Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of 4-fluorophenylmagnesiumbromide (1.0 M in THF, 4.4 mL, 4.4 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1973 g, 1.08 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.3152 g, 88.9%). EI-MS m/z 330 (M+H+) Rt (1.65 min).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH2:32])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4S(C3C=CC(C)=CC=3)(=O)=O)=[N:12][N:11]=2)[CH2:3]1.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52].N1C=CC=CC=1.[OH-].[Na+].Cl>C(Cl)(Cl)Cl.O1CCOCC1>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:51]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=5[O:44][CH3:43])(=[O:53])=[O:52])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][NH:19]4)=[N:12][N:11]=2)[CH2:5]1
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1N
Reactant: COc1ccccc1S(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccccc1S(=O)(=O)Nc1cc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cn[nH]c3c2)cnc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 39 %

Procedure:
5-{4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-2-(methyloxy)-3-pyridinamine (150 mg, 0.254 mmol) was dissolved in chloroform (3 ml) then 2-(methyloxy)benzenesulfonyl chloride (79 mg, 0.382 mmol) was added. Pyridine (0.082 ml, 1.018 mmol) was added to the reaction mixture and it was stirred at room temperature for 5 h. The compound was dissolved in 1,4-dioxane (2 ml) and 2M sodium hydroxide (2 ml) and stirred at room temperature for 3 h. The reaction mixture was neutralized to pH 7 with 2M HCl, then the solvent was removed under a stream of nitrogen. The solid was dissolved in DMSO then filtered through a filter tube and purified by Mass Directed Automated Preparative HPLC. The solvent was removed under nitrogen to give the title compound as a white solid (60 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1.[C:24]([CH:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([CH:28]1[CH2:29][CH2:30][CH:31]([C:34]([N:1]2[CH2:6][CH2:5][C:4]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)=[CH:3][CH2:2]2)=[O:35])[CH2:32][CH2:33]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)C4CCC(C(C)(C)C)CC4)CC3)cc2)C(=O)O1

Procedure:
Using an analogous procedure to that described in Example 20, the TFA salt of Example 2 was reacted with 4-tert-butylcyclohexanecarboxylic acid in place of N-acetylglycine, to give the title compound. Yield=208 mg, 58%.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[NH2:33].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:21]=[CH:20][C:19]=1[NH2:33]
Reactant: Ic1cnc2cc(-c3ccncc3)ccn12
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1Cl
Yield: 46 %

