Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][C:17](=S)[C:12]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:2][CH3:3].CC(C)=[O:24]>CI.O>[O:24]=[C:17]1[CH:16]=[C:15]([C:19]([OH:21])=[O:20])[O:14][C:13]2[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]3[C:10](=[CH:11][C:12]1=2)[CH2:9][CH2:8][CH2:7][CH2:6]3
Reactant: CC(C)=O
Reactant: CCCc1c2c(cc3c(=S)cc(C(=O)O)oc13)CCCC2
Solvent: CI
Solvent: O
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10-propyl-6,7,8,9-tetrahydro-4-thioxo-4H-naphtho[2,3-b]pyran-2-carboxylic acid (0.025 g), methyl iodide (3 drops), acetone (10 ml) and water (4 drops) was stirred in the dark at ambient temperature for 2 days. Concentration of the reaction mixture in vacuo gave a brown solid which on crystallisation from acetone gave the title compound as a light-yellow solid, mp 245°-8°.
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[Li]CCCC.CN([CH:40]=[O:41])C.[NH4+].[Cl-]>C(OCC)C.[Li]CCCC.O>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:40]=[O:41])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=O)ccc1OCc1ccccc1)C(C)C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
n-BuLi (2.5 M in hexane, 19 mL, 47.5 nmol) was added to a solution of to (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (prepared as described in WO 94/11337, Example 1) (8.9 g, 18.52 mmol) in dry diethyl ether (100 mL) kept at −40° C. under nitrogen atmosphere. After 1.5 hour of stirring, additional n-BuLi (10 mL, 25 mmol) was added and after 2 hours another n-BuLi (5 mL, 12.5 mmol) was added. The reaction was then stirred for 15 minutes and DMF (6 mL, 77.8 mmol) was added followed by additional DMF (5 mL, 64.8 mmol) after 20 minutes of stirring. The temperature was allowed to rise to room temperature and after 35 minutes of stirring, NH4Cl (sat.) was added followed by water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica (toluene-triethylamine 90:10) to afford 8 g (100%) of a yellowish oil; 1H NMR (CDCl3) δ0.90 (m, 12H), 2.12-2.40 (m, 4H), 2.95 (m, 2H), 4.44 (t, 1H), 5.10 (s, 2H), 6.95 (d, 1H), 7.15-7.36 (m, 10H), 7.70 (dd, 1H), 7.91 (s, 1H), 9.88 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][NH2:13].CO>C(Cl)(Cl)Cl.Cl>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([CH3:11])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CNN
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(N)C(=O)NCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of Benzyl isocyanate (1.85 mL, 15.0 mmol) in 7.5 mL of CHCl3 was treated with methyl hydrazine (795 μL, 15.0 mmol) at 0° C. and stirred at the same temperature for 2 h. The resulting mixture was dissolved in 1N HCl (200 mL) and the solution was washed with CHCl3 (50 mL×3). The aqueous phase was adjusted to pH 12 with 2 M NaOHaq and then extracted with CHCl3 (100 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from hexane-CHCl3 to afford (1.7 g, 9.5 mmol, 63%) as a colorless crystal. Rf=0.44 (CHCl3:MeOH=9:1); 1H NMR (400 MHz, DMSO-d6) δ 7.28-7.19 (5H, m), 4.47 (2H, s), 4.20 (2H, d, J=6.3 Hz), 2.96 (3H, s); 13C NMR (99.5 MHz, DMSO-d6) δ 159.3, 141.1, 128.1, 127.1, 126.5, 43.1, 37.8; LC/MS [ESI+] (m/z) 180.3 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Zn]>[C:24]([C:23]1[CH:28]=[CH:29][C:20]([CH2:19][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:21][CH:22]=1)([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
A solution of 4 g (16 mmol) of 5,6,7, 8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carbonyl chloride and 4 g (16 mmol) of methyl 4-bromomethylbenzoate in 20 ml of dimethoxyethane was added dropwise to a solution or suspension of 0.56 g of bis(triphenylphosphine)palladium(II) dichloride and 2.1 g of zinc powder in 40 ml of dimethoxyethane at room temperature. The reaction mixture was then refluxed for 6 h. After cooling, solids were filtered off and the filtrate was heated with active carbon and filtered hot. The filtrate was concentrated and yielded after recrystallization 3x from methanol and finally from isopropanol 0.9 g of the title compound of melting point 103°-104° C.
