Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:7][GeH:8]([Cl:10])[Cl:9]>>[CH3:3][CH:2]([CH2:4][Ge:8]([Cl:10])([Cl:9])[Cl:7])[C:1]([OH:6])=[O:5]
Reactant: Cl[GeH](Cl)Cl
Reactant: C=C(C)C(=O)O
Product: CC(C[Ge](Cl)(Cl)Cl)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
84.7 ml (0.1 mol) of methacrylic acid was added dropwise over 5 minutes to 18 g (0.1 mol) of crude trichlorogermane which had been cooled to 5° C. in an ice bath. The mixture was stirred at the same temperature for one hour and then at room temperature for 1.5 hour. The precipitated crystal was filtered by suction, washed with 10ml of n-hexane which had been dried over potassium chloride for four times, dried by suction and kept in a desiccator containing phosphorus pentoxide at 65° C. for one hour with reducing the pressure by a vacuum pump which uses potassium hydroxide containing trap to obtain 17.03 g of crystalline 2-methyl-3-(trichlorogermyl)propionic acid:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:7](/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)\[C:8]#[N:9])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1cccnc1
Product: COc1ccc(/C=C(\C#N)c2cccnc2)cc1OC
Yield: 73.7 %

Procedure:
3-Pyridineacetonitrile (1.18 g) was condensed with 3,4-dimethoxybenzaldehyde (1.66 g) through Method B (production step 2), to thereby yield the target product (yield: 1.96 g, 74%).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3C(OCC)=O)[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=O)(C)(C)C.[CH2:29](N(CC)CC)C.C(OC(=O)C)(=O)C.O>Cl.O1CCCC1>[CH3:28][C:21]1[CH:22]=[C:16]2[C:15]3[C@H:11]([CH2:10][CH2:9][NH:8][C:6](=[O:5])[CH3:29])[CH2:12][CH2:13][C:14]=3[CH:19]=[CH:18][N:17]2[N:20]=1
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@H](CCNC(=O)OC(C)(C)C)CC3
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCC[C@@H]1CCc2ccn3nc(C)cc3c21
Temperature: 100 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of ethyl (9S)-9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (140 mg, 0.361 mmol) in 12M hydrochloric acid (4 mL) was stirred at 100° C. for 3 days, and concentrated under reduced pressure. To a mixture of the residue and triethylamine (503 μL, 3.61 mmol) in tetrahydrofuran (3.6 mL) was added acetic anhydride (102 μL, 1.08 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (69.7 mg, yield 75%, >99.9% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD-H mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9](C=O)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.C(O[CH:17]([O:21][CH2:22]C)[O:18][CH2:19]C)C.[N+]([O-])([O-])=O.[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:22][O:21][CH:17]([O:18][CH3:19])[C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(OCC2CO2)cc1
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(OC)c1ccc(OCC2CO2)cc1
Reaction time: 6 h
Yield: 100 %

