Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.O[Li].O.OO>O1CCCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[O:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Cc1cccc(N)c1O
Agent: OO
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2nc(Nc3ccc(Br)cc3)oc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-6-methylphenol (0.74 g, 6.0 mmol) and 4-bromophenyl isothiocyanate (1.28 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 303[M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH:20]=[CH2:21])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:22])[CH:20]=[CH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,7-dimethylnon-8-enoate (2.7 g, 8.25 mmol) in THF/water (40 mL, 1:1) was added methanol (20 mL) followed by LiOH (0.987 g, 41.2 mmole) at room temperature. The reaction mass was stirred at room temperature overnight. Solvent was evaporated under reduced pressure and the residue was diluted with water (100 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solutions to pH˜3 and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduce pressure to get crude compound. The crude compound was purified by column chromotography (Silica gel, 3% methanol in DCM) to get 2.1 g (85%) of desired compound as gummy liquid. 1H NMR (400 MHz, DMSO-D6): δ ppm 12.2-12.02 (bs, 1H), 6.92-6.85 (m, 1H) 5.72-5.66 (m, 1H), 4.98-4.85 (dd, J=1.6, 2.8 Hz, 2H), 4.03-3.95 (m, 1H), 2.58-2.56 (m, 1H) 2.15-2.02 (m, 1H), 1.45-1.36 (m, 10H), 1.27-1.21 (m, 5H), 0.95-0.93 (m, 3H), 0.84-0.74 (m, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.Cl.Cl.[NH2:13][CH:14]([CH2:23][CH3:24])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH:1]([NH:13][CH:14]([CH2:23][CH3:24])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16])=[O:3]
Reactant: CCC(N)C(=O)c1cccnc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=CO
Product: CCC(NC=O)C(=O)c1cccnc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (2.39 ml) was added dropwise formic acid (0.97 ml) under ice-cooling, and the mixture was stirred at 50° C. for 30 minutes. The mixture was ice-cooled again, and diluted with tetrahydrofuran (9 ml). To the mixture were added 2-amino-1-(3-pyridyl)-1-butanone dihydrochloride (600 mg) and triethylamine (1.41 ml), and the mixture was stirred under ice-cooling for 1.5 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-diethyl ether to obtain 2-formylamino-1-(3-pyridyl)-1-butanone (440 mg) as colorless powder.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][S:7]([C:10]2[CH:11]=[N:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:35])[C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=4[C:31]([F:34])([F:33])[F:32])[CH2:19][CH2:18]3)=[C:14](Br)[CH:15]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][CH2:5][NH:6][S:7]([C:10]2[CH:11]=[N:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:35])[C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=4[C:31]([F:34])([F:32])[F:33])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCN(c2ncc(S(=O)(=O)NCCC3CC3)cc2Br)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cc(F)ccc1C(F)(F)F)N1CCN(c2ccc(S(=O)(=O)NCCC3CC3)cn2)CC1
Reaction time: 24 h
Yield: 23.1 %

Procedure:
To a stirred solution of 5-bromo-6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]-pyridine-3-sulfonic acid (2-cyclopropylethyl)amide (0.100 g, 0.173 mmol) in methanol (5.0 mL) was added Pd/C (0.050 g, 12 mol %). The mixture was placed under an atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified by column chromatography, eluting with a solvent gradient of 35% ethyl acetate and 65% hexane to yield the desired product (0.020 g, 24%). 1H NMR (300 MHz, CDCl3) δ 8.58-8.57, 7.87-7.83, 7.76-7.71, 7.26-7.23, 7.08-7.04, 6.65-6.62, 4.60-4.56, 4.00-3.93, 3.86-3.64, 3.32-3.28, 3.04-2.97, 1.40-1.33, 0.59-0.53, 0.43-0.37, 0.025-0.008. 13C NMR (75 MHz, CDCl3) δ166.1, 162.6, 159.7, 148.2, 136.7, 129.7, 125.1, 124.7, 116.8, 116.5, 114.9, 114.7, 105.8, 46.5, 44.3, 44.2, 43.4, 41.4, 34.4, 8.2, 4.2. MS (ES+) m/z 501 (M+1).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:47][C:48]1[N:52]([CH3:53])[C:51]([CH3:54])=[N:50][N:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:47][C:48]3[N:52]([CH3:53])[C:51]([CH3:54])=[N:50][N:49]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nnc(CCl)n1C
