Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:26])[S:12][C:11]([C:13]3[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=3)=[N:10][C:9]2([F:25])[F:24])=[CH:4][CH:3]=1.C1[CH:28]=[CH:29][C:30]2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N)CCC>CN(C=O)C.ClCCl>[CH2:31]([NH:33][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([F:26])[C:9]([F:24])([F:25])[N:10]=2)=[CH:14][CH:15]=1)[CH2:30][CH2:29][CH3:28]
Reactant: O=C(O)COc1ccc(C2=NC(F)(F)C(F)(c3ccc(Cl)cc3)S2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCCCN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCNC(=O)COc1ccc(C2=NC(F)(F)C(F)(c3ccc(Cl)cc3)S2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 2-(4-(5-(4-chlorophenyl)-4,4,5-trifluoro-4,5-dihydrothiazol-2-yl)phenoxy)acetic acid (45.7 mg, 114 μmol) in DMF (5.7 mL) were added the coupling agents HOBt (18.4 mg, 136 μmol) and EDC.HCl (26.1 mg, 0.136 mmol). Then, butylamine was added (13.6 μL, 136 μmol) and the mixture was stirred for 2 h at room temperature. When the reaction was completed, it was diluted with dicloromethane (20 mL) and washed with H2O (3×5 mL). The organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was absorbed onto silica then subjected to flash chromatography (SiO2, hexane:AcOEt, 6:4), obtaining 18.1 mg of N-butyl-2-(4-(5-(4-chlorophenyl)-4,4,5-trifluoro-4,5-dihydrothiazol-2-yl)phenoxy)acetamide (35% yield). RMN1H (CDCl3, 400 MHz): δ 8.03-7.93; (m, 2H), 7.64; (d, J=8.3 Hz, 2H), 7.45; (d, J=8.4 Hz, 2H), 7.09-7.01; (m, 2H), 6.48; (bs, 1H), 4.58; (s,), 3.53-3.26; (m, 2H), 1.59-1.50; (m, 2H), 1.41-1.34; (m, 2H), 0.98-0.90; (m, 3H) ppm. RMN19F (CDCl3, 400 MHz): δ −78.81; (dd, J=217.4, 9.8 Hz), −103.30; (dd, J=217.3, 8.8 Hz), −130.96; (m, J=9.3 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25]C)=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:27]([C:29]1[O:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=1)[CH3:28]>>[CH2:27]([C:29]1[O:30][C:31]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]45[CH2:19][CH2:18][C:17]([CH2:22][C:23]([OH:25])=[O:24])([CH2:20][CH2:21]4)[O:16][CH2:15]5)=[CH:12][CH:13]=3)=[N:6][CH:7]=2)=[O:36])=[C:32]([CH3:34])[N:33]=1)[CH3:28]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cn4)cc3)(CC1)CO2
Reactant: CCc1nc(C)c(C(=O)O)o1
Product: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)nc2)o1

Procedure:
The title compound was prepared analogous to Example 12, starting from methyl 2-(4-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (114 mg, 0.32 mmol) and 2-ethyl-4-methyloxazole-5-carboxylic acid (60.2 mg, 0.39 mmol). The crude product was purified on prep-HPLC to afford the title compound as off-white solid after drying (28 mg, 17% yield). HR/MS (M+H)+ found 476.2166. calc. 476.2185, RT: 2.76 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (s, 1H), 8.98 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.01 (d, J=12.0 Hz, 2H), 7.95 (d, J=12.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 3.91 (s, 2H), 2.86 (q, J=8.0 Hz, 2H), 2.36 (s, 2H), 2.25 (s, 2H), 2.09-1.90 (m, 8H), 1.36 (t, J=8.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19](N3CCCCC3)=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(=[O:30])CC>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:20])=[O:30])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC(=O)O
Reactant: O=C1CCC(CCC(=O)N2CCCCC2)(c2ccc(Cl)c(Cl)c2)C(=O)N1
Agent: Cl
Product: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Reaction time: 18 h

Procedure:
The compound obtained in EXAMPLE 2 is taken up in 0.5 ml of propionic acid and placed in a tube sealed under vacuum. After 18 hours at 145° C., the reaction mixture and diluted with 10 ml of 1 N HCl. After one day, the product which crystallizes is filtered, drained and dried. 100 mg of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9](=[CH:12]N(C)C)[CH:10]=O)[CH:6]=[CH:7][CH:8]=1.[OH:18][CH:19]([CH2:23][CH3:24])[CH2:20][NH:21][NH2:22]>C1C=CC=CC=1>[OH:18][CH:19]([CH2:23][CH3:24])[CH2:20][N:21]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=2)[CH:12]=[N:22]1
Reactant: CN(C)C=C(C=O)c1cccc(C(F)(F)F)c1
Reactant: CCC(O)CNN
Solvent: c1ccccc1
Product: CCC(O)Cn1cc(-c2cccc(C(F)(F)F)c2)cn1