Procedure:
A total of 8.5 g. (0.0477 mole) of the above aldehyde and 8.5 g. (0.0574 mole) of triethylorthoformate was then added to a 50 ml. round bottom flask equipped with magnetic stir bar and reflux condenser. A solution of 0.25 g. (0.003 mole) ammonium nitrate was dissolved in 5 ml. of warm ethanol and added rapidly to the reaction mixture. The mixture was stirred for 6 hrs. at room temperature, neutralized with excess sodium carbonate, filtered, and the solvent removed under vacuum. The resulting oil (100% yield) had no residual aldehyde as determined by NMR. No further purification was needed.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:20]Br)=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:20][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[O:19])[CH:8]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-chloropyrimidin-2-one hydrochloride (502 mg), α-bromo-4-methoxyacetophenone (687 mg), triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2 hours, during which the suspension formed a solution from which a solid crystallised out. The solid was crystallised from acetone to give the title pyrimidinone: yield. 449 mg; m.p. 212°-214° C.: λmaxEtOH 222.5 nm (ε 19850), 277 nm (ε 18000), 330 nm (ε 3725).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CN([CH:26]=[O:27])C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[CH:26]=[O:27]
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(C=O)c(F)c2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a 1-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, a THF solution (300 ml) of 23.2 g (100 mmol) of 3,5-difluoro-4′-propylbiphenyl was cooled down to −70° C. under nitrogen atmosphere, and 69 ml (110 mmol) of n-butyllithium (1.6M hexane solution) was added dropwise thereto. The solution was stirred at 70° C. for one hour, and then a THF solution (10 ml) of 9.3 ml (120 mmol) of DMF was added dropwise and further stirred for one hour. The reaction mixture was poured into 200 ml of 1N hydrochloric acid and extracted with 200 ml of heptane. The heptane layer was washed in turn with 200 ml of water, 200 ml of a saturated aqueous sodium hydrogencarbonate solution and 200 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the concentrated residue was purified by means of a silica gel column chromatography (developing solvent: heptane/toluene=4/6) to obtain 26.0 g (100 mmol, yield: 100%) of 3,5-difluoro-4-formyl-4′-propylbiphenyl as colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[C:57]([SiH:61]([CH3:63])[CH3:62])([CH3:60])([CH3:59])[CH3:58]>ClC(Cl)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38][Si:61]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:63])[CH3:62])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C[SiH](C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.82 g, 5.76 mmol) in dichloroethane (100 mL) was added triethylamine (1.285 mL, 9.22 mmol), tert-butyldimethylsilane (1.912 mL, 11.52 mmol), and palladium(II) acetate (0.647 g, 2.88 mmol). The mixture was flushed with N2 and was heated to 60° C. After 2 h, the reaction was cooled to rt, was filtered through a pad of celite and silica gel to remove the solids which were washed with 25% EtOAc in hexanes. The filtrate was concentrated under reduced pressure and was treated with 20 mL of acetic acid, 10 mL of THF and 3 mL of water. After stirring for 1 h the solids that formed were collected by filtration and were washed with water to give (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.62 g, 5.27 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=8.28 Hz, 2H), 7.21 (d, J=8.28 Hz, 2H), 5.30 (dd, J=6.15, 1.63 Hz, 1H), 4.75 (d, J=1.76 Hz, 1H), 4.62 (s, 1H), 3.92 (s, 4H), 3.08 (td, J=10.92, 4.27 Hz, 1H), 2.35-2.22 (m, 2H), 2.17-2.06 (m, 1H), 2.02-1.84 (m, 2H), 1.71 (s, 3H), 1.01 (s, 6H), 0.99 (br. s., 3H), 0.98 (s, 9H), 0.94 (s, 6H), 1.78-0.90 (m, 16H), 0.32-0.28 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.P(=O)(O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)cc2s1
Reactant: O=C1CCCCC1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3=CCCCC3)c2s1
Temperature: 80 °C
Yield: 91 %

Procedure:
A solution (0.2 M) of methyl 5-(4-chlorophenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in acetic acid was treated with acetic anhydride (2.5 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.1 eq.). The mixture was heated at 80° C. for 3.5 days. After cooling down it was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO, (saturated solution) and brine then dried and concentrated. The crude was purified by flash chromatography on silica gel (1:9 to 1:4 AcOEt/petroleum ether) affording the title compound (91%) as a solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34](Cl)[S:35][CH:36]=2)=[O:31])[CH3:28])[CH:18]=[C:19]([F:26])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:26][C:19]1[CH:18]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[S:35][CH:36]=2)=[O:31])[CH3:28])[CH:16]=[C:15]([F:14])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cccc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 52.2 %

Procedure:
3-Trifluoromethylphenylboronic acid (62.7 mg, 0.33 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (44.6 mg, 0.11 mmol) was reacted using Pd(PPh3)2Cl2 (10.5 mg, 0.015 mmol), Cs2CO3 (143.4 mg, 0.44 mmol) as described above to give the title compound (29 mg, 44%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:13][O:14][CH3:15].[CH3:16][CH2:17]CCCC.C([Li])CCC.C(I)C>O1CCCC1.O>[CH2:16]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:13][O:14][CH3:15])[CH3:17]
Reactant: CCCCCC
Reactant: COCOc1cccc2c(Br)cccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCI
Product: CCc1cccc2c(OCOC)cccc12
Temperature: -60 °C
Reaction time: 1 h

