Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]1[CH:7]=[C:8]([N+:29]([O-:31])=[O:30])[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([C:16]#[N:17])=[C:11]2[N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=1)C(=O)C.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C1COCC1.CO>[Br:28][C:24]1[CH:23]=[C:22]([NH:18][C:11]2[C:10]3[C:15](=[C:6]([CH2:5][N:2]([CH3:3])[CH3:1])[CH:7]=[C:8]([N+:29]([O-:31])=[O:30])[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:16]#[N:17])[CH:27]=[CH:26][CH:25]=1
Reactant: CNC
Reactant: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(CBr)cc([N+](=O)[O-])cc12
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of dimethylamine in THF (2.0 M; 115 ml; 230 mmol) at 0° C. was added a solution of 8-bromomethyl 4[(3-bromophenyl)-N-acetylamino]- -6-nitro-3-quinolinecarbonitrile (11.6 g, 23 mmol) in 115 ml of THF during 15 m. After warming to 25° C. the mixture was stirred for 2 h. The THF was evaporated off, and the residue was refluxed in 230 ml of methanol with 12.7 g (92 mmol) of potassium carbonate for 1 h. The mixture was cooled, saturated with CO2, and concentrated. The residue was partitioned with methylene chloride and water. The organic layer was washed with water, dried, and concentrated. The residue was subjected to chromatography on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give 6.0 g yellow solid, mp 223-226° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18].C(O)(C)C>[Pt].C1(C)C=CC=CC=1>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(O)CNc1c(N)cnc2ccc(Br)cc12
Reaction time: 72 h

Procedure:
1-[(6-Bromo-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol (17.2 g, 50.5 mmol), toluene (150 mL) and isopropanol (20 mL) were added to a Parr flask containing 5% platinum on carbon (1.7 g) wetted with toluene. The flask was evacuated three times, charged with hydrogen to 30 psi, and shaken for 72 hours. The reaction mixture was filtered through a pad of CELITE filter agent. The CELITE was washed with several portions of dichloromethane followed by methanol. The filtrate was concentrated to provide crude 1-[(3-amino-6-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol as a brown oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH:18]=[CH:19][CH:20]([CH3:27])[CH2:21][C:22](OCC)=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([O:14][CH2:15][CH:16]([CH3:28])[CH2:17]/[CH:18]=[CH:19]/[CH:20]([CH3:27])[CH2:21][CH2:22][OH:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC(C)C=CCC(C)COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(/C=C/CC(C)COCc1ccccc1)CCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of 0.432 g. (11.36 mmoles) of lithium aluminum hydride in 20 ml. of anhydrous ether was stirred with ice bath cooling while a solution of 1.73 g. (5.68 mmoles) of rac. ethyl 8-benzyloxy-3,7-dimethyl-4-octenoate in 20 ml. of anhydrous ether was added over a 25 minute period keeping the temperature at 0°-5° C. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours at the end of which time 1.6 ml. of saturated sodium sulfate solution was cautiously added with ice bath cooling. After stirring for 16 hours at room temperature, the slurry was filtered on Celite and the filter cake was washed thoroughly with ether. Concentration in vacuo of the combined filtrate and washes yielded 1.46 g. of a colorless oil. This material was chromatographed on 50 g. of silica gel. Elution with 2:1 parts by volume, 1:1 parts by volume and 1:2 parts by volume hexane-ether afforded 1.38 g. of rac. E-8-benzyloxy-3,7-dimethyl-4-octen-1-ol which was evaporatively distilled giving 1.37 g. (92%) of colorless oil, b.p. 107°-108° C. (bath temperature) (0.03 mm Hg.).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O.Cl.Cl.[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:11](=[O:13])[CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[F:1])[O:14][CH2:15][CH3:16])=[CH:35][CH:36]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a solution of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid (12.0 g) in DMF (600 ml) was added [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (18.2 g) and 1-hydroxybenzotriazole. The mixture was cooled to 0–5° C. and EDC (15.8 g) and trietylamine (62 ml) were added. The mixture was stirred 1 h at 0–5° C. and over night at rt. The solvent was evaporated and the residue was dissolved in CH2Cl2 and washed with H2O (600 ml), and brine (300 ml). The aqueous layers were extracted with more CH2Cl2 (2×300 ml). The combined organic layers were dried (Na2SO4) and the solvent was evaporated. CC(CH2Cl2/2 N NH3 in MeOH 97:3 to 19:1) afforded 10.2 g (40%) of (RS)-[(4-{[2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester. White foam. MS 498.2 ([M+H]+).