Procedure:
A mixture of 10 g. of 2-(m-trifluoromethylphenyl)-3-dimethylaminoacrolein, 5 g. of 2-hydroxybutylhydrazine and 100 ml. of benzene is refluxed for 2.5 hours. The benzene is evaporated off, ether added, and the reaction mixture cooled to obtain a precipitate which is recovered by filtering, washed with pentane, dissolved in methylene chloride, dried, treated with charcoal and filtered. The resulting solution is treated by addition of pentane and the resulting precipitate recovered by filtering, washed with pentane and dried under reduced pressure to obtain 1-(2-hydroxybutyl)-4-(m-trifluoromethylphenyl)-pyrazole, m.p. 77°-79°C.
Reaction SMILES: N[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.O1CCCC1.N([O-])=O.[Na+]>C(O)(=O)C>[C:12]1([C:3]2[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][O:6][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1noc(N)c1-c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nocc1-c1ccccc1
Yield: 54.9 %

Procedure:
In an analogous manner to that described in J. Org. Chem. 50 (13) 1985, 2372-2375, 7.6 g (32.72 mmol) of ethyl 5-amino-4-phenyl-3-isoxazolecarboxylate in 160 ml of glacial acetic acid, 50 mo of water and 80 ml of tetrahydrofuran were treated portionwise at 15°-20° while stirring within 1hour with a total of 22.6 g of sodium nitrite. The reaction mixture was thereafter poured into 1 liter of water and extracted 3 times with 400 ml of methylene chloride each time. The organic phases were combined and first washed twice with 1 liter of saturated sodium bicarbonate solution each time and then once with 1 liter of water, dried, filtered and concentrated in a vacuum, whereby after chromatography on silica gel and elution with methylene chloride there were obtained 3.9 g (55%) of ethyl 4-phenyl-3-isoxazolecarboxylate as a yellow oil which was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH2:8]([O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCO)=[O:14])[CH2:9][CH2:10][CH3:11].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:8]([O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:26][CH2:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:5]([O:4][C:1]([CH3:2])=[O:3])[CH:6]=1)=[O:14])[CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOC(=O)Nc1ccccc1C(CCO)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1ccccc1CCCc1cccc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic anhydride (0.42 ml, 0.42 mmol) was added to a solution of N-butyloxycarbonyl-2-(3-hydroxy-1-phenylpropyl)aniline (1.21 g, 3.7 mmol), triethylamine (0.77 ml, 5.56 mmol) and DMAP (5 mg) in DCM (25 ml). After stirring at room temperature for 90 minutes the reaction mixture was diluted with DCM (25 ml), washed with 10% aqueous citric acid solution (40 ml), saturated aqueous sodium bicarbonate solution (40 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (1.39 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4F)[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([NH:1][S:38]([C:35]4[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=4)(=[O:40])=[O:39])=[CH:3][CH:4]=3)=[N:8][C:9]=2[N:10]([CH2:26][CH2:27][CH2:29][CH3:28])[C:11]1=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C)cc4)cc3)nc21