Procedure:
Combine 3-iodo-7-pyridin-4-yl-imidazo[1,2-a]pyridine (2.18 g, 6.8 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (crude material from previous step, excess), potassium carbonate (2.8 g, 3 equiv.), dioxane (30 mL), and water (15 mL). De-gas thoroughly with nitrogen then add dichloro-bis(triphenylphosphine) palladium (II) (0.143 g, 3 mol %). Heat reaction at 80° C. overnight. Concentrate to dryness then slurry in DCM and filter via Celite®, washing with DCM. Concentrate filtrate then purify by silica plug (Hexanes→1:1 Hexanes:Ethyl Acetate→2.5% Methanol:DCM→5% Methanol:DCM) to give an orange-yellow solid (1.42 g, 46%). MS (ES), m/z 321.1 (M+1).
Reaction SMILES: C(=O)=O.[P:4]([Cl:7])(Cl)Cl.[C:8]([NH:12][CH2:13][CH:14]([OH:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl.CC(C)=O>[C:8]([N:12]1[CH2:13][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:29][P:4]1[Cl:7])([CH3:10])([CH3:11])[CH3:9]
Reactant: CCCCCCCCCCCCCCC(O)CNC(C)(C)C
Reactant: ClP(Cl)Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCC1CN(C(C)(C)C)P(Cl)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a CO2 (s)/acetone cooled solution of 10.5 ml (0.077 mol) of phosphorus trichloride in 150 ml of dichloromethane is added dropwise a solution of 24.0 g (0.077 mol) of 1-tert-butylamino-2-hexadecanol and 21.3 ml (0.153 mol) of triethylamine in 37.5 ml of dichloromethane over a five minute period. When the addition is completed, the cooling bath is replaced with a 50° C. water bath for 1 hour. This is then stirred at room temperature for 16 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=2)[C:11](O)=[O:12])=[N:6][CH:7]=1.Cl.[F:29][C:30]([F:41])([F:40])[C:31]1[N:36]=[CH:35][C:34]([C@H:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=2)[C:11]([NH:39][C@@H:37]([C:34]2[CH:35]=[N:36][C:31]([C:30]([F:40])([F:29])[F:41])=[CH:32][CH:33]=2)[CH3:38])=[O:12])=[N:6][CH:7]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)nc3)cc(C3=NO[C@H](c4ccccn4)C3)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoic acid (2.9 g, 5.57 mmol) in N,N-dimethylformamide (28 mL) were added (1R)-1-[6-(trifluoromethyl)pyridin-3-yl]etanamine hydrochloride salt (1.52 g, 6.69 mmol), EDC (1.60 g, 8.36 mmol), HOAT (190 mg, 1.39 mmol) and triethylamine (3.1 mL, 22.3 mmol). The reaction mixture was stirred at ambient temperature. After 2 h, the mixture was heated to 50° C. After 1 h, the mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Ethyl acetate (200 mL) was added the mixture was heated to 70° C. The solution was cooled and placed in the refrigerator for product to precipitate out. The precipiatated solid was filtered, washed with cold ethyl acetate and dried under reduced pressure gave the title compound (2.17 g). HRMS 532.1972 (M+1). 1H NMR (500, MHz, CDCl3) δ 8.80 (s, 1H), 8.61-8.60 (d, J=4.9 Hz, 1H), 8.51 (s, 1H), 8.45-8.44 (m, 2H), 8.15 (t, J=1.5 Hz, 1H), 7.91-7.89 (m, 1H), 7.74-7.71 (dd, J=7.8, 6.1 Hz, 2H), 7.68-7.67 (d, J=8.1 Hz, 1H), 7.62-7.60 (m, 1H), 7.57-7.55 (d, J=7.8 Hz, 1H), 7.25-7.23 (m, 1H), 6.69-6.67 (d, J=6.8 Hz, 1H), 5.93-5.89 (dd, J=9.9, 7.9 Hz, 1H), 5.44-5.38 (m, 1H), 3.94-3.86 (m, 2H), 2.4 (s, 3H), 1.70-1.68 (d, J=7.1 Hz, 3H).
Reaction SMILES: CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:13]1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:60]1[C:64]([CH3:65])=[CH:63][S:62][C:61]=1[C:66]([O:68][CH3:69])=[O:67]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:13][C:60]1[C:64]([CH3:65])=[CH:63][S:62][C:61]=1[C:66]([O:68][CH3:69])=[O:67]
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Reactant: COC(=O)c1scc(C)c1Br
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1scc(C)c1C
Temperature: 97.5 °C
Yield: 73 %

Procedure:
Methyl boronic acid (0.94 g, 16.02 mmol), potassium phosphate (6.8 g, 32.04 mmol) and BINAP (1.33 g, 2.14 mmol) were added to a solution of methyl 3-bromo-4-methylthiophene-2-carboxylate (Prepared according to the procedure reported in Bioorganic Med. Chem. Lett., 2007, 15, 5, 2127-2146, 2.5 g, 10.68 mmol) in a toluene (60 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. Palladium acetate (0.24 g, 1.07 mmol) was added to the reaction mixture under nitrogen and the tube was sealed. The reaction mixture was heated at 95-100° C. for 20 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The celite cake was washed with ethyl acetate (100 ml). The combined filtrate was concentrated under reduced pressure to obtain residue, which was dissolved in ethyl acetate (150 ml) and washed with water (2×30 ml). The separated organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound 9a (1.32 g, 73%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1>ClCCl.N1C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: Nc1nccs1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 70 %

