Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC.Cl.C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>O1CCOCC1.CO.C(Cl)Cl.[Cu](I)I.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.O.C(#N)C>[C:23]([C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: N#CC1(c2ccc(Br)nc2)CCC(F)(F)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Temperature: 80 °C
Yield: 73.4 %

Procedure:
To a microwave vial was added 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (276 mg, 0.918 mmol), tributyl(1-ethoxyvinyl)tin (663 mg, 1.84 mmol), copper iodide (26.2 mg, 0.138 mmol), PdCl2(PPh3)2 (32.2 mg, 0.0459 mmol) and acetonitrile (7.3 mL). The vial was purged under nitrogen, capped then heated in an oil bath at 80° C. for 16 hours. After cooling to room temperature the crude reaction mixture was filtered through celite with acetonitrile and the volatiles were then removed under reduced pressure. The residue obtained was dissolved in 1,4-dioxane (20 mL), treated with 1.5; N aqueous HCl (20 mL) and stifled vigorously at room temperature for 1.5 hours. The mixture was then made basic by adding solid potassium carbonate and transferred to a 250-mL separatory funnel with water (50 mL). The aqueous layer was extracted with AcOEt (3×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was treated with a saturated solution of potassium fluoride in methanol (6 mL), stifled for a few minutes, diluted with DCM, adsorbed onto silica gel and purified by silica gel chromatography to afford 1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as a white solid (178 mg, 73%). LC-MS (m/z) 265.0 (MH+); tR=1.21. 11-1 NMR (300 MHz, CDCl3) δ ppm 8.86 (d, J=2.0 Hz, 1 H), 8.09 (dd, J=8.3, 0.5 Hz, 1 H), 7.95 (dd, J=8.3, 2.5 Hz, 1 H), 2.73 (s, 3 H), 2.46-2.14 (m, 8 H).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.C([O:21]B(OC(C)C)OC(C)C)(C)C.C(O)(=O)C.OO>C1COCC1>[C:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([OH:21])=[CH:8][CH:9]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Agent: OO
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)Oc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Sec-butyllithium (53.2 mmoles, 41 ml of 1.3M in hexane) was added dropwise at -78° C. to 4-bromo-t-butoxybenzene (53.2 mmoles, 12.2 g) in 200 ml THF, stirred at -78° C. for 1 hour, and added slowly to a solution of triisopropylborate (58.5 mmoles, 11.0g) in 50 ml THF while maintaining the temperature below -60° C. The mixture was allowed to warm gradually to -20° C. Chilled acetic acid (80 mmoles,9.6 ml) was added. Hydrogen peroxide (58.5 mmoles, 5.9 ml of 30% diluted with 5 ml water) was added dropwise over 15 minutes while maintaining the temperature below 0° C. After stirring 10 minutes, the solution was washed with ammonium sulfate solution, dried, and concentrated. The residue was triturated with hexane and filtered to yield 4.2 g of 4-t-butoxyphenol. (MS).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:23])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)CCl>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:15]1[CH3:23])[CH3:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 22.5 g (0.15 mole) of phthalic anhydride and 61.0 g (0.30 mole) of 77.5 percent active 1-ethyl-2-methylindole in 120 ml of ethylene dichloride chilled to 0° to 5° C. by means of an ice bath, there was added in small portions 32.0 g (0.24 mole) of aluminum chloride. The mixture was maintained at 0°-5° C. for an additional 15 minutes, allowed to warm to room temperature and stirred overnight. Then, 240 ml of water was added to the reaction mixture and the ethylene dichloride layer was separated from the acidic aqueous layer. The organic layer was extracted with 600 ml of 3.5 percent aqueous sodium hydroxide. The alkaline extract was acidified with dilute hydrochloric acid and the separated solid collected, washed with water and dried to obtain 24.0 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R°=R1 =R2 = R3 =Y1 =H; R5 =CH3 ; R6 =CH2CH3), a slightly pink solid having a melting point of 184°-185° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:1]1([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:30]4[CH2:31][CH2:32][CH:27]([CH2:26][OH:25])[CH2:28][CH2:29]4)=[CH:15][C:14]=3[C:21]([F:22])([F:23])[F:24])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(C(F)(F)F)c1
Reactant: OCC1CCNCC1
Product: OCC1CCN(Cc2ccc(N3CCC(CN4CCCC4)CC3)c(C(F)(F)F)c2)CC1