Reaction SMILES: CON(C)[C:4](=[O:11])[CH:5]([O:7][CH2:8][CH:9]=[CH2:10])[CH3:6].[CH:13]([Mg]Br)=[CH2:14].Cl>O1CCCC1>[CH2:8]([O:7][CH:5]([CH3:6])[C:4](=[O:11])[CH:13]=[CH2:14])[CH:9]=[CH2:10]
Reactant: C=CCOC(C)C(=O)N(C)OC
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CCOC(C)C(=O)C=C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(±)-N-Methoxy-N-methyl-2-(prop-2-en-1-yloxy)propanamide (1.26 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Vinylmagnesium bromide (11.4 mL, 0.7 M solution in tetrahydrofuran, 8.00 mmol, 1.1 equiv) was added and the mixture was stirred at −78° C. for 10 minutes. Hydrochloric acid (5 mL, 4 M aqueous) was added, the mixture was warmed to ambient temperature and extracted with chloroform (2×30 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 30:70; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][O:8][CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: N=C(NO)c1ccc(Cl)cc1F
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C=CONC(=N)c1ccc(Cl)cc1F
Temperature: 30 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 (378 g, 2 mol, 1.0 eq) and Amberlyst® A21 (20 wt %, 75.6 g) in toluene PhMe (5.6 L, 15 vol) was added ethyl propiolate (275 g, 2.8 mol, 1.4 eq) at 30° C. The reaction was stirred at 30° C. overnight and checked by LC-MS. Reaction was then filtered and the filtrate was concentrated under vacuum, and 550 g ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40 was obtained as a yellow oil with 83% LC purity (Scheme 15).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]3[C:10]([CH2:11][N:12]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cccnc1[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ncccc3F)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol) and triethylamine (0.035 ml, 0.25 mmol) in dichloromethane (0.6 ml) was added methanesulfonyl chloride (0.20 ml, 0.25 mmol) at room temperature. Stirring for 20 h was followed by partitioning between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5 ml-portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (46 mg, 77%) as white solid. MS m/e: 476 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Ba+2].[OH-]>CCO>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[CH:4][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1])=[CH:21][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in the General Method 2 using 81.1 g (942 mmol) of 3-methyl-butan-2-one, 100 g (474 mmol) of 4-benzyloxy benzaldehyde, 10 g of anhydrous barium hydroxide and 500 mL of EtOH.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1.Br[C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=1)[CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>O.CC1CCCO1>[CH3:3][N:4]1[CH:8]=[C:7]([C:19]2[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:6]=[N:5]1
Reactant: O=C(O)CCOCCc1cccc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Temperature: 20 °C
Yield: 5.9 %

Procedure:
2-Methyltetrahydrofuran (142.1 mL) was added to Pd-118 (4.52 g) to give a red solution. To this solution was added a solution of sodium hydroxide (41.6 g) in water (473.5 mL), followed by a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (81.81 g) in 2-methyltetrahydrofuran (142.1 mL), followed by the solution of 3-(3-bromophenethoxy)propanoic acid (94.7 g, prepared as in Preparation 3, Step (ii)) in 2-methyltetrahydrofuran (585 mL solution volume). The mixture was then heated to reflux and at reflux for 30 min then allowed to cool to 20° C. The mixture was filtered through GF/F filter paper then the layers separated. 20% w/w Citric acid (568.2 mL) was added to the separated aqueous layer, followed by 2-methyltetrahydrofuran (568.2 mL). After mixing, the layers were separated, the organic layer diluted with 2-methyltetrahydrofuran (to make the solution up to 950 mL) and filtered to give a small sample of the subtitled compound as an off-white solid (5.63 g). 800 mL of the filtrate (total volume 930 mL) was passed through a cartridge filter containing charcoal. The solution was partially evaporated under vacuum to give a solution measuring 490 mL and split into 2 portions. Firstly half of the solution was cooled to 20° C. and added to dibutyl ether (400 mL) at 20° C. to give a precipitate which was stirred at 20° C. for 2 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50° C. under vacuum to afford the sub-titled compound (34.1 g). The second half of the solution was added to dibutyl ether (400 mL) at 65° C. to give a precipitate which was maintained at 65° C. for 10 min then cooled to 15° C. and stirred for 1 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50° C. under vacuum to afford the subtitled compound as a white solid (30.5 g). MS [M+H]+=275.2 (MultiMode+) 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.43 (s 1H), 7.37 (d, 1H), 7.24 (t, 1H), 7.05 (d, 1H), 3.86 (s, 3H), 3.62 (t, 2H), 3.61 (t, 2H), 2.80 (t, 2H), 2.45 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:37]([O-:39])=[O:38].NN>C(O)C>[NH2:26][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[CH:4][C:3]([N+:37]([O-:39])=[O:38])=[C:2]([NH2:1])[N:7]=2)=[N:13][CH:14]=1