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cc1nnc(Cn2nnc3c(N4CC(F)(F)C(F)(F)C4)nc(C(C)(C)C)nc32)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS(m/e): 428.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-2-methylbenzoic acid (15.1 g, 0.070 mol) in tetrahydrofuran (180 mL) and methanol (45 mL) was slowly added (trimethylsilyl)diazomethane (2.0M in hexanes, 42 mL, 0.084 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h, at which time it was concentrated in vacuo to afford methyl 4-bromo-2-methylbenzoate (16 g, 100%) as a yellow oil. The residue was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): 7.78 (d, 1H), 7.42 (s, 1H), 7.38 (d, 1H), 3.88 (s, 3H), 2.58 (s, 3H). MS (EI) for C9H9BrO2: 230 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2[NH:12][N:13]=[C:14]([NH:15][CH3:16])[C:10]=2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21].C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2=[N:12][N:13]([C:33]([O:35][CH3:36])=[O:34])[C:14]([NH:15][CH3:16])=[C:10]2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH3:20])[C:7]1=[O:21]
Reactant: COC(=O)Cl
Reactant: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2c(NC)n(C(=O)OC)nc2n(Cc2cccc(Cl)c2)c1=O
Reaction time: 20 h
Yield: 86 %

Procedure:
To a mixture of 7-(3-chlorobenzyl)-3-methylamino-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.0 g, 2.9 mM) and triethylamine (1.2 ml, 8.6 mM) in dioxane (50 ml) was added dropwise methyl chloroformate (0.66 ml, 8.5 mM) at room temperature and the mixture was allowed to stir at the same temperature for 20 hours. The mixture was concentrated to dryness and the residue was triturated with water (10 ml). Recrystallization from chloroform/methanol gave colorless crystals (1.0 g, 86%), m.p. 164°-166° C.
Reaction SMILES: [Li+].[OH-].[CH2:3]1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41](F)[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1.Cl>C(Cl)Cl.O.CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([CH3:3])[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2ccc(NCc3ccc(Cl)cc3-c3ccc(C(=O)NCCC(=O)O)nc3)cc2)ccc1F
Temperature: 25 °C

Procedure:
A 1M aqueous solution of LiOH (2.0 mL, 2.0 mmol) was added to a THF (2.0 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(5-chloro-2-(((3′,4′-difluoro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (32 mg, 0.06 mmol) and the resulting mixture was stirred at room temperature. After 1 h the resulting mixture was neutralized with 2M aqueous HCl, diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM and the combined extracts were dried (Na2SO4), and concentrated. The product was dissolved in Et2O (5-7 mL) and then added to heptane (25 mL). The resulting mixture was contracted slowly to about half volume (15 mL). The solid was collected by filtration, washed with heptane (3 mL×2) and dried in vacuo to yield the title compound.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O-])([O-])=[O:6].[K+].[K+].[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:22].Cl>O>[Cl:11][C:12]1[C:17]([C:18]([F:20])([F:21])[F:19])=[C:16]([CH:15]=[CH:14][C:13]=1[OH:22])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(O)c(Cl)c1C(F)(F)F
Yield: 11.7 %

Procedure:
Chloroform (6.7 g, 2.0 eq.) was added dropwise to a stirred mixture of Ca(OH)2 (8.95 g, 120 mmol.), K2CO3 (13.5 g, 98 mmol.), 2-chloro-3-(trifluoromethyl)phenol (5.0 g, 22 mmol.), and H2O (50 mL) at 60-70° C. over 2 h. The reaction mixture was cooled, and acidified with conc. HCl. The product was extracted into EtOAc and dried over Na2SO4. Solvent was evaporated, the crude product was separated and purified through a silica column, eluting with hexane and EtOAc (3:2) to give 580 mg (10%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.[CH2:28](I)[CH2:29][CH3:30].C(=O)([O-])O.[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:28][CH2:29][CH3:30])[N:15]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:14]=2[CH:26]=1
Reactant: CCCI
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccc(C)cc3)c2c1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1 g of 6-[[2-mercapto-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 15 ml of N,N-dimethylformamide, mixed with 0.3 ml of propyl iodide, 0.55 g of potassium hydrogen carbonate and 97 mg of dicyclohexano-18-crown-6, and the mixture was stirred for 48 hours at 20° C. It was filtered, and the filtrate was concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 1.06 g was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([O:14][CH2:13][CH2:12][O:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][O:24][O:25][CH3:26])(=[O:17])=[O:16])[CH:8]=2)[N:3]1[CH2:27][C:28]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[H][H]>[Ni].N.CCO>[O:1]=[C:2]1[C:10]2([O:11][CH2:12][CH2:13][O:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][O:24][O:25][CH3:26])(=[O:17])=[O:16])[CH:8]=2)[N:3]1[CH2:27][C:28]1([CH2:35][NH2:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COOC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2CC1(C#N)CCCCCC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COOC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2CC1(CN)CCCCCC1
