Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C@H:12]([OH:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: Cc1cccc(C)c1COc1cccc([C@H](O)CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (WO 02/100341, 3 g, 9.6 mmol) in methanol (64 ml) was added cerium chloride (3.55 g, 14.4 mmol). The reaction mixture was stirred for 10 minutes at room temperature, cooled to 0° C., and NaBH4 (0.400 g, 10.6 mmol) was added. The stirring continued at 0° C. for 4 hours, and the reaction was quenched with few drops of 50% aqueous acetic acid. Water (60 ml) and chloroform (60 ml) were added, and the reaction mixture was extracted with chloroform (3×25 ml). The organic layer was washed with water (2×) and brine (2×). The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography using chloroform: methanol (95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=[N:19][OH:20]
Reactant: NO
Reactant: Cn1c(C=O)nc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(C=NO)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a stirred suspension of 1-Methyl-1H-benzoimidazole-2-carbaldehyde (980 mg, 6.61 mmol) in H2O (10 ml) was added a solution of Sodium Acetate (3.25 g, 39.68 mmol) and Hydroxylamine hydrochloride (1.38 g, 19.84 mmol) in 10 ml of H2O. The reaction was stirred at rt for 2 hr and the thick precipitate was collected by filtration, washed with water and dried under vacuum to give 1.02 g (94%) of a white solid. 1H NMR (DMSO-d6) δ 12.06 (1H, s), 8.28 (1H, s), 7.65 (1H, d, J=7.5 Hz), 7.60 (1H, d, J=6.8 Hz), 7.32 (1H, t, J=7.2 Hz), 7.23 (1H, t, J=6.8 Hz), 4.00 (3H, s).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH3:43])=[CH:34]/[CH:35]=[CH:36]/[C:37]([CH2:41][CH3:42])([OH:40])[CH2:38][CH3:39])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH3:43])=[CH:34]/[CH:35]=[CH:36]/[C:37]([CH2:38][CH3:39])([OH:40])[CH2:41][CH3:42])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CCC(O)(/C=C/C=C(\C)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/C=C(\C)c1cccc(CCc2ccc(CO)c(CO)c2)c1)CC
Reaction time: 0.5 h

Procedure:
340 mg of (4E,6E)-7-(3-{2-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}phenyl)-3-ethylocta-4,6-dien-3-ol (0.5 mmol) are dissolved in 10 ml of THF and 1.5 ml (1.5 mmol) of a tetrabutylammonium fluoride solution (1M in THF) are added dropwise. After 30 minutes, 10 ml of methanol are added and the mixture is concentrated under reduced pressure. After purification of the residue by chromatography on a silica column, a colourless oil is obtained (m=163 mg; Y=88%).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][CH:10]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])[C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][CH:10]([CH:16]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[OH:17])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)C)cc1)C(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: CC(C)(C)c1ccc(CC(C(=O)O)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (7.43 g, 20.7 mmol) in tetrahydrofuran-methanol (20 ml-20 ml) was added sodium hydroxide at room temperature, and the mixture was stirred overnight at room temperature. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallization from hexane-ethyl acetate gave (2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionic acid (5.51 g, 81%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[O:18])=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCC(F)(F)F
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 18 %

Procedure:
As described in example 53g, 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (49 mg, 0.16 mmol) was converted, using 2,2,2-trifluoroethylamine hydrochloride instead of cyclobutylamine, to the title compound (11 mg, 18%) which was obtained as a colorless oil. MS: m/e=388.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:8]=[CH:7][C:6]([C:18]#[N:19])=[C:5]2[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:23]([Cl:35])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br>C(Cl)(Cl)Cl>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH:13]4[CH2:17][CH2:16][O:15][CH2:14]4)=[C:2]([N:1]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:18]#[N:19])[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: BrCCCCCBr
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(N)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#Cc1cnc2cc(OC3CCOC3)c(N3CCCCC3)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 25 °C

Procedure:
To a single-neck reaction flask (50 ml) were added 6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (20 mg, 0.041 mmol), anhydrous potassium carbonate powder (10 mg) and chloroform (5 ml). To the flask was added 1,5-dibromopentane (10 mg). The mixture was stirred at the room temperature. After the reaction finished, the mixture was filtered. The filtrate was rotary-evaporated to dryness. The residue was purified with thin layer chromatography (developing solvent: chloroform:methanol=9:1) to give a pure product.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29]C)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1-c1cccc2[nH]c3c(c12)CCN(C(=O)c1ccccc1)CC3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4O)c3c2CC1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 87.7 %

