68 (s, 1H), 5.90 (s, 1H), 4.26 (q, 2H), 2.58 (m, 2H), 2.44 (d, 1H), 2.15 (s, 3H), 1.31 (t, 3H), 1.25 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:12]([O:14]CC)=[O:13])[CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1(c2ccccc2)CCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(c2ccccc2)CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-phenyl-2-tetrahydrofuroate (170 mg, 0.77 mmol) in methanol (6 ml) was added 0.5N NaOH (1.5 ml, 0.75 mmol). After stirring at room temperature overnight, it was partitioned between dilute acetic acid and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine and dried over MgSO4, filtered and concentrated to afford the title compound as a white crystalline solid which was used without further purification. 400 MHz 1H NMR (CD3OD): δ 7.54 (m, 2H); 7.34 (m, 3H); 4.07 (m, 2H); 2.79 (m, 1H); 2.18 (m, 1H); 1.98 (m, 2H).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=2)[N:8]=1.Cl>O1CCOCC1>[CH3:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)[N:8]=1
Reactant: COC(=O)c1ccc(-c2csc(C)n2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(C(=O)O)s2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
Aqueous LiOH (1N, 1.5 mL) is added to a solution of methyl 5-(2-methylthiazol-4-yl)-thiophene-2-carboxylate (81 mg, 0.34 mmol) in dioxane (1 mL). The reaction is stirred at room temperature for 2 hours. Aqueous HCl (1N, 4 mL) is added and the resultant precipitate is collected by filtration, washed with water, and dried to give the desired product (53 mg, 69%). 1H NMR (300 MHz, DMSO) δ 8.03, 7.69, 7.59, 2.70.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1.[Cl-].[NH4+]>[Cu](I)I.C(OCC)C.CCCCCC>[CH2:14]([CH:21]1[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C1C=CCC1
Reactant: [Li]CCCC
Agent: I[Cu]I
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCC1CCC(=O)C1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Diethyl ether (800 ml) and tributylphosphine (83 ml) were added to copper iodide (41.4 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −78° C., and then n-butyllithium (1.65 M, a hexane solution) (19 ml) was added dropwise at a temperature of −70° C. or lower. The stirring was continued at −78° C. for 20 minutes, and 2-cyclopentene-1-one (17.0 g) in a diethyl ether (150 ml) solution was added dropwise at a temperature of −70° C. or lower. After the mixture had been stirred at −78° C. for another 20 minutes, it was warmed to −40° C., and stirred for another 2.5 hours. Then, a saturated aqueous solution of ammonium chloride (600 ml) was added at −40° C., and the mixture was warmed to room temperature. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/20 by volume) to give 3-butyl-cyclopentanone (15.4 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[O:19]=[C:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.N1C=CC=CC=1.C(O)(=O)C>[OH-].[Na+]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:24]3[CH2:23][CH2:22][NH:21][C:20](=[O:19])[CH2:25]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: O=C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(=O)C3)cc21
Yield: 32.4 %

Procedure:
A mixture of 1-ethyl-7-chloro-1,4-dihydro-6-fluoro-4-oxoquinoline-3-carboxylic acid (0.80 g), 2-oxopiperazine (3.0 g) and 4 ml pyridine was heated for 18 hours. The reaction mixture was evaporated under vacuum, an aqueous solution of caustic soda was added to adjust the pH to 10, ice cooled and the undissolved matter was collected and washed with a small amount of an aqueous solution of NaOH. The filtered product was suspended in water, acidified with acetic acid, filtered and washed. The product obtained was dissolved in an aqueous solution of NaOH and acidified with acetic acid. The precipitate was filtered, washed and dried to obtain 0.32 g (32%) of 1-ethyl-1,4-dihydro-6-fluoro-7-(3-oxo-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CO.[OH-].[K+].[CH2:15]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH:32]=[O:33])[C:26]=1[F:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[CH2:15]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH:32]([OH:33])[C:10]2[C:4]3[C:5](=[N:6][CH:7]=[CH:2][CH:3]=3)[NH:8][CH:9]=2)[C:26]=1[F:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncccc23)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 50.6 %

