Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][CH3:18])[CH2:22][CH2:23]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: CCCC1CCNCC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CCN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 4-N-propylpiperidine (18 mg, 0.14 mmol), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. LC/MS showed the presence of the target compound and no starting material after 24 h. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a white solid. This solid was triturated in acetone, filtered, washed with acetone and diethyl ether to give the title compound (15 mg, 38%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1C(C)C([O-])=O.[Na+].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32](Br)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]
Reactant: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Reactant: CC(C(=O)[O-])c1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium 2-(2-thiazolyl)propionate (148 mg) is introduced into DMF (5 ml), and 2-(1-benzothien-2-yl)-5-[(2-bromobutanoyl)amino]benzamide (Example 8A; 171 mg), HATU (291 mg) and 4-methylmorpholine (194 mg) are added. The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated and the residue is purified by preparative HPLC. 101 mg (36% of theory) of product are isolated.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[CH2:6]([N:5]([CH2:8][CH3:9])[CH2:4][CH2:3][O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7]
Reactant: Oc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCOc1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
A solution of 108.5 g (0.630 mol; 1.2 eq.) of N-(2-chloroethyl)-N,N-diethylamine hydrochloride in 65 ml of water is added slowly (over about 55 minutes) to a mixture containing 50 g (0.531 mol) of phenol and 46.3 g (1.158 mol; 2.2 eq.) of NaOH in 270 ml of water. The mixture is stirred for 3 hours 30 minutes at 20° C. and then for 45 minutes at 55° C. The phases are separated by settling and the supernatant oil diluted in 100 ml of DCE is washed with (i) 100 ml of 2.5% sodium hydroxide and then (ii) with 100 ml of 5% sodium hydroxide. The product is dried over sodium sulfate and then concentrated. 81.4 g of crude N,N-diethyl-N-(phenoxyethyl)amine are obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]([C:10]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)=CCOc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)c1coc2ccccc12
Temperature: 100 °C
Yield: 52 %

Procedure:
A solution of 1-iodo-2-(3-methylbut-2-enyloxy)benzene (5 g, 17.3 mmol) in propionitrile (10 mL) and diisopropylethylamine (9 mL, 52 mmol) is degassed with argon for 15 min. To this solution is added palladium acetate (423 mg, 1.73 mmol) and the reaction is heated to 100° C. overnight. The reaction is then cooled to room temperature and passed through a pad of celite, washing the filter cake with ethyl acetate (50 mL). The ethyl acetate and amine base are then removed under vacuum. The crude reaction mixture is then chromatographed using 100% hexanes to yield title compound as a colorless oil in 52% yield (1.3 g): 1H NMR (300 MHz, CDCl3) δ 7.7 (s, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.32-7.24 (m, 2H), 3.11-3.07 (m, 1H), 1.32 (2s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[N:25]1[C:8](=[O:10])[C:7]2[C:2](=[N:3][C:4]([S:13][CH3:14])=[N:5][CH:6]=2)[NH:1][C:26]1=[O:27]
Reactant: Cc1cccc(Cl)c1N=C=O
Reactant: CCOC(=O)c1cnc(SC)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)n(-c3c(C)cccc3Cl)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.7 %

Procedure:
To a solution of 100 mg of ethyl 4-amino-2-(methylsulfanyl)pyrimidine-5-carboxylate in 4 mL of N,N-dimethylformamide, 56 mg of sodium hydride was added, and the resulting mixture was stirred at room temperature for 5 minutes. To the reaction mixture, 118 mg of 2-chloro-6-methylphenyl isocyanate was added, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture, ethyl acetate and a 1 N aqueous hydrochloric acid solution were added and the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The precipitated solid was solidified with methanol and collected by filtration, whereby 100 mg of the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:10]([CH3:28])[CH:9]=2)[CH:5]=[C:4]([CH3:29])[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:10]([CH3:28])[CH:9]=2)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(CN3CCNCC3)c(C)c2)cc(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.9 %