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A mixture of 1-{[2′-oxo-5′-{[(2S)-2-(methoxyoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxolane-2,3′-indol]-1′(2′H)-yl]methyl}cycloheptanecarbonitrile (0.37 g, 0.74 mmol, 1 eq) and Raney Nickel (0.4 g) in 2N ammonia/EtOH (30 mL) was treated with hydrogen gas at 50 p.s.i. on a Parr Shaker Apparatus for 18 hours. The mixture was filtered to remove the catalyst. The catalyst was washed with 2N ammonia/EtOH and the combined filtrates were concentrated to yield the title compound as an oil (0.25 g, 68% yield). NMR (500 MHz, DMSO-d6): consistent. MS (API-ES+) m/z 508 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](CO)[S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.[CH:26]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:26][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CSC(CO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CSCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a stirred solution of 3-tert-butoxycarbonyl-5-hydroxymethylthiazolidine (1.9 g, 8.7 mmol), methyl 4-hydroxybenzoate (1.3 g, 8.7 mmol), and Ph3P (3.2 g, 12.2 mmol) in THF (10 ml) was added DIAD (2.2 g, 10.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:9, v/v) as eluent to give methyl 4-(3-tert-butoxycarbonyl-4-thiazolidinyl)methoxybenzoate (1.6 g, 52%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.49 (s, 9H), 3.11–3.19 (m, 2H), 3.88 (s, 3H), 4.04–4.31 (m, 3H), 4.61 (m, 2H), 6.96 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H).
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[C:18]([C:20]1[N:21]=[C:22]([C:37]2([CH3:41])[CH2:40][O:39][CH2:38]2)[NH:23][C:24]=1[C:25]1[C:26]([CH3:36])=[CH:27][C:28]([CH3:35])=[C:29]([CH:34]=1)[C:30]([O:32]C)=[O:31])#[N:19].CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[C:18]([C:20]1[N:21]=[C:22]([C:37]2([CH3:41])[CH2:40][O:39][CH2:38]2)[NH:23][C:24]=1[C:25]1[C:26]([CH3:36])=[CH:27][C:28]([CH3:35])=[C:29]([CH:34]=1)[C:30]([OH:32])=[O:31])#[N:19]
Reactant: COC(=O)c1cc(-c2[nH]c(C3(C)COC3)nc2C#N)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C3(C)COC3)nc2C#N)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 5-(4-cyano-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 203.1) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 312 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:23][O:24]C3CCCCO3)=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:43].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:43][C:16]([C:18]3[S:19][C:20]([CH2:23][OH:24])=[CH:21][N:22]=3)=[CH:15][CH:14]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (366 mg) in acetic acid (3.1 mL) was added ammonium acetate (773 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (117 mg, yield 39%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). MS: 481 (MH+).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34](O)=[O:35]>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:35]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CN(C(=O)c1cc(Cl)cc(Cl)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dichlorobenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dichlorobenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 538 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C[OH:21].[OH-].[K+]>O>[OH:21][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCO
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1

Procedure:
2-(2-fluoro-4-biphenylyl)propionic acid (1 g.) ethylene glycol (10 ml.) and potassium hydroxide (0.8 g.) were refluxed under nitrogen for 24 hours. The mixture was diluted with water, washed with ether, acidified with hydrochloric acid and extracted with ether. The ether extract was washed with water, dried and evaporated to dryness. The product was subjected to thin layer chromatography to give 2-(2-hydroxy-4-biphenylyl)propionic acid, which was recrystallized from light petroleum (b.p. 80° - 100°C.) to give the purified acid having a m.p. of 112° - 119°C.