Procedure:
Into a round bottom flask was added 5-chloro-1H-pyrrolo[2,3-b]pyridine (80, 0.524 g, 3.43 mmol, prepared as described in Example 9) in methanol (5.00 mL, 0.123 mol). Potassium hydroxide (0.800 g, 14.2 mmol) and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (614, 1.02 g, 3.5 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ethyl acetate to give compound 615 (710 mg, 46%). MS (ESI) [M+H+]+=444.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10]C)=[O:9].[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
To a stirring solution of methyl 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoate (200 mg, 0.49 mmol) in tetrahydrofuran (15 mL) was added lithium hydroxide (102.5 mg, 2.45 mmol) in water (5 mL) and the resultant reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure, the residue was acidified using 1N HCl solution to pH 5 and then extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (120 mg, 63%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[CH3:18]I>C1COCC1>[CH3:18][O:3][CH2:4][CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of sodium hydride (0.10 g, 2.6 mmol, 60% in mineral oil) in THF (6.0 mL) at 0° C., was treated with a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (0.56 g, 2.6 mmol, racemic, AstaTech) in THF (6.0 mL). After 15 min, methyl iodide (0.16 mL, 2.6 mmol) was added. The mixture was allowed to warm to RT and stir for 1.5 h. The reaction was then quenched with water, and extracted with four portions of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated. Flash chromatography using a 40 g silica gel cartridge, eluting with a gradient from 0-15% MeOH in DCM afforded the purified desired product, as the second product to elute (60 mg, 10%). 1H NMR (500 MHz, CDCl3): δ 3.90 (br s, 2H), 3.37 (dd, 1H), 3.34 (s, 3H), 3.25 (dd, 1H), 2.99-2.92 (m, 1H), 2.90-2.79 (m, 2H), 2.72 (td, 1H), 2.57 (br s, 1H), 2.15 (br s, 1H), 1.45 (s, 9H); LCMS (M+H)+: 231.2.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (22.6 mg, 61.4%), MS (ISP) m/z=452.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(methylsulfonyl)acetic acid.
Reaction SMILES: [C:1]([P:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].P.[Cu:23](Br)[Br:24]>CO>[Cu:23][Br:24].[C:18]([P:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Br[Cu]Br
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: P
Solvent: CO
Product: [Cu]Br

Procedure:
50 ml of degassed, anhydrous methanol were heated at reflux temperature, and 2.36 g (7.9 mmole) of 2-(di-tert.-butylphosphino)biphenyl were slowly added to the methanol until the phosphine compound had completely dissolved. 0.59 g (2.6 mmole) of copper(II) bromide was then added in portions to the solution. After addition of the copper bromide the solution was heated for a further 15 minutes at reflux temperature and the solution was then cooled. After cooling the solution a precipitate formed that was filtered off and was washed with a small amount of ethanol and diethyl ether and then dried. 0.93 g (1.1 mmole) of the abovementioned compound was obtained. The yield was 80% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[CH2:6][NH:7][C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:17]([CH2:19][CH3:20])[CH3:18])[CH:11]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:3][C:4]([CH:5]1[C:22]2[C:27](=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:17]([CH2:19][CH3:20])[CH3:18])[CH:11]=2)=[N:7][CH2:6]1)=[O:32])[CH3:2]
Reactant: CCOC(=O)C(CNC(=O)Cc1cccc(OC(C)CC)c1)c1ccc(OC)c(OC)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CN=C(Cc2cccc(OC(C)CC)c2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.2 %

Procedure:
To a stirred solution of 3-[2-(3-sec-butoxy-phenyl)-acetylamino]-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester (11.2 g, 25.3 mmol) in dichloromethane (140 mL) was added phosphorus pentachloride (7.85 g, 37.7 mmol). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was diluted with dichloromethane and washed with cold saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous sodium chloride solution (50 mL). The aqueous phase was extracted with dichloromethane (3×50 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vauo to afford 1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline-4-carboxylic acid ethyl ester (11.0 g, 99% yield) as a yellow oil. The crude product was used in the next step reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1.[H-].[Na+].[CH3:19]OS(OC)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:19])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Brc1ccccc1-c1nc2ccccc2[nH]1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2Br)nc2ccccc21
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
To a flask were added 3.3 g 2-(2-bromophenyl)-1H-benzimidazole and 100 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 0.63 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 2.0 g Dimethylsulfate were added and the mixture was heated to 22 C for 30 minutes. The mixture was quenched slowly with 100 ml water, extracted with ethyl acetate and then extracted into a 1M hydrochloric acid solution. The solution was washed with ethyl acetate and then basified with 3M sodium hydroxide. Following extraction with ethyl acetate and solvent removal, the solid was dissolved in a hot mixture of 20 ml hexane with 4 ml 2-propanol. After cooling to 5 C, the product was filtered, washed with hexane and dried giving 2.9 g of a white solid.