Procedure:
6.9 g of 5-bromo-1-methoxymethoxy naphthalene was dissolved in 100 ml of anhydrous tetrahydrofuran and cooled to -60° C. 21.3 ml of a hexane solution containing 1.6M of n-butyl lithium was gradually added to the solution. After stirring at -40° C.--60° C. for one hour, the reaction solution was cooled to -65° C. and 4.2 ml of ethyl iodide was slowly dropped. After the dropping, the temperature was warmed upto the room temperature, water was added and the solution was extracted with ethyl acetate. After washing the extract with an aqueous saturated solution of sodium chloride and drying over anhydrous magnesium sulfate, the solvent was distilled off. When the residue was purified on silica gel column chromatography (7% ethyl acetate/hexane), 5.5 g of the above-captioned compound was obtained as a pale yellow oily product.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([O:6][Si](C(C)(C)C)(C)C)[CH3:5].Cl.O.C(OCC)(=O)C>CO.C(#N)C>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([OH:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of 0.45 g (1.28 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol ((2S,3R)/(2R,3R)=91/9)) in 5 mL of methanol was added 0.25 mL of concentrated hydrochloric acid at room temperature. After the completion of the dropwise addition, stirring was performed at room temperature for 18 hours. Then, 10 mL of water was added to stop the reaction, and extraction was performed with 20 mL of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product as a colorless oil. A quantitative analysis was performed by HPLC. Thereby, the title compound was obtained in a yield of 77% ((2S,3R)/(2R,3R))=90/10) (HPLC, column: CAPCELL PAK C18 TYPE MG manufactured by Shiseido Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=3/7, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 26 minutes (2S,3R), 17 minutes (2R,3R). 1H-NMR (400 MHz, CDCl3) (2S,3R) δ: 0.98 (d, 3H, J=6.6 Hz), 2.50 (brs, 1H), 3.21 (s, 1H), 4.11-4.23 (m, 3H), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H); (2R,3R) δ: 1.93 (dd, 3H, J=6.3, 1.2 Hz), 2.25 (d, 1H, J=5.2 Hz), 3.15 (s, 1H), 3.96 (d, J=11.0 Hz), 4.08 (q, 1H, J=6.3 Hz), 4.35 (d, J=11.2 hz), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H)).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:12][C:9]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(I)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Ic1ccc(Oc2ccc(I)cc2)cc1
Reaction time: 16 h

Procedure:
The bis-mesylate of PEG-400 (15.3 g, 27.5 mmol) in dry DMF (110 ml) was reacted with 4-iodophenol (12.1 g, 55.0 mmol) and potassium carbonate (7.6 g, 55.0 mmol) at 77° C. under an atmosphere of N2. After stirring for 16 hrs, the reaction was allowed to cool, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up with EtOAc (500 ml), washed with 1 M aqueous sodium hydroxide (200 ml), water (200 ml) and brine (200 ml), dried (Na2SO4), filtered, and evaporated in vacuo to provide a light brown syrup. Flash column chromatography (silica, 1%-5%; CH3OH in CH2Cl2) provided bis-(4-iodophenyl) ether of polyethylene glycol-400 which was slightly contaminated with unreacted mesylates. The product was further purified by dissolving 10.5 g in DMF (100 ml). Sodium methoxide (400 mg) was added. The reaction flask was immersed in an oil bath and warmed to 93° C. After stirring for 16 hrs, the reaction was allowed to cool, diluted with EtOAc (500 ml), washed with water (200 ml) and brine (200 ml) repeatedly (3 times), dried (Na2SO4), filtered and evaporated in vacuo to provide a light yellow syrup. Flash column chromatography (silica, 5% CH3OH in CH2Cl2) provided bis-(4-iodophenyl) ether of polyethylene glycol-400 as a light yellow syrup (8.3 g). 1H NMR (300 MHz) analysis of the product indicates that the average number of ethylene oxide units is eight (n=8).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([N:21]([CH3:20])[CH2:22][CH2:23][CH3:24])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: CCCNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
5-(2-Oxo-pyrrolidin-1-yl)-isophthalic acid monomethyl ester (D63) (1.0 g, 3.8 mmol) was dissolved in DMF (7 ml) and treated with N-methyl propylamine (0.42 g, 5.7 mmol), HOBt (0.62 g, 4.56 mmol) and EDC (1.02 g, 5.32 mmol) and the resulting solution was stirred overnight at room temperature. It was then evaporated to dryness and the residue was partitioned between EtOAc and dil.HCl. The organic phase was separated, washed with dil.HCl (×2), dil.NaHCO3 (×3) and brine (×1). It was dried (MgSO4) and evaporated to leave the crude product which was purified by silica chromatography eluting with DCM/MeOH to afford the pure title compound (D64) (0.40 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([Cl:14])[C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:19]=1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Yield: 24.4 %