Reaction SMILES: [CH2:1]1[CH2:28][O:27][C:3]2([C:20]3[C:19](=[O:21])[C:18]4[C:9](=[C:10]([OH:23])[C:11]5[CH2:12][CH2:13][CH:14]([OH:22])[CH2:15][C:16]=5[CH:17]=4)[C:8](=[O:24])[C:7]=3[CH:6]=[CH:5][CH:4]2[CH2:25][CH3:26])[O:2]1.C(Cl)(Cl)Cl.[Br:33]Br.N(C(C)(C)C#N)=NC(C)(C)C#N>O.C(Cl)(Cl)(Cl)Cl>[Br:33][CH:12]1[CH2:13][CH:14]([OH:22])[CH2:15][C:16]2[CH:17]=[C:18]3[C:9]([C:8](=[O:24])[C:7]4[CH:6]=[CH:5][CH:4]([CH2:25][CH3:26])[C:3]5([O:2][CH2:1][CH2:28][O:27]5)[C:20]=4[C:19]3=[O:21])=[C:10]([OH:23])[C:11]1=2
Reactant: BrBr
Reactant: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)CCC(O)C4)C12OCCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(Br)CC(O)C4)C12OCCO2
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixture of 9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (657 mg), chloroform (33 ml), carbon tetrachloride (13 ml) and water (26 ml) was stirred at room temperature, and bromine (530 mg) and azobisisobutyronitrile (130 mg) were added thereto, and the resulting mixture was stirred at the same temperature as above for 1 hour. From the reaction mixture, the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ether to give 7-bromo-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (576 mg). M.P., 173°-176° C.
Reaction SMILES: Cl.[C:2]([O:7][CH2:8][CH2:9][NH2:10])(=[O:6])[C:3]([CH3:5])=[CH2:4].C(N(CC)CC)C.[F:18][C:19]([F:25])([F:24])[S:20](Cl)(=[O:22])=[O:21].CCOCC>C(Cl)Cl>[C:2]([O:7][CH2:8][CH2:9][NH:10][S:20]([C:19]([F:25])([F:24])[F:18])(=[O:22])=[O:21])(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(=O)OCCN
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCNS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 15 g (0.091 mol) of 2-aminoethyl methacrylate hydrochloride (available from Aldrich) in 250 ml of anhydrous methylene chloride was added 18.4 g of redistilled triethylamine (0.182 mol). After the mixture was stirred at room temperature for 1 hour, 15.3 g trifluoromethane sulfonylchloride (0.091 mol) was added. The resulting mixture was further stirred at room temperature overnight. About 200 ml ether was added. The mixture was filtered to remove the precipitate formed. The filtrate was sequentially washed with 2×100 ml of 5% HCl, 100 ml of saturated NaHCO3, 2×100 ml brine, and then dried over MgSO4. The solvents were removed by rotavap. About 14.5 g of viscous liquid was obtained. The product was further purified by recrystallization from 1:1 hexane/chloroform to give about 12 g white solid (51%) having a melting point of 55-58° C.