Procedure:
8-(4-Amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione was condensed with 4-toluenesulfonyl chloride under the conditions previously described to give the stated sulfonamide as an off white solid (59%); 1H NMR(DMSO-d6, 300 MHz) δ13.49 (s, 1H), 10.28 (s, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.45–7.25 (m, 7H), 7.21 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 4.02 (s, 2H), 4.01 (t, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.75–1.60 (m, 2H), 1.40–1.25 (m, 2H), 0.94 (t, J=7.5 Hz, 3H); EI-HRMS m/e calculated for C30H31N5O4S (M+) 557.2097, found 557.2090.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:10][C:9]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:30]O>ClCCl.[Cl-].[NH4+]>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9](=[O:29])[CH2:10]2)=[CH:14][C:15]=1[OH:30]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(B3OC(C)(C)C(C)(C)O3)c2)CC1=O
Reactant: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(O)c2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
One an one-half (1.5 g, 3.56 mmol) of (4R)-tert-butyl-4-[4-chloro-3-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl))phenyl]-2-oxopyrrolidinecarboxylate was dissolved in 10 mL dichloromethane. To this solution, 3 equiv. of 35% hydrogen peroxide (10.68 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with saturated ammonium chloride aqueous solution and extracted with dichloromethane (3 times). The combined organic layers were dried over Na2SO4 and concentrated to dryness to provide tert-butyl (4R)-4-(4-chloro-3-hydroxyphenyl)-2-oxopyrrolidinecarboxylate (68a) as a clear oil (1.2 g, 95% yield). 1H-NMR (400 MHz, CD3OD): δ 2.63-2.69 (dd, J=17.2, 9.2 Hz, 1H), 2.80-2.87 (dd, J=17.2, 8.4 Hz, 1H), 3.47-3.54 (m, 1H), 3.61-3.66 (m, 1H), 4.12-4.11 (t, J=2.4 Hz, 1H), 7.24-7.22 (d, J=8.0 Hz, 1H), 6.82-6.82 (d, J=2.0 Hz, 1H), 6.73-6.75 (d, J=2.0 Hz, 1H); MS (ESI) m/z 334.01 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:33][CH2:34][C:35]([F:47])([F:46])[C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])[C:30]([OH:32])=[O:31])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C[O-].[Na+:50]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:33][CH2:34][C:35]([F:47])([F:46])[C:36]([F:44])([F:45])[C:37]([F:42])([F:43])[C:38]([F:39])([F:40])[F:41])[C:30]([O-:32])=[O:31])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[Na+:50]
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)[O-]

Procedure:
Starting with the 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid prepared in Example 14 and sodium methoxide (1.0 mol/l in methanol), a procedure analogous to that as shown in Example 27 was repeated to give sodium 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[N:6][C:5]=1[O:14][CH2:15][CH:16]([F:18])[F:17].[OH-].[Na+]>>[F:18][CH:16]([F:17])[CH2:15][O:14][C:5]1[N:6]=[C:7]([NH2:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)nc1OCC(F)F
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared from 2-(2,2-difluoro-ethoxy)-6-amino-5-nitro-nicotinic acid methyl ester (1.3 g, 4.8 mmol) and 1 M NaOH in analogy to example 1e. Yield: 0.88 g (70%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH:37]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C(OCc1ccccc1)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(-c3cnc(C4CCCN4C(=O)OCc4ccccc4)[nH]3)cc2)c1
Temperature: 85 °C
Yield: 64.1 %

Procedure:
2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid benzyl ester (2.14 g, 5.01 mmol), (3-tert-Butoxycarbonylaminophenyl)-boronic acid (1.19 g, 5.01 mmol), Pd(PPh3)4 (289 mg, 0.251 mmol) and K2CO3 (5.5 mL of 2 M aqueous solution, 11.02 mmol) were combined with 1,2-dimethoxyethane (20 mL). The suspension was stirred while N2 was bubbled through the solution for 24 min. A reflux condenser was attached and the suspension was heated to 85° C. for 17 hours. It was then cooled, diluted with ethyl acetate (150 mL), washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (25% to 50% EtOAc/hexanes) to provide 2-[5-(3′-tert-Butoxycarbonylamino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid benzyl ester (1.73 g, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19](Cl)=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Cl:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[Cl:43]C(Cl)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2([Cl:43])[CH:21]=[CH:20][CH:19]=[C:18]([F:23])[CH2:17]2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Cl:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cl)Cl
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(C2(Cl)C=CC=C(F)C2)c(F)c(NC(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Methyl 4-(bis(tert-butoxycarbonyl)amino)-3-chloro-6-(4-chloro-3-fluorophenyl)-5-fluoropicolinate (2.1 g, 3.94 mmol) was dissolved in dichloroethane (20 mL) and trifluoroacetic acid (0.598 mL, 7.76 mmol) was added at rt. The reaction mixture was stirred overnight at room temperature then concentrated under vacuum. The product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in dichloromethane) to provide the title compound as a white solid (1.64 g, 98%): 1H NMR (300 MHz, CDCl3) δ 7.80 (dd, J=22.0, 8.5 Hz, 2H), 7.50 (dd, J=8.3, 7.6 Hz, 1H), 6.51 (s, 1H), 4.02 (s, 3H), 1.56 (s, 9H); ESIMS m/z 431 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[N:12]=1.S(Cl)(Cl)=O.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[S:9][CH:10]=2)[CH:14]=1
Reactant: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: Cc1ccncc1-c1nc(-c2cccc(C(=O)N(C)C)c2)cs1