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)c4ccccc4C3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Product: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]isoindoline-1,3-dione and 20 mmol of hydrazine were stirred in ethanol at 75° C. for two hours. The reaction was concentrated and purified by column chromatography 5-10% methanol/methylene chloride to obtain [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[Br:27][CH2:28][CH2:29]Br>CN(C=O)C>[Br:27][CH2:28][CH2:29][N:23]1[CH:24]=[C:20]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:12])=[O:13])[CH:7]=2)[CH:21]=[N:22]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCBr)c2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.0 g; 2.93 mmol) in DMF (50 mL) was added NaH (176 mg; 4.4 mmol; 60%) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour, added 1,2-dibromoethane (0.83 g; 4.4 mmol), warmed to r.t. and stirred overnight. The mixture was poured into ice-water (50 mL) and extracted by EtOAc (50 mL×3). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=2/1) to afford 0.48 g (37%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](C)[C:19]=1[CH3:25])([O-:17])=[O:16]>CCOCC>[CH3:25][C:19]1([CH2:2][C:1]([OH:8])=[O:7])[C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=[CH:21][CH2:20]1
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC1(CC(=O)O)CC=CC=C1[N+](=O)[O-]
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was refluxed for 0.5 hr, concentrated, and treated with 10% sodium hydroxide until almost all of the solid dissolved. Hydrogen peroxide (30%) was then added to the dark red mixture until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 1-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of 4-methyl-2-oxindole as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5](C(OCC)=O)([CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([O:34]C)=[CH:32][CH:33]=3)[CH:20]=2)=[C:13]([Cl:36])[CH:12]=1)[NH:6]C(=O)C)C.B(Br)(Br)Br>ClCCl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][C:14]2[C:15]([Cl:17])=[CH:16][C:11]([CH2:10][C@@H:5]([C:4]([OH:42])=[O:3])[NH2:6])=[CH:12][C:13]=2[Cl:36])=[CH:20][C:21]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31](=[O:34])[NH:30][CH:29]=1
Reactant: CCOC(=O)C(Cc1cc(Cl)c(Sc2ccc(OC)c(Cc3ccc(OC)nc3)c2)c(Cl)c1)(NC(C)=O)C(=O)OCC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N[C@@H](Cc1cc(Cl)c(Sc2ccc(O)c(Cc3ccc(=O)[nH]c3)c2)c(Cl)c1)C(=O)O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a cooled (-74°) solution of N-acetyl-3,5-dichloro-4-(4'-methoxy-3'-(6-methoxy-3-pyridylmethyl)phenylthio)-α-carbethoxy-phenylalanine ethly ester (0.39 g) in dry dichloromethane (10 ml) was added boron tribromide (0.58 ml) with stirring. The mixture was stirred whilst warming to room temperature and stirred for 5 hours. The reaction mixture was worked up and refluxed with concentrated hydrochloric in glacial acetic acid in a manner similar to that as described in Exampl 1 to afford DL-4-(4'-Hydroxy-3'-(6-oxo-3(1H)-pyridylmethyl) phenylthio)-3,5-dichlorophenylalanine as a cream solid (0.20 g, 70%), m.p. 261°-264°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][CH2:19]Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:17][O:18][CH3:19]
Reactant: COc1ccc(Br)c(O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1cc(OC)ccc1Br
Temperature: 23 °C
Yield: 91.1 %

Procedure:
Protected haloorganoboronic acid 14 was synthesized by a multi-step process. To a stirred mixture of 2-bromo-5-methoxyphenol (Albert, 2002) (2.19 g, 10.8 mmol) and K2CO3 (4.46 g, 32.3 mmol) in acetone (55 mL) was added chloromethyl methyl ether (1.63 mL, 21.5 mmol). The mixture was refluxed for 3 h and then allowed to cool to 23° C. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was then purified by flash chromatography (SiO2, hexanes:EtOAc 95:5) to provide 2-bromo-5-methoxy-1-methoxymethoxybenzene as a colorless liquid (2.43 g, 92%).