Procedure:
A 50 mL round-bottom flask maintained with an inert atmosphere of nitrogen was charged with tert-butyl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine-1-carboxylate (350 mg, 0.880 mmol, 1.00 equiv) and dichloromethane (5 mL). Trifluoroacetic acid (0.5 mL) was added dropwise at 0° C. The resulting solution was stirred for 5 h at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 270 mg (crude) of 1-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 296 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:33])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27]([NH2:28])=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]2)[CH:18]=1)[CH3:12]>O=S(Cl)Cl.C(Cl)Cl>[CH2:11]([O:13][C:14](=[O:33])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27]([NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[CH:26][C:25]([C:29]([CH3:32])([CH3:31])[CH3:30])=[N:24]2)[CH:18]=1)[CH3:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of 4-chlorobenzoic acid (312 mg, 2.0 mmol) in SOCl2 (10 mL) was heated to reflux for 2 h. After removal of the solvent, the residue was dissolved into CH2Cl2 (5 mL) and was dropped into a solution of Example Z (315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C., was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4) and filtered. After concentrated under reduced pressure, the residue was purified by flash chromatography to afford 3-{3-[3-t-butyl-5-(4-chloro-benzoylamino)-pyrazol-1-yl]-phenyl}-propionic acid ethyl ester (290 mg, 64%). 1H-NMR (CDCL3): 8.02 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.36 (t, J=8.4 Hz, 3H), 6.87 (s, 1H), 4.06 (q, J=7.6 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.40 (s, 9H), 1.12 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 454 (M+H+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.C(OCC)C>C(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([NH:15][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])[CH:26]=[CH:25][CH:24]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2ccccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(chlorosulfonyl)-benzoate (2.25 g, 8.73 mmol) in methylene chloride (20 mL) was added dropwise to a solution of ethyl 3-aminobenzoate (1.44 g, 8.73 mmol) and triethylamine (1.21 mL, 8.73 mmol) in methylene chloride (10 mL) at 0 C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water (20 mL), aqueous HCl (1 M, 20 mL) and aqueous NaOH (1 M, 20 mL), dried (MgSO4—, filtered and concentrated in vacuo to give an orange oil. Trituration with ethyl ether gave N-(3′-carboethoxyphenyl)-2-(carbomethoxy)benzenesulfonamide as white solid. 1H NMR (200 MHz, CDCl3): δ 1.31, t, J=6.0 Hz, 3H, 4.00, s, 3H, 4.29, q, J=6.0 Hz, 2H, 7.23-7.61, m, 5H, 7.66-7.92, m, 3H, 8.26, br s, 1H.
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[CH3:26][O:27]/[N:28]=[C:29](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:30](O)=[O:31]>O.O1CCCC1>[CH3:26][O:27]/[N:28]=[C:29](/[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)\[C:30]([NH:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12)=[O:31]
Reactant: CO/N=C(\C(=O)O)c1cscn1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
On the other hand, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.365 g) was suspended in a mixture of water (10 ml) and tetrahydrofuran (15 ml). While cooling with ice, triethylamine (1.01 g) was added to form a solution. To this ice-cooled solution was added dropwise the above active solution of (Z)-2-methoxyimino-2-(thiazol-4-yl)acetic acid over one hour. During the time triethylamine (total 0.78 g) was added in parts at suitable times to keep the reaction mixture at pH 6-7. After completion of the dropping, the mixture was stirred for 45 min under cooling with ice. Then the temperature was raised gradually to 15° C. After the mixture was stirred for 20 minutes at that temperature, the tetrahydrofuran was evaporated under reduced pressure. Then the aqueous layer was adjusted to pH 2-3 with 2N-HCl. The precipitates were filtered, washed with water, and dried in vacuo over phosphorus pentoxide to give the title compound (0.90 g). Further, ethyl acetate (20 ml) was added to the filtrate and the mixture was shaked. The insoluble matter formed on the interface between the aqueous layer and the ethyl acetate layer was filtered, and dried in vacuo over phosphorus pentoxide to give the title compound (0.61 g).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[N:14]=2)=[CH:8][C:7]=1[CH3:25])(O)=[O:2].C(N(CC)CC)C.ClC(OC(C)=C)=O.[Si]([O:47][NH2:48])(C(C)(C)C)(C)C>ClCCl>[OH:47][NH:48][C:1]([CH2:4][O:5][C:6]1[C:7]([CH3:25])=[CH:8][C:9]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH3:24])[N:14]=2)=[CH:10][C:11]=1[CH3:12])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)O
Agent: C=C(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)NO
Reaction time: 1 h
Yield: 8.3 %