Procedure:
A solution of 4-acetyl-benzenesulfonyl chloride (50 mmol) and 2-aminothiazole (50 mmol) in dichloromethane and pyridine (300 mL, 8:2) was stirred for one day. After concentrated in vacuo, the residue was diluted with ethyl acetate (500 mL) and the solution was washed with 1N HCl solution, sat NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized in ethyl acetate to give 4-acetyl-N-thiazol-2-yl-benzenesulfonamide (35 mmol) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20](O)=[O:21])=[CH:4][CH:3]=1.O1CCCC1.C(Cl)(=O)OCC.[NH3:36]>O.C(N(CC)CC)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([NH2:36])=[O:21])=[CH:4][CH:3]=1
Reactant: N
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(N)=O)n2Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of the compound obtained in Example 22 (4) (0.23 g) and tetrahydrofuran (7 ml), triethylamine (0.19 ml) and ethyl chlorocarbonate (0.1 ml) were added at 0° C. and the mixture was stirred at the same temperature for 20 minutes. An ammonia gas was blown into the-mixture at 0° C. and the mixture was stirred at the same temperature for 30 minutes. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was recrystallized (ethyl acetate) to obtain 0.06 g of the desired product as a white crystal.
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.CO[CH:48]1[CH:52]([CH2:53][C:54]([O:56][CH3:57])=[O:55])[CH2:51][CH:50](OC)O1.[F:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1.FC(F)(F)C(O)=O>ClCCCl>[CH3:57][O:56][C:54](=[O:55])[CH2:53][C:52]1[CH:51]=[CH:50][N:65]([C:64]2[CH:66]=[CH:67][C:61]([F:60])=[CH:62][CH:63]=2)[CH:48]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CC1CC(OC)OC1OC
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Reaction time: 16 h
Yield: 80.9 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, to a mixture of crude methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)-acetate (120 mg, ~0.58 mmol) and 4-fluoroaniline (50 μL, 0.53 mmol) in 1,2-dichloroethane (10 mL) was added trifluoroacetic acid (0.2 mL, 0.26 mmol). After 16 hours at 80° C., the resultant mixture was partitioned between EtOAc and 1M pH 7 phosphate buffer. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to a crude oil, which was purified via flash column chromatography with 0-15% EtOAc/hex gradient eluant to yield 100 mg (77%) of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an oil. 1H NMR: δ 7.34-7.30 (m, 2H), 7.10 (t, 2H, J=8.6 Hz), 6.96-6.94 (m, 2H), 6.28 (t, 1H, J=2.2 Hz), 3.72 (s, 3H), 3.56 (s, 2H). Anal. Calculated for C13H12NO2F.0.6 H2O: C, 63.98; H, 5.45; N, 5.74. Found: C, 64.01; H, 5.04; N, 5.65.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][NH:19]C=O)=[CH:16][NH:15][C:14]1=[S:22])[CH2:7]2.[ClH:23].CS(C)=O>C(O)(C)C>[ClH:23].[NH2:19][CH2:18][C:17]1[N:13]([C@H:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[C:14](=[S:22])[NH:15][CH:16]=1
Reactant: O=CNCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)O
Product: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A mixture of (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide (19.1 g, 59.0 mmol), prepared as in Example 30, and 25 mL of concentrated hydrochloric acid (12.0 M, 25 mL, 300 mmol) in 400 mL of isopropanol was heated to reflux over 12 minutes and stirred for 1 hour 40 minutes. The mixture was distilled removing 150 mL of isopropanol. The mixture was gradually cooled to room temperature and stirred for 3 hours 45 minutes. The material was isolated by filtration and the filter residue was washed with 75 mL of isopropanol. Drying in vacuo at 110° to 125° C. with a nitrogen bleed gave (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride (15.6 g, 47.1 mmol), m.p. 251.9° C. [α]D +10.2° (C=0.500, DMSO).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=[C:8](S(C)(=O)=O)[N:7]=1)=[O:5])C.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C>[CH2:19]([O:20][C:8]1[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=1)[CH3:18]
Reactant: CCOC(=O)c1cc(CC)nc(S(C)(=O)=O)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(CC)cc(C(=O)O)n1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of 6-ethyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester (100 mg, 0.39 mmol) in ethanol (4 mL), sodium ethylate (134 mg, 1.94 mmol) is added. The reaction mixture is stirred for 2 h, ethanol is evaporated and the residue is dissolved in EtOAc (25 mL). The org. solution is washed with 1M aq. KHSO4, followed by brine, dried over MgSO4, filtered and evaporated give 2-ethoxy-6-ethyl-pyrimidine-4-carboxylic acid as a yellow oil (35 mg); LC-MS: tR=0.72 min, [M+H]+=197.07.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][O:13][CH2:14][CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH:15]1[NH:16][CH2:17][CH2:18][N:19]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:20]1
Reactant: COCC1CNCCN1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC1CN(c2ncc(C(=O)OC)cn2)CCN1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.74 mmol) in DCM (4.70 mL) was added to a stirred solution of 2-(methoxymethyl)piperazine (226 mg, 1.74 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.752 mL, 4.35 mmol) in DCM (4.00 mL) at 25° C. under nitrogen. The resulting solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and diluted with MeOH. The resulting mixture was filtered. The filtrate was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (346 mg, 75%) as a yellow solid. This was used directly with no further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[C:3]([NH:5][C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[O:51]=[C:52](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[N:36]1([CH2:35][CH2:34][O:33][C:30]2[CH:31]=[CH:32][C:27]([CH:2]3[C:3](=[O:4])[N:5]([C@@H:6]([C@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:20])[C:7]([NH:9][C:10]4[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=4)=[O:8])[C:52](=[O:51])[NH:1]3)=[CH:28][CH:29]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCCN4CCOCC4)cc3)C2=O)n1
Reaction time: 0.33 h