Procedure:
A 0° C. solution of 3-benzoyl-10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (936 mg, 2.36 mmol) in CH2Cl2 (20 mL) was treated with BBr3 (0.75 mL, 7.94 mmol). The reaction was stirred at room temperature under nitrogen for 16.5 hours. The reaction was cooled to 0° C. and slowly quenched with saturated NH4Cl solution. After stirring at room temperature for 1.7 hours the reaction was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated in vacuo to give 792 mg (88%) of a yellow foam as the title compound: MS m/z 383.3 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46]1([CH:52](O)[CH2:53][CH3:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:54][CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24]
Reactant: CCC(O)N1CCCCC1
Reactant: CNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCN4CCCCC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-methylurea (2.0 g) was dissolved in N,N-dimethylformamide (50 ml), and triphenylphosphine (2.8 g), piperidinopropanol (0.9 g), and diethyl azodicarboxylate (1.9 g) were added to the solution. The mixture was stirred at room temperature for 2 hr. Triphenylphosphine (2.8 g), piperidinopropanol (0.6 g), and diethyl azodicarboxylate (1.9 g) were then again added to the reaction solution, followed by stirring at room temperature for additional 10 hr. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 650 mg (yield 25%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][C:4]=1C(OCC)=O)[CH3:2].[OH-].[K+]>C(O)CO>[CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1[nH]cc(CC)c1CC
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CCc1c[nH]cc1CC
Temperature: 160 °C
Reaction time: 2.5 h

Procedure:
Ethyl 3,4-diethylpyrrole-2-carboxylate obtained in Step (6) (2.056 g, 10.53 mmol), ethylene glycol (100 ml), and potassium hydroxide (3.5 g) were placed in a light-shielded reaction vessel equipped with a reflux condenser. Then, the inside of the reaction vessel was replaced with nitrogen and the mixture was stirred at 160° C. for 2.5 hours. After that, the reaction solution cooled to room temperature was poured into ice water, and extracted with ethyl acetate, and the extract was washed with an aqueous solution of sodium bicarbonate, water, and a saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, thereby to obtain 3,4-diethylpyrrole. Again, 3,4-diethylpyrrole obtained by this reaction, benzyl-5-acetoxymethyl-4-n-butyl-3-methylpyrrole-2-carboxylate obtained in Step (3) (7.21 g, 21 mmol), acetic acid (10 ml), and ethanol (150 ml) were fed into a light-shielded reaction vessel equipped with a reflux condenser, and was refluxed for 18 hours. After the reflux, the resultant was cooled to room temperature, ethanol (50 ml) was added, and was left standing at 0° C. for 5 hours. The precipitated crystal was filtered out and thoroughly washed with ethanol to yield 2,5-bis(5-benzylcarbonyl-3-n-butyl-4-methyl-2-pyrroylmethyl)-3,4-dimethyl-1H-pyrrole (5.25 g, 72% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13]>C(O)(=O)C>[CH3:13][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[Br:5]
Reactant: Cc1cccc(C)c1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (>90% yellow fuming HNO3) is slowly added to a solution of 2-bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 mL) cooled in an ice bath (above freezing point). The resulting mixture is allowed to warm to room temperature, stirred for 1 hour, and heated at 80° C. for 2 hours or until the reaction is complete by GC/MS analysis following micro-scale base work-up. The reaction mixture is cooled to room temperature and poured into ice/water with stirring. The resulting yellow precipitates are collected by suction filtration and air dried to obtain 2,6-dimethyl-3-nitrobromobenzene.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1.C[O:21][B:22](OC)[O:23]C.C[Si](Cl)(C)C.[C:32]12([OH:43])[CH2:40][CH:36]([C:37]1([CH3:39])[CH3:38])[CH2:35][CH2:34][C:33]2([OH:42])[CH3:41]>CCCCCC.C1COCC1.CCOCC>[C:32]12([OH:43])[CH2:40][CH:36]([C:37]1([CH3:39])[CH3:38])[CH2:35][CH2:34][C:33]2([OH:42])[CH3:41].[CH3:18][C:16]1([CH3:19])[CH2:15][O:14][C:13]([C:9]2[CH:8]=[C:7]([B:22]([O-:23])[O-:21])[CH:12]=[CH:11][CH:10]=2)=[N:17]1
Reactant: COB(OC)OC
Reactant: CC1(C)COC(c2cccc(Br)c2)=N1
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)COC(c2cccc(B([O-])[O-])c2)=N1
Reaction time: 1.5 h
Yield: 49.6 %