Procedure:
By the reaction in the same manner as in Example 60 using 3-[2-(4-methylpyridin-3-yl)-1,3-thiazol-4-yl]benzoic acid (248 mg), thionyl chloride (0.09 ml) and aqueous dimethylamine solution (50%, 5 ml), the title compound (200 mg) was obtained as colorless powder crystals.
Reaction SMILES: [C:1]([C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:10]3=[CH:9][C:8]=2[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:22]([O:21][C:19]([N:17]1[CH2:16][CH2:15][N:11]2[C:12]3[CH:13]=[CH:14][C:6]([C:1](=[N:31][CH2:30][C:29]4[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=4[O:27][CH3:26])[CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=3[CH:9]=[C:10]2[CH2:18]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCCC(=O)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 8-butyryl-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.0 g, 2.9 mmol) in CH2Cl2 (20 mL), cooled to 0° C., was added 2,4-dimethoxybenzyl amine (0.5 mL, 3.2 mmol) and Et3N (1.2 mL, 9 mmol). To this mixture was added a solution of TiCl4 (1.8 mL, 1M, 1.8 mmol) in CH2Cl2 dropwise via an addition funnel. Upon completion of addition, the reaction was stirred at room temperature for 6 h before it was quenched with a saturated solution of NaHCO3. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered, and concentrated to give a crude product that was used immediately without further purification.
Reaction SMILES: COC([C@]12C(C)(C)[C@H](CC1)CC2=O)=O.[CH3:15][O:16][C:17]([C@@:19]12[C:25]([CH3:27])([CH3:26])[C@@H:22]([CH2:23][CH2:24]1)[CH:21]=[C:20]2[O:28][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])=[O:18]>>[CH3:15][O:16][C:17]([C@:19]12[C:25]([CH3:27])([CH3:26])[C@H:22]([CH2:23][CH2:24]1)[CH:21]=[C:20]2[O:28][S:29]([C:32]([F:35])([F:33])[F:34])(=[O:31])=[O:30])=[O:18]
Reactant: COC(=O)[C@@]12CC[C@@H](C=C1OS(=O)(=O)C(F)(F)F)C2(C)C
Agent: COC(=O)[C@]12CC[C@H](CC1=O)C2(C)C
Product: COC(=O)[C@]12CC[C@H](C=C1OS(=O)(=O)C(F)(F)F)C2(C)C

Procedure:
The title compound was prepared from 7b by the general procedure described for compound 9a. Brownish oil (68%). 1H NMR (300 MHz, CDCl3) δ ppm 5.81 (d, J=3.74, 1H), 3.77 (s, 3H), 2.51 (dd, J=3.67, 3.67 Hz, 1H), 2.39 (ddd, J=3.71, 8.76, 12.47 Hz, 1H), 2.03-2.13 (m, 1H), 1.65 (ddd, J=3.68, 9.18, 12.65 Hz, 1H), 1.24 (ddd, J=3.72, 9.18, 12.64 Hz, 1H), 1.11 (s, 3H), 0.97 (s, 3H). Exact mass calculated for C12H15F3O5S m/e 328.06. found 328.44.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[F:32]C1C=CC(CCBr)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:32][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Fc1ccc(CCBr)cc1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc(F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(4-fluorophenyl)ethylbromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH3:2].[Cl:12][CH:13]=[CH:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:12]/[CH:13]=[CH:14]/[CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:1][CH3:2]
Reactant: CCNCc1cccc(Br)c1
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCN(C/C=C/Cl)Cc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4.28 g (20 mmol) of N-ethyl-3-bromobenzylamine in 30 ml of N,N-dimethylfcrmamide were added 2.44 g (22 mmol) of 1,3-dichloropropene and 1.70 g (12 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 8 hours at 60° C., poured into 40 ml of ethyl acetate, washed with 40 ml ×2 of water and 40 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 3.70 g (yield: 64%) of the above identified compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29](O)=[O:30])[C:22]3=[O:32])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([NH:37][CH3:36])=[O:30])[C:22]3=[O:32])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)O)C3=O)CC2)c2ccc(Cl)cc2n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described as example 208, (3S)-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid, methyl amine, HATU, and diisopropylethylamine are reacted to afford the product. LC-MS 488 (M++1). 1H NMR (CD3OD) δ 7.86 (d, 1H), 7.50 (s, 1H), 7.30 (d, 1H), 6.30 (s, 1H), 4.65 (m, 1H), 4.00 (m, 2H), 3.70 (m, 5H), 3.30 (m, 5H), 2.75 (s, 3H), 1.98 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H).