Procedure:
Prepared from the product of Example 63 and 4-hydroxymethylpiperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:22]([O-])=O)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:22])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C2=CCC(c3ccccc3)([N+](=O)[O-])C=C2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccc(C2=CCC(N)(c3ccccc3)C=C2)cc1

Procedure:
The dinitro derivative from Example 1 (10g) was dissolved in glacial acetic acid (1.51) and refluxed. To the refluxing solution, stannous chloride dihydrate (50g) in 50ml of concentrated hydrochloric acid was slowly added over fifteen minutes. After the addition was complete, the reflux was continued for another fifteen minutes. Upon cooling, a dark grey precipitate appeared. This was filtered off, washed with water, boiled in 100ml of 20% aqueous sodium hydroxide and washed with water again. During the washing process, the precipitate turned from grey to orange. To further purify the material, it was refluxed in pyridine with decolorizing charcoal, filtered through Whatman No. 2 paper, and was crystallized from 40% aqueous pyridine. Analysis proved the material to be 4,4'-diamino-p-terphenyl.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@@H:8]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:9]2>>[ClH:1].[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:9]2
Reactant: CCCN[C@@H]1CCc2c(cccc2OC)C1
Agent: Cl
Product: CCCNC1CCc2c(cccc2OC)C1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Aqueous HCl 37% w:w (1.1 eq) is added dropwise under reflux for ˜5 min into the mixture obtained to precipitate the N-propyl MAT.HCl. The suspension is cooled down to 20° C. (Tramp=−20° C./h). The suspension is post-stirred at 20° C. for minimum 30 min and filtered. The cake is washed twice with EtOAc (2×1 vol.). The wet solid is dried under vacuum at 40° C. giving an off white solid. Yield: 95.0% from (III)
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.C(O)(=O)C.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1>O>[N+:1]([C:4]1[C:9]([CH:10]=[S:29]2[CH:30]=[CH:31][N:32]=[C:28]2[NH2:27])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1nccs1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(C=S2C=CN=C2N)c([N+](=O)[O-])cc1OC
Yield: 71.1 %