Procedure:
n-BuLi (2.5 mL of a 2.5 M solution in hexane, 6.23 mmol) was added dropwise with stirring to a solution of 6 (1.51 g, 5.93 mmol) in THF (9.5 mL) at −78° C. under argon. After 30 min a solution of trimethylborate (0.7 mL, 5.93 mmol) in THF (2 mL) was added and the mixture stirred for 1.5 h; thereafter, the resulting yellow solution was quenched with TMSCl (0.75 mL, 5.93 mmol) and allowed to reach rt. After 1 h (+)-pinanediol (1.01 g, 5.93 mmol) dissolved in a minimum amount of anhydrous Et2O was added one portion to the solution, and then stirred overnight. The reaction mixture was partitioned in Et2O (16 mL) and H2O (10 mL) and the aqueous phase extracted with Et2O (2×10 mL). The combined organic phases were dried on MgSO4, filtered and concentrated to give an orange oil, which was purified by chromatography (7:3 EtPet/EtOAc) and crystallization (EtPet), affording 7 (1.14 g, 54%) as a white crystalline solid, mp 98-101° C., [α]D=+11.2 (c 1.5, CHCl3). IR (KBr): 1646 cm˜1. 1H NMR (CDCl3): δ 0.81 (3H, s, pinanyl CH3), 1.22 (1H, d, J=10.5 Hz, pinanyl Hendo), 1.33 (3H, s, pinanyl CH3), 1.40 (6H, s, 2CH3), 1.50 (3H, s, pinanyl CH3), 1.5-2.5 (5H, m, pinanyl protons), 4.22 (2H, s, CH2O), 4.47 (1H, dd, J=8.8, 2.0 Hz, pinanyl CHOB), 7.43 (1H, t, J=7.7 Hz, H5 arom.), 7.92 (1H, dt, J=7.7, 1.5 Hz, H6 arom.), 8.05 (1H, dt, J=7.7, 1.5 Hz, H4 arom.), 8.43 (1H, br s, H2 arom.). 13C NMR (CDCl3): δ24.4, 26.9, 27.5, 28.8 (2C), 29.1, 35.9, 38.6, 40.0, 51.9, 68.0, 78.8, 79.5, 86.8, 128.1, 131.2, 135.0, 137.8, 162.5, (CB and aromatic quaternary C not seen). EI-MS: m/z 353 (M+), 338 (base peak), 323, 282, 242, 202, 186, 130, 103, 67, 55. Anal. Calcd for C21H28NO3B: C, 71.39; H, 7.99; N 3.96. Found: C, 71.01; H, 8.65; N, 3.89.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C=O.[C:22](=O)([O-])[OH:23].[Na+].O>CS(C)=O>[OH:23][CH2:22][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C
Yield: 632.5 %

Procedure:
A mixture of methyl 3,5-bis(trifluoromethyl)benzeneacetate (Description 1, 10.0 g, 35 mmol), paraformaldehyde (1.15 g, 38.5 mmol) and sodium hydrogen carbonate (84 mg, 1 mmol) in dimethylsulfoxide (10 mL) was heated at 45° C. for 1 hour, cooled and water (200 mL) was added. The mixture was extracted with ether (2×200 mL) and the combined organic fractions were washed with water (4×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25) to give the title compound as a colorless oil (2.0 g, 10%). 1H NMR (400 MHz, CDCl3) δ 2.27 (1H, t, J 7.0 Hz), 3.76 (3H, s), 3.94–3.99 (2H, m), 4.01–4.15 (1H, m), 7.77 (2H, s) and 7.83 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].B1([C:49]2[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=2)OCCCO1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OS(=O)(=O)C(F)(F)F
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1cccnc1
Temperature: 95 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(trifluoromethanesulfonyl)oxybenzoate (1.43 g, 2.8149 mmol) in toluene (32 ml) were added tetrakistriphenylphosphine palladium (98 mg, 0.0848 mmol), aqueous solution of sodium carbonate (2M aqueous solution, 3.66 ml), lithium chloride (239 mg, 5.6381 mmol) and ethanolic solution (5.9 ml) of pyridine-3-boronic acid 1,3-propanediol cyclic ester (684 mg, 4.2222 mmol) and the mixture was heated with stirring at 95° C. for 16 hours. The reaction solution was diluted with ethyl acetate (200 ml), washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.20 g, 2.7459 mmol, 98%).
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=3)[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: Nc1cnc2c(n1)CCNCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Br
Product: Nc1cnc2c(n1)CCN(C(=O)c1ccc(Cl)cc1)CC2