Procedure:
To solution of (2,4,5-trichloro-phenoxy)-acetic acid (150 mg, 0.59 mmol), 2-amino isonicotinic acid methyl ester (179 mg, 1.18 mmol) and DMAP (144 mg, 1.18 mmol) in DMF 13 mL was added PyBOP (614 mg, 1.18 mmol) at room temperature. Reaction mixture was stared at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:1) to give 2-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.056 g, 24.45% yield).
Reaction SMILES: [Zn:1](CC)CC.[CH:6]1[CH:25]=[CH:24][C:22](=[O:23])/[C:8](=[CH:9]/[NH:10][CH2:11][CH2:12][NH:13]/[CH:14]=[C:15]2/[CH:16]=[CH:17][CH:18]=[CH:19][C:20]/2=[O:21])/[CH:7]=1>C1COCC1>[CH:17]1[CH:18]=[CH:19][C:20](=[O:21])/[C:15](=[CH:14]/[NH:13][CH2:12][CH2:11][NH:10]/[CH:9]=[C:8]2/[CH:7]=[CH:6][CH:25]=[CH:24][C:22]/2=[O:23])/[CH:16]=1.[Zn:1]
Reactant: CC[Zn]CC
Agent: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Solvent: C1CCOC1
Product: [Zn]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The Et2Zn (0.4 ml, 1.0 M in hexane) and Salen (N′N′-bis(3-tert-butyl-5-bromo-salicylidene)-1,2-diaminocyclohexane (0.4 mmol) and were dissolved in dried THF (20 ml). The mixture was stirred under argon at 25° C. for 24 hours. After that the compound Salen-Zn was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC(CCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
A solution of 50 g of 3,4-difluorophenyl acetonitrile in 50 ml of THF is added dropwise at 20° C. to a suspension of 14.4 g of 60% sodium hydride in oil in 250 ml of THF, and the reaction mixture is left tirring for three hours at RT. It is cooled in an ice bath, a solution of 68.2 g of 1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 50 ml of THF is added dropwise and the reaction mixture is left stirring overnight at RT. It is acidified by adding a pH 2 buffer solution, and the THF is then evaporated off under vacuum. The aqueous phase is extracted with ether, the organic phase is washed twice with a pH 4 buffer solution, with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with toluene and then with a toluene/AcOEt (100:3; v/v) mixture. 50 g of the expected product are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])(=O)C.[Na+].C(Cl)(Cl)(Cl)[Cl:21].S(Cl)(Cl)(=O)=O>C(O)(=O)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[Cl:21])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
119.5 g of benzoyl acetic acid ethyl ester and 53.4 g of sodium acetate sicc. were dissolved in 1 l of glacial acetic acid and 100 ml of carbon tetrachloride at 40° C. A solution of 52 ml of sulphuryl chloride (density 1.67) in 50 ml of glacial acetic acid was added dropwise with vigorous stirring at 35°-40° C over a period of one hour. The reaction mixture was then stirred for one hour at 40° C and poured on about 10 l of water. The precipitated oily product was taken up with ethyl acetate and treated in the usual manner. 124 g of α-chlorobenzoylacetic acid ethyl ester were obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.[H][H]>C(OCC)(=O)C.O.[Pt](=O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N)nc1Br
Yield: 98.7 %

Procedure:
2-Bromo-3-methoxy-6-nitropyridine (Desc. 5; 9.0 g, 38.6 mmol) and platinum (IV) oxide hydrate (250 mg) in ethyl acetate (250 ml) was hydrogenated at 20 psi hydrogen for 1 hour. The catalyst was removed by filtration and the filtrate concentrated to give the product as a yellow solid (7.73 g, 38.1 mmol, 99% yield).