Reaction SMILES: [OH:1][C@@:2]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].Cl.[OH-].[Na+]>CC#N>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C@@H:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)[OH:1]
Reactant: COCCCC[C@@](O)(c1ccccc1Oc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1ccccc1Oc1ccccc1)[C@@H]1CCCNC1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)piperidine-1-carboxylate (1.97 g, 4.19 mmol) in MeCN (100 mL) was added 2 N aq HCl (100 mL) slowly at rt. The resulting solution was stirred at rt until no starting material remained (˜16 h), basified to pH=10 with 10 N aq NaOH, and evaporated under reduced pressure to remove MeCN. The aq layer was extracted with CH2Cl2 (4×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo to afford (S)-5-methoxy-1-(2-phenoxyphenyl)-1-((R)-piperidin-3-yl)pentan-1-ol (1.56 g, quantitative) as a free amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C@H:5]([NH:19]C(OC(C)(C)C)=O)[CH2:6][CH2:7][C:8](=O)[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=1)[CH3:2].Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:5]1[CH2:6][CH2:7][C:8]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[N:19]1)=[O:27])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCC(c2cc(F)c(F)c(F)c2)=N1
Yield: 80.2 %

Procedure:
To a solution of (R)-2-t-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)valeric acid ethyl ester (22.2 g) in ethyl acetate (30 mL) was added 4 N hydrochloric acid/ethyl acetate (163 mL), and the resultant solution was stirred at room temperature for 3 hours. Solvent was removed by distillation under reduced pressure, and the resulting residue was diluted with ethyl acetate and sodium bicarbonate water. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, to thereby obtain the titled compound (12.4 g). The physical properties of this crude product were as follows.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH2:9]OC)[CH:5]=[C:4](OCOC)[C:3]=1[C:16](=[O:18])C>C(O)C>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][C:3]([CH:16]=[O:18])=[CH:4][CH:5]=1
Reactant: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Solvent: CCO
Product: COc1ccc(C=O)cc1
Yield: 114.5 %

Procedure:
In 45 ml of ethanol were dissolved 6.00 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone obtained in Production Example 11 and 3.65 g of the p-methoxybenzaldehyde obtained in Production Example 25, and the solution was cooled to 0° C. and 55 of a saturated solution was cooled to 0° C. and 55 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution. The mixture was stirred for 24 hours. After the reaction, the reaction liquid was diluted with water and neutralized with 6N hydrochloric acid, and the formed precipitate was recovered by filtration to obtain 8.17 g (yield=86.3%) of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)chalcone.
Reaction SMILES: [K].CC(C)([O-])C.[CH3:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:19]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](=[O:40])[CH:36](Cl)[CH2:37][CH3:38])=[CH:34][C:29]=2[O:28][C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.C(O)(=O)C>[CH2:19]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35]([CH:36]([C:8]([CH3:7])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:37][CH3:38])=[O:40])=[CH:34][C:29]=2[O:28][C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCC(Cl)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C(=O)OCC)C(CC)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
23.00 g (204.96 mmol) potassium-tert.-butoxide are placed in 1200 mL DMSO and 36.00 g (206.67 mmol) diethyl 2-methyl-malonate are added. 64.00 g (194.07 mmol) 3-benzyl-6-(2-chloro-butyryl)-3H-benzoxazol-2-one are added batchwise while being cooled at 40° C. Then the mixture is stirred for 1 h, the reaction mixture is diluted with ice water and neutralised with 15 mL glacial acetic acid. The reaction mixture is extracted with DCM, the org. phase is concentrated by rotary evaporation i. V. and the residue is separated on silica gel (eluant cyclohexane/EA).