Procedure:
This compound was prepared analogous to Example 29 from 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide and p-chloro-benzoyl chloride.
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH2:27]([O:29][C:30]([CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:31])[CH3:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:27]([O:29][C:30](=[O:31])[CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:35][CH2:34]1)[CH3:28]
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: CCOC(=O)CN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (376 mg, 1.96 mmol) and Et3N (275 μL, 1.96 mmol) in anhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (346 mg, 1.44 mmol) and DMAP (17 mg, 0.14 mmol) and stir the resulting solution for 15 min. Add 1-(Ethoxycarbonylmethyl)piperazine (63) (224 mg, 1.30 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with EtOAc (3 times). Filtrate the combined organic layer through a short pad of silica gel and remove solvent. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/MeOH 9+1) to obtain {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid ethyl ester (66) (426 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 1.26 (t, 3H, J=7.1 Hz); 2.45-2.70 (br.m, 6H); 2.89 (t, 2 H, J=7.7 Hz); 3.26 (br.s, 2H); 3.43-3.56 (br.m, 2H); 3.61-3.76 (br.m, 2H); 3.80 (s, 3H); 3.83 (s, 6H); 4.18 (q, 2H, J=7.1 Hz); 6.41 (s, 2H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[CH2:39]([O:41][C:42](=[O:57])[C:43]1[CH:48]=[C:47]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[CH:46]=[C:45]([CH2:55]Br)[CH:44]=1)[CH3:40]>ClCCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:55][C:45]4[CH:44]=[C:43]([CH:48]=[C:47]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[CH:46]=4)[C:42]([O:41][CH2:39][CH3:40])=[O:57])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(CBr)cc(COCCOC)c1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1cc(COCCOC)cc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1

Procedure:
A mixture of example 2 step (ii) (0.41 g) and bis[trimethylsilyl]trifluoroacetamide (0.73 g) in 1,2-dichloroethane (10 ml) was heated at reflux for 1 hour. The product from step (i) (0.45 g) was added and the mixture was heated at reflux for 7 hours. The mixture was evaporated and the residue purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.52 g.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1C[O:12][CH2:11]C1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[O:22][CH3:23].CN(C=O)C>C(OCC)(=O)C.O>[F:14][C:15]1[C:16]([O:22][CH3:23])=[C:17]([F:21])[CH:18]=[CH:19][C:20]=1[CH:11]=[O:12]
Reactant: COc1c(F)cccc1F
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)ccc(C=O)c1F
Reaction time: 0.5 h

Procedure:
Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C(OC=C)(=O)C>CCCCC>[OH:1][C@@H:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CC(O)CCCCCCCC(=O)OC
Solvent: CCCCC
Solvent: C=COC(C)=O
Product: C=C[C@H](O)CCCCCCCC(=O)OC
Temperature: 30 °C
Reaction time: 72 h
Yield: 36.6 %

Procedure:
To a solution of methyl 9-hydroxy-10-undecenate (5.293 g) in pentane (100 ml) was added vinyl acetate (11.38 ml) and Lipase PS (AMANO SEIYAKU Co., Ltd.) (1.235 g) and then shaken for 72 hours at 30° C. The reaction mixture was filtrated and the filtrate was poured into ethyl acetate, washed with saturated brine, dried over magnesium sulfate anhydride, and then evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2) to give (R)-methyl 9-hydroxy-10-undecenate (1.937 g, 36.7%).