Procedure:
A solution of example 108 (1.15 g) in dichloromethane (30 ml) at 0° C. was treated with triethylamine (0.52 g) followed by isopropenyl chloroformate (0.41 g), and the mixture was stirred for 1 h. O-tert-butyldimethylsilylhydroxylamine (0.50 g) was then added and the mixture was stirred for a further 18 h. The reaction mixture was washed with 10% citric acid (20 ml), saturated sodium bicarbonate (20 ml) and the concentrated to dryness in vacuo. A solution of the residual solid in tetrahydrofuran (30 ml) and water (5 ml) was then treated with a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1 ml) and stirred 1 h. the resultant crude mixture was concentrated on to silica and purified by chromatography, eluting with 5% methanol in dichloromethane, to provide the title compound as a white solid (0.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:36])[CH2:33][C:34]#[CH:35]>C(NCC)C.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>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][CH2:33][CH2:32][OH:36])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(C#CCCO)c21
Reaction time: 18 h

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.074 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and 3-butyn-1-ol (0.02 mL) in 7 mL diethylamine is stirred at room temperature for 3 days. The reaction is partitioned between CH2Cl2 and H20. The aqueous is extracted 3× with CH2Cl2. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S chromatography (eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L), 7% MeOH/CH2Cl2 (1L)) affords the product as a tan residue. The residue is dissolved in a minimal amount of CH2Cl2 and hexanes are added to affect recrystallization. The solution is placed in the freezer for 18 h after which the product is collected and dried (0.037 g, 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21]CC)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:19](=[O:21])[CH2:18][O:17][CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COCCN
Product: COCCNC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A mixture of ethyl 1-benzyloxycarbonylpiperidine-4-oxyacetate (2.4 g) and 2-methoxyethylamine (5 ml) was heated on a steam bath for 6 hours. The amine was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (10 ml), washed sequentially with dilute citric acid solution (5 ml), water (5 ml) and saturated aqueous sodium chloride (5 ml), dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography, eluting with hexane/ethyl acetate (1:3) to give N-2-methoxyethyl-1-benzyloxycarbonylpiperidine-4-oxyacetamide (500 mg) as a colourless oil. NMR: (d6DMSO): δ1.4-1.5(2H,m); 1.75-1.9(2H,m); 3.0-3.4(9H,m); 3.55(1H,m); 3.65-3.8(2H,m); 3.9(2H,s); 5.1(2H,s); 7.3(5H,m); 7.6(1H, br. t); m/e 351(M+H)+, 373 (M+Na)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([N:39]2[CH2:44][CH2:43][C:42]([OH:51])([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:41][CH2:40]2)[CH2:36][NH:37][CH3:38])[CH:31]=[CH:32][C:33]=1[Cl:34].C(OCC)C>O1CCCC1.ClCCl>[ClH:27].[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([N:39]2[CH2:40][CH2:41][C:42]([OH:51])([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:43][CH2:44]2)[CH2:36][N:37]([CH3:38])[C:12](=[O:14])[CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: CNCC(c1ccc(Cl)c(Cl)c1)N1CCC(O)(c2ccccc2)CC1
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1cccc(CC(=O)N(C)CC(c2ccc(Cl)c(Cl)c2)N2CCC(O)(c3ccccc3)CC2)c1
Product: Cl
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A solution of 3-isopropoxyphenylacetic acid (670 mg) and 1,1'carbonyldiimidazole (590 mg) in tetrahydrofuran (15 mL) was stirred at reflux for 0.5 hours. The reaction was cooled to 23° C. and treated with a solution of N-[2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethyl]methylamine (940 mg) in tetrahydrofuran (40 mL). The reaction was stirred at 23° C. for 18 hours. The reaction was evaporated to a gold oil. The oil was partitioned between diethylether (100 mL) and 1 N hydrochloric acid (150 mL). The organic layer was treated with hydrochloric acid (g)/ether and evaporated to give a yellow oil which was dissolved in dichloromethane (10 mL) and added dropwise to diethylether (500 mL). The title compound precipitated as a white solid (480 mg); mp 127-132° C.; MS: m/z=555(M+1); NMR: 1.23 (d,3), 1.25 (d,3), 1.75 (m,2), 2.4 (m,1), 2.7 (m,1), 2.83 (s,3), 3.13 (m,2), 3.43 (m,2), 3.54 (s,2), 3.73 (m,1), 4.52 (m,1), 5.37 (m,1), 6.38 (d,1), 6.66 (s,1,), 6.73 (d,1), 7.01 (m,3,), 7.22 (m,2,), 7.46 (d,2), 7.7 (s,2,), 8.05 (s,1), 11.73 (s,1). Analysis Calculated: C, 61.95; H, 6.37; N, 4.66; Found: C, 61.94; H, 6.3; N, 4.56.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1C=CC=CC=1.CCOC(C)=O>[O:7]([C:23]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=Cc1ccc(OC2CCN(C(=O)Oc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a stirred mixture of phenol (0.83 g) and 4-(piperidin-4-yloxy)benzaldehyde (2 g) in dry benzene (20 ml), 1,1'-carbonyldiimidazole (1.58 g) was added and the reaction mixture was stirred at 80° C. for 12 h. At the end of this time, the reaction mixture was diluted with EtOAc, washed with H2O, dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel using 5 to 15% (gradient elution) ethyl acetate in petroleum ether to afford 1.9 g (61%) of the title compound.
Reaction SMILES: BrBr.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Cu](C#N)[C:15]#[N:16].Cl>ClCCl.O.CN(C)C=O>[C:15]([C:7]1[CH:6]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:10]=[CH:9][C:8]=1[OH:11])#[N:16]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: N#C[Cu]C#N
Agent: BrBr
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1O
Reaction time: 38 h
Yield: 77.4 %