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].C1C=CC(CCBr)=CC=1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20](=[O:25])[C:19]2=[O:26]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: BrCCc1ccccc1
Product: O=C1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using the commercially available 5-chloroisatin (purchased from Fisher Scientific) and 2-phenethyl bromide (purchased from Fisher scientific). 1H NMR δ 7.54 (s, 1H), 7.44 (d, 1H), 7.27 (m, 5H), 6.64 (d, 1H), 3.95 (t, 2H), 2.99 (t, 2H).
Reaction SMILES: [NH2:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O1CCOCC1>[C:16]([NH:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)P(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(Cc1ccccc1)P(O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (±)1-Amino-2-phenylethyl phosphonous acid (19) (70 mmol) in dioxane (200 mL) and aqueous 1 M NaOH (75 mL) at 0° C. was added dropwise benzyl chloroformate (20 mL). The pH of the solution during this addition was kept at 8-9 with the simultaneous addition of aqueous 1M NaOH (75 mL). The reaction mixture was stirred at room temperature for a further 16 hours and then was concentrated in vacuo to half volume. Washed with diethyl ether (2×75 mL) and then acidified to pH1 with the addition of concentrated aqueous hydrochloric acid. Extracted with ethyl acetate (3×80 mL) and the combined organic phases were washed with water (1×20 mL), dried over anhydrous MgSO4, filtered and evaporated in vacuo which gave (±)N-CBZ-1-amino-2-phenylethyl phosphonous acid (20) (15.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH:19]=[N:18][N:17]=[N:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)=[CH:21][CH:22]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(-n2cnnn2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(-n2cnnn2)cc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 4-(1H-tetrazol-1-yl)benzoic acid to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-tetrazol-1-yl)benzamide. MS (Q1) 421.0 (M)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH2:23])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:8][NH2+:7]1)=[O:5].[NH:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:35]([O:34][C:32]([NH:24][C@H:25]([C:29]([N:7]1[CH2:8][C@H:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH2:23])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:10][C@H:6]1[C:4]([O:3][CH3:2])=[O:5])=[O:30])[CH:26]([CH3:27])[CH3:28])=[O:33])([CH3:37])([CH3:38])[CH3:36]
Reactant: C=Cc1ccc2ccnc(O[C@H]3C[NH2+][C@H](C(=O)OC)C3)c2c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc2ccnc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Intermediate 1 in DMF was added Boc-(L)-Val (1.05 eq), followed by iPr2NEt (3.5 eq) and TBTU (1.05 eq). The resulting reaction mixture was stirred 12 h at RT and partitioned between EtOAc and 1N aq. HCl. The organic layer was further washed with sat. aq. NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (hexane/EtOAc=7/3) to give the title compound as a colourless oil. MS (ES+) C27H35N3O6 requires: 497. Found: 498 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1N[C@@H:6](C)[CH2:5][N:4]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:25]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:13][C:12]=3[CH:11]=2)[CH2:3]1.C(OC(=O)[NH:41]C1CCNCC1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[C:25]([C:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:17]3[S:18][C:10]([CH2:9][N:4]4[CH2:3][CH2:2][CH:1]([NH2:41])[CH2:6][CH2:5]4)=[CH:11][C:12]=3[N:13]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 6-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, using piperidin-4-yl-carbamic acid tert-butyl ester in place of 2,6-dimethyl-piperazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (25 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C@@H:4]2[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:28])[N:5]2[CH:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[CH:7]=1>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]1[S:3][C@@H:4]2[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16](=[O:28])[N:5]2[CH:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: CC1=CC(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1=CC(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