Procedure:
Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.19 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (160 μL, 122 mg, 0.94 mmol) and was transferred via cannula to a solution of diphosgene (16 μL, 26 mg, 0.13 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted with 0-100% ethyl acetate in hexanes and the isolated material further purified by preparative thin layer chromatography using silica gel eluted with ethyl acetate. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as an off white solid (32 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[C:18](OC(=O)C)(=[O:20])[CH3:19].CCN(CC)CC>C1COCC1.C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH:7]([O:10][C:18](=[O:20])[CH3:19])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(OC(C)=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (prepared according to J. Org. Chem. 2003, 60, 7219) (1.9 g, 7.8 mmol) in THF (25 mL), cooled to −78° C., was slowly added DibalH (1 M in toluene; 11.0 mL, 11.0 mmol) under an argon atmosphere, followed by stirring of the solution at −78° C. for 1 h. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl (30 mL). The mixture was allowed to warm up to RT, and a 10% aqueous Na2CO3 solution (20 mL) and CH2Cl2 (70 mL) were subsequently added. The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2Cl2 (25 mL), acetic anhydride (2.21 mL, 23.4 mmol), NEt3 (3.26 mL, 23.4 mmol) and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) were subsequently added and the reaction mixture was stirred at RT overnight. The organics were washed with a saturated aqueous NaHCO3 solution (10 mL) and 1M aqueous HCl, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 3:1 to 1:1) to give the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.5; MS: 310.0 [M+Na]+, 597.3 [2M+Na]+.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1.[CH2:17]([NH:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]([OH:37])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[CH2:17]([N:24]([CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([OH:37])=[C:32]([C:33](=[O:34])[NH2:35])[CH:36]=1)[CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1csc(-c2ccc(OCC3CO3)cc2)n1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nccs3)cc2)ccc1O

Procedure:
A solution of 6.50 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-thiazole and 7.25 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 150 ml of isopropanol is heated under reflux for 18 hours and the solvent is subsequently removed in a rotary evaporator. The 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(thiazol-2-yl)-phenoxy]-2-propanol, obtained in the form of an oil, is further processed in that form.