Procedure:
Bromine (15.9 ml) was added to a solution of 4-trifluoromethylphenol (50 g) in dichloromethane (300 ml) at room temperature and the mixture was stirred for 38 hours. The reaction mixture was successively washed with aqueous sodium bisulfite solution and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude 2-bromo-4-trifluoromethylphenol (78.5 g) as oil. N,N-dimethylformamide (250 ml) was added to the crude product and copper cyanide (I) (27.6 g), and the mixture was heated to reflux for 2 hours under Ar. This hot reaction mixture was poured into a solution of ferric chloride hexahydrate (137.5 g) and hydrochloric acid (35 ml) in water (400 ml), and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate, and the ethyl acetate was successively washed with dilute hydrochloric acid and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane to obtain 2-cyano-4-trifluoromethylphenol (34.6 g, mp. 149.5°-151° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]2[CH2:27][C:26](=[O:28])[NH:25][CH:24]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[CH3:36])[C:23]32[C:44]2[C:39](=[CH:40][C:41]([Cl:45])=[CH:42][CH:43]=2)[NH:38][C:37]3=[O:46])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:45][C:41]1[CH:40]=[C:39]2[NH:38][C:37](=[O:46])[C:23]3([CH:22]([C:16]4[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=4[O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH2:27][C:26](=[O:28])[NH:25][CH:24]3[C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[CH3:36])[C:44]2=[CH:43][CH:42]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 105.5 %

Procedure:
A solution of racemic (2′S,3S,4′R)-4′-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.7 g, 1 mmol) in TFA (10 mL) was stirred at r.t. for 0.5 h. The solution was diluted with DCM, washed with 1N Na2CO3 aq. (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated to give title compound as a yellow solid (Yield: 0.6 g).