Procedure:
To a heated solution of 6-nitroveratraldehyde (84 g, 0.4 mole), 500 ml of toluene, and 1 ml of acetic acid was added a suspension of 2-aminothiazole (50 g, 0.44 mole) and 250 ml of toluene. The material was refluxed until 7 ml of water was collected using a Dean-Stark apparatus. The solid was removed and the filtrate was concentrated leaving a light solid which was recrystallized from benzene to yield 84 g (71%) of the product, m.p. 125°-130°.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][O:9][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:6]=1
Reactant: Cc1nc(CCO)c(C)o1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CCOc2ccc([N+](=O)[O-])cc2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
2-(2,5-Dimethyl-4-oxazolyl)ethanol (17.0 g) and 4-fluoronitrobenzene (17.0 g) were dissolved in N,N-dimethylformamide (150 ml), and 60% sodium hydride in oil (6.0 g) was added dropwise to the solution under vigorous stirring. After stirring at room temperature for 1 hour, the reaction mixture was poured into water (1 l) and the crystals which separated out were collected by filtration and recrystallized from ethyl acetate-hexane to give 4-[2-(2,5-dimethyl-4-oxazolyl)ethoxy]nitrobenzene (27.5 g. 87.0%). Colorless columns, m.p. 97°-98° C. Elemental analysis for C13H14N2O4, Calcd.: C, 59.94; H, 5.38; N, 10.68. Found: C, 59.72; H, 5.44; N, 10.63.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29](=[O:30])[N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])([CH3:17])[CH3:18]
Reactant: CCCCCCCNCCCCCCO
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCN(CCCCCCO)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Lithium aluminum hydride (189 mg, 5 mmols) was added to an anhydride THF solution (7 ml) of the above amide (454 mg, 2 mmols), and the resulting mixture was refluxed for 2 hours under argon atmosphere. The reaction mixture was diluted with ether (30 ml), and an aqueous saturated solution of ammonium chloride (0.4 ml) was added to the mixture, and stirred for 30 minutes at room temperature, and dried with anhydrous potassium carbonate. And the mixture solution was filtered through a pad of Cerite. The filtrate was concentrated to obtain the residue, which was crystallized from ether and hexane, and 6-heptylamino-1-hexanol 223 mg (yield 52%) was obtained as colorless crystals. This amine (213 mg, 1 mmol) was added to a chloroform solution (2 ml) of 2,6-diisopropylphenylisocyanate (207 mg, 1 mmol), and stirred for 2 hours at room temperature. The solvent was evaporated, and the obtained residue was purified through silica gel column chromatography (silica gel 15 g, developer: chloroform:methanol=98:2). The resulting crystals were recrystallized from acetone-hexane to obtain 370 mg of N′-(2,6-diisopropylphenyl)-N-heptyl-N-(6-hydroxyhexyl)urea (yield: 88%) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[C:36]=2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:41]1[C:36]2[S:35][N:34]=[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:43])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCN)nsc12
Reactant: O=C(O)c1ccc(I)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To a solution of 4-iodobenzoic acid (270 mg, 0.8 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (130 μL, 0.9 mmol) and 4-methylmorpholine (182 μL, 1.7 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-t-butylbenzo[d]isothiazole-7-sulfonamide (270 mg, 0.8 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 6:4 ethyl acetate:hexanes provided N-(3-(7-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (355 mg). 1H NMR (300 MHz, CDCl3): 8.01 (dd, 1H), 7.96 (d, 1H), 7.78 (d, 2H), 7.59 (d, 2H), 7.53 (t, 1H), 7.44 (t, 1H), 6.15 (t, 1H), 5.09 (s, 1H), 3.70 (dd, 2H), 3.57 (dd, 2H), 1.90-1.99 (m, 2H), 1.24 ppm (s, 9H). MS (m/z): 573 (M+H)+ confirmed by LC-MS, tr=13.92 min (Method Y) MW=572 confirmed by LC-MS, tr=13.92 min (Method Y) MH+=573.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(SCc2ccccc2)nc1
Yield: 72.8 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloro-5-methyl pyridine (200 mg, 1.5 mmol), K2CO3 (325 mg, 2.3 mmol), benzylmercaptan (292 mg, 2.3 mmol) and DMSO (1.5 ml) at 150° C. for 4 h gave the title compound (235 mg, 69%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]Br.N1C=CC=CC=1>C(Cl)Cl>[Br:34][CH2:13][CH2:12][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[O:10][CH:9]=1
Reactant: COc1cccc2c(CCO)coc12
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c(CCBr)coc12
Yield: 52.1 %

Procedure:
This compound was prepared by the same method as for intermediate 25, using 4.15 g (21.6 mmol) of 2-(7-methoxybenzofuran-3-yl)-ethanol, 6.8 g (25.9 mmol) of triphenylphosphine, 1.34 mL (25.9 mmol) of bromine, and 3.5 mL (43.2 mmol) of pyridine in 70 mL of CH2Cl2, to afford 2.87 g (52%) of the title compound after flash chromatography on SiO2 (25% CH2Cl2/hexanes to 100% CH2Cl2 gradient): MS (ESI) m/z 254 [M]+.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1([CH2:14][C@H:15]2[C@H:19]([C:20](OC)=[O:21])[O:18][C:17]([CH3:25])([CH3:24])[N:16]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>CCOCC>[C:20]([C@@H:19]1[O:18][C:17]([CH3:24])([CH3:25])[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C@H:15]1[CH2:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C(=O)c2ccccc2)OC1(C)C
Reaction time: 0.5 h