Zinc powder (1.8 g) was added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylate (1.0 g) in a mixture of dimethylformamide (7.5 ml) and acetic acid (2.5 ml), and the mixture was stirred for 1.5 hours, followed by filtration of the reaction mixture, and the filtered zinc was washed with dimethylformamide (2 ml). The filtrate and the washings were combined and the combined solution was poured into a mixture of ethyl acetate (30 ml), ice-water (30 ml) and 10% hydrochloric acid (2 ml), after which the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layer was combined, and the combined solution was in turn washed with water, a saturated sodium chloride aqueous solution, dried over magnesium sulfate, after which the solvent was distilled off. The residue was crystallized by adding a small quantity of ether, after which the precipitated crystals were collected by filtration and dried to give colorless crystals of 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylic acid (0.45 g), mp 204° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:27])[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=2)([OH:19])[C:15]([F:18])([F:17])[F:16])=[C:9]([Cl:28])[CH:8]=1>N1C=CC=CC=1>[Cl:28][C:9]1[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][C:10]=1[CH:13]([CH3:27])[C:14]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[CH:21]=1)([OH:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: c1ccncc1
Product: CC(c1ccc(NS(C)(=O)=O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
Methanesulfonyl chloride (60 mg) was added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (38 mg) in pyridine (1 ml). The mixture was stirred for 30 min at room temperature. Purification by preparative HPLC (Phenomenex Gemini Axia-C18 column, solvent gradient 20-95% CH3CN in 0.1% HCOOH[aq]) gave the title compound (41 mg) as a white foam. MS (m/e)=443.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate (2.23 g, 5.87 mmol) in 1,4-dioxane (20 ml) was added HCl in 1,4-dioxane (4 M, 15 ml, 60.0 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]2([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[C:3]1=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]2([CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[C:3]1=[O:24]
Reactant: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2(CCCNC2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution comprising tert-butyl 2-methyl-1-oxo-3-phenyl-2,6-diazaspiro[3.5]nonane-6-carboxylate (1.2 g, 3.63 mmol) and TFA (1.399 ml, 18.16 mmol) in DCM (20 ml) was stirred at RT for 4 days. The reaction mixture was concentrated in vacuo and the resulting crude product was dissolved with methanol (5 ml) and passed through a 10 g SCX-2 cartridge. The product was eluted with 2M NH3 in methanol (70 ml) and the relevant fractions were combined and concentrated in vacuo to afford the title compound as a yellow oil;
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:61]([C:68]1[CH:76]=[CH:75][C:71]([C:72](O)=[O:73])=[CH:70][CH:69]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:72](=[O:73])[C:71]1[CH:70]=[CH:69][C:68]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:76][CH:75]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 58.3 %

Procedure:
DIPEA (45 mg, 0.35 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt. (60 mg, 0.14 mmol) in DMF (1 mL). HOBT (19 mg, 0.14 mmol) and EDCI.HCl (27 mg, 0.14 mmol) were then added at room temperature. After 2 minutes, 4-phenoxybenzoic acid (25 mg, 0.12 mmol) was added the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 35 mg (58.3% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-phenoxy-benzamide. LCMS Purity: 90.02%, HPLC Purity: 92.82%, 1H NMR (CDCl3): δ 7.8 (dd, 2H), 7.8-7.7 (dd, 1H), 7.6 (m, 2H), 7.4-7.3 (m, 3H), 7.2-7.1 (t, 2H), 7.1-7.0 (m, 4H), 4.4-4.3 (dd, 1H), 4.3-4.2 (dd, 1H), 4.0 (m, 2H), 3.8-3.6 (m, 4H), 3.4 (t, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C@H:9]1[CH2:10][C@H:5]([OH:4])[CH2:6][C@@H:7]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:8]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)O[C@@H]1C[C@@H](OC(=O)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)O[C@@H]1C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of 7.45 g of (1R,3R,5S)-2,2-dimethyl-propionic acid 3-acetoxy-5-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl ester and 2.76 g of potassium carbonate in 52 ml of methanol and 24 ml of water was stirred at 22° for 6 h after which time t.l.c. showed completion of the reaction. The mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was dried over MgSO4 and evaporated to give 6.49 g of the pure (t.l.c.) title compound as a white solid, m.p. 39-42°. IR (nujol): 3240m (OH), 1731s (C═O); MS (EI): 273/10 (M−tert-butyl).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C[Si](C)(C)CCOCN1C=CN=C1C=O.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:35][C:34]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: COC(=O)c1ccc(CNCCCCNC(=O)OC(C)(C)C)cc1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that methyl 4-formylbenzoate was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and 1,1-dimethylethyl (4-aminobutyl)carbamate was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[C:7]([NH2:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[C:8]2[O:9][CH2:12][C:13](=[O:14])[NH:10][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(N)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cccc2c1OCC(=O)N2
Yield: 60.8 %

Procedure:
6-Ethyl-2-aminophenol (0.88 g, 6.4 mmol), 2-chloroacetyl chloride (0.80 g, 7.0 mmol) and K2CO3 (1.86 g, 13.5 mmol) were mixed according to GP1. Purified by column chromatography (SiO2; CH2Cl2/MeOH 99:1) to give the title compound (0.69 g, 61%). Rf=0.54 (heptanes/EtOAc 1:1); 1H NMR (CDCI3) d 9.29 (s, 1H), 6.92-6.85 (m, 2H), 6.71 (dd, J=7.0 Hz, J=2.6 Hz), 4.62 (s, 2H), 2.65 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) d 166.8, 141.6, 133.0, 126.1, 124.4, 122.5, 114.0, 67.3, 22.9, 14.4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O.O>O1CCOCC1>[NH2:1][C:2]1[C:10]([I:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(N)ccc1C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(N)c(I)cc1C(=O)O
Yield: 49.1 %

Procedure:
To a stirred and heated (25° C.) solution of 5 g of 4-amino-2-methoxy benzoic acid in 75 ml of 1,4-dioxane were added 6.9 g of grinded 1-iodo-2,5-pyrrolidinedione. The mixture was stirred in an oil bath at 105° C. for 3 hours. After the addition of 300 ml of water, the crystallized product was filtered off and dried, yielding 4.3 g (48.9%) of 4-amino-5-iodo-2-methoxybenzoic acid; mp. 180.6° C. (interm. 5).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[CH3:51][O:52][C:53](=[O:68])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:63][CH2:64][N:65]([C:20](=[O:22])[CH2:19][NH:18][C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[O:17])[CH2:66][CH2:67]1)=[O:61]
Reactant: COC(=O)c1ccccc1C(=O)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
DIPEA (233 mg, 1.80 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (161 mg, 0.63 mmol) in DMF (5 mL), HOBt (85.6 mg, 0.63 mmol) and EDCI.HCl (276 mg, 1.44 mmol) at room temperature. After 2 minutes 2-(piperazine-1-carbonyl)-benzoic acid methyl ester (143 mg, 0.58 mmol) was and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with cold water and the product extracted with ethyl acetate. The organic layer was separated, washed with 10% HCl solution, NaHCO3 solution, and brine, dried over sodium sulphate and concentrated to afford 106 mg (37.9% yield) of 2-(4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carbonyl)-benzoic acid methylester, LC-MS purity: 98.96%, 1H NMR: (DMSO) δ 8.6 (bs, 1H), 7.9 (d, 3H), 7.8-7.6 (m, 5H), 7.54 (t, 1H), 7.54-7.46 (t, 2H), 7.44-7.36 (t, 2H), 4.1 (d, 1H), 3.8 (s, 3H), 3.6 (d, 4H), 3.4 (bs, 2H), 3.1 (bd, 2H).