Procedure:
2.36 ml (2 mmol) of a 0.76N solution of phenyllithium in ether are sprayed at -75° into 355 mg (1 mmol) of 3-t-butyl 5-methyl (4S,5R)-4-(cyclohexylmethyl)-2, 2-dimethyl-3,5-oxazolidinedicarboxylate in 20 ml of ether and the reaction mixture is stirred at this temperature for 30 minutes, subsequently poured into 50 ml of saturated ammonium chloride solution and extracted three times with 150 ml of ether each time. The three ether extracts are washed in succession with in each case 70 ml of 2N sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, combined, dried over magnesium sulphate, filtered and evaporated. The residual oil (540 mg) is chromatographed on 30 g of silica gel with a 98:2 mixture of toluene and ethyl acetate as the eluting agent, whereby there are obtained 300 mg of t-butyl (4S,5R)-5-benzoyl-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a white solid, MS: 401 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:29][O:30][CH2:31][CH3:32].Cl>O1CCCC1>[CH2:31]([O:30][CH2:29][O:21][C:20](=[O:22])[CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:23])[CH3:32]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCOC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a mixture of 3.6 g of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid and 50 ml of dry tetrahydrofuran was added 0.5 g of 50% sodium hydride and the mixture was stirred for 30 minutes. To this mixture was further added 2.5 g of chloromethylethyl ether and the whole was reacted for 3 hours at room temperature. After the reaction was complete, the solvent was removed by distillation under reduced pressure. The residue thus obtained was neutralized with diluted hydrochloric acid, and then extracted with ethyl ether. The ether layer separated was washed with water and dried. The ether was removed by distillation to yield crystals. Recrystallization of the crystals from petroleum ether yielded 3.0 g of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid-ethoxymethyl ester as colorless prisms, melting at 60°-61° C. Analysis--Calculated for C22H22ClNO5 : C, 63.48; H, 5.17; N, 3.42. Found: C, 63.53; H, 5.33; N, 3.37.
Reaction SMILES: [I:1]I.[F:3][C:4]([F:25])([F:24])[C:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH2:22][CH3:23])[CH:15]=1)([O:10][CH2:11][O:12][CH3:13])[C:6]([F:9])([F:8])[F:7].S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1>[F:3][C:4]([F:24])([F:25])[C:5]([C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:20])=[C:18]([I:1])[CH:19]=1)([O:10][CH2:11][O:12][CH3:13])[C:6]([F:8])([F:7])[F:9]
Reactant: II
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(I)c1O
Temperature: 60 °C
Yield: 84.7 %

Procedure:
Iodine (13.3 g) was added to a mixed solution of 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenol (3.63 g, 10.5 mmol) in pyridine (50 mL) at room temperature, followed by heating in an oil bath at an external temperature of 60° C. overnight. A 1 mol/L sodium thiosulfate aqueous solution was added to the reaction solution at room temperature, followed by extraction with ethyl acetate-water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 4.20 g of the title compound (yield: 85%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCCO
Product: Cc1[nH]c2c(c1C(=O)NCCO)CCCC2=O
Yield: 84.6 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-aminoethanol 0.13 g (2.1 mmol) was reacted. The reaction solution was concentrated and purified by a silica gel column, eluted with CH2Cl2/MeOH (10:1), to give 0.20 g (85%) of the titled compound as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:23])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl>[N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][N:4]([C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
A mixture of ethyl piperazine-1-carboxylate (300 mg, 1.90 mmol), 4-nitrophenyl carbonochloridate (460 mg, 2.28 mmol) and Et3N (576 mg, 5.69 mmol) in anhydrous CH2Cl2 (7 mL) was stirred at room temperature for 24 h, and then the reaction mixture turned to a yellow solution. Extraction with NaHCO3(aq.) until the organic layer turns to transparent solution. And then the organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1.5) to give 1-ethyl 4-(4-nitrophenyl) piperazine-1,4-dicarboxylate (172 mg, 45% yield). C14H17N3O6; pale yellow solid; mp 125-128° C.; IR vmax (neat) 3512, 3082, 2983, 2930, 2867, 1730, 1701, 1594, 1523, 1459, 1425, 1348, 1288, 1209, 1163, 1085, 1055, 996, 957 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, d, J=8.8 Hz), 7.28 (1H, t, J=8.8 Hz), 4.17 (2H, q, J=6.8 Hz), 3.66 (2H, br s), 3.56 (6H, br s), 1.28 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 155.7, 155.1, 151.9, 144.7, 124.9 (2×), 122.1 (2×), 61.8, 44.5, 43.8, 43.4 (2×), 14.8.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=1.Br[CH2:17][C:18]([NH:20]C1C=CC(Br)=CC=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:6]([CH2:17][C:18]([NH2:20])=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CBr)Nc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 223.1 %

Procedure:
DMF (20 ml) was added to 1-(4-hydroxyphenyl)ethanone (1.81 g, 13.3 mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol), and potassium carbonate (4.25 g, 30.7 mmol), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate), and powderized with ethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative (3.44 g). The title compound was obtained by similar operations as in Reference Example 20, Reference Example 21, Example 10 and Example 6 and using this compound.