Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH:34]=O)[CH3:33]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:29])[N:27]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:22][CH:21]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1c(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.19 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-N-methoxy-N, 1,4-trimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxamide (compound 49, 0.650 g, 1.45 mmol) in ethyl acetate (12 ml) was added DMF (0.65 ml) and DMF acetal (0.207 g, 0.233 ml, 1.74 mmol) sequentially at room temperature. The reaction mixture was then stirred at room temperature for 15 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The precipitated out product was filtered and washed with ether (10 ml) to obtain the title compound (0.600 g, 82.19%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:28]=[C:27]([CH3:29])[O:26][N:25]=4)[N:13]3[N:12]=2)=[CH:7][N:6]=[N:5]1.[NH:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH3:31][N:30]([CH2:2][CH2:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:28]=[C:27]([CH3:29])[O:26][N:25]=4)[N:13]3[N:12]=2)=[CH:7][N:6]=[N:5]1)[CH3:32]
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4cnnn4CCBr)nn23)no1
Reactant: CNC
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cnnn4CCN(C)C)nn23)no1
Yield: 44.2 %

Procedure:
A solution of 6-({[1-(2-bromoethyl)-1H-1,2,3-triazol-5-yl}methyl}oxy)-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (125 mg, 0.27 mmol) in DMF (5 ml) and Me2NH (2.0 M in THF, 4 ml, 8 mmol) were heated at 80° C. for 4 h in a sealed tube. The reaction mixture was concentrated under reduced pressure and then taken up in MeOH/CH2Cl2 and dry loaded onto silica. The mixture was purified by column chromatography on silica using 1.5% MeOH/CH2Cl2 containing 1% NH3 as eluent to yield the desired phthalazine (50 mg, 44%). 1H NMR (360 MHz, CDCl3) δ 8.69 (1H, d, J=8.0 Hz), 8.18 (1H, d, J=8.0 Hz), 8.07 (1H, s), 7.98 (1H, t, J=7.6 Hz), 7.82 (1H, t, J=7.6 Hz), 6.85 (1H, s), 5.86 (2H, s), 4.66 (2H, t, J=6.9 Hz), 2.92 (2H, m), 2.59 (3H, s), 2.32 (6H, s). m/z (ES+) 420 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([Cl:18])=[O:14])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)C(C(=O)O)CC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(C(=O)Cl)CC2
Reaction time: 2 h

Procedure:
6-Methoxy-indane-1-carboxylic acid, 6.0 g (31 mmol), a compound of Formula 3, was dissolved in 50 ml of methylene chloride and reacted at ambient temperature with 4.0 ml (46 mmol) of oxalyl chloride in the presence of one drop of DMF. After 2 hours, the reaction mixture was brought to reflux and maintained for 15 minutes. It was then concentrated under vacuum and stirred for about 30 minutes, yielding 6-methoxy-indane-1-carboxylic acid chloride, which was sufficiently pure to be used for the next step.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[H-].[Na+].[CH3:22][O:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][C:26]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]>CN(C=O)C>[CH:2]1([CH2:7][CH2:8][N:9]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:40])=[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH:27]=2)[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:1]1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Reactant: Cc1ccc(S(=O)(=O)NCCC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(CCC2CCCCC2)S(=O)(=O)c2ccc(C)cc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
To a solution of N-2-cyclohexylethyl-p-toluenesulfonamide (300 mg) in DMF (5 mL) was added NaH (56 mg of a 60% dispersion in mineral oil). After gas evolution subsided, 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (example 1178D, 266 mg) was added. After stirring at ambient temperature for 1.5 h, the reaction was quenched by addition of water (10 mL), and diluted with 50% EtOAc/hexane (50 mL). The organic solution was washed with water (10 mL), brine (2×10 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give the title compound as a colorless oil (250 mg, 70%).
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)C(=O)NC2SC(SC[C:16](O)=[O:17])=CN=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C([O:47][C:48](=[O:59])[C:49]([S:52][C:53]1[S:57][C:56]([NH2:58])=[N:55][CH:54]=1)([CH3:51])[CH3:50])C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:16](=[O:17])[NH:58][C:56]2[S:57][C:53]([S:52][C:49]([CH3:51])([CH3:50])[C:48]([OH:47])=[O:59])=[CH:54][N:55]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: CC(C)(C)C1CCC(NC2CCCCC2)CC1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Product: CC(C)(Sc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C(C)(C)C)CC2)s1)C(=O)O

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Example 38) via (4-tert-butyl-cyclohexyl)-cyclohexyl-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:42])[C:25]([CH3:41])([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH3:26]>>[CH3:22][O:23][C:24](=[O:42])[C:25]([N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:10]([CH:11]([C:13]4[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=4[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:29]=[N:28]1)([CH3:41])[CH3:26]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Reactant: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COC(=O)C(C)(C)n1cc(-c2cnc3[nH]cc(C(C)c4c(Cl)ccc(F)c4Cl)c3c2)cn1

Procedure:
Prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridine and 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]-propionic acid methyl ester according to the Suzuki coupling procedure described in Example 1. Purification by flash column chromatography using 0→70% EtOAc in hexanes afforded the title compound as a light yellow solid. MS (ES+): m/z 475.06/477.04 (100/68) [MH+]. HPLC: tR=2.51 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[ClH:1].[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]1[N:13]([CH3:25])[C:12]2[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:38])=[O:39])=[CH:32][CH:31]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1F)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1ccccc1F)n2C)c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(2-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (60 mg, 0.15 mmol) and (4-amino-phenyl)-methanesulfonamide (28 mg, 0.15 mmol) as a white solid (30 mg, 34%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.58 (s, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.49-7.53 (m, 2H), 7.33-7.40 (m, 1H), 7.17-7.27 (m, 4H), 7.09-7.12 (m, 1H), 6.79 (s, 2H), 5.76 (d, J=6.0 Hz, 1H), 4.72 (d, J=5.4 Hz, 2H), 4.18 (s, 2H), 3.67 (s, 3H), 3.46 (s, 3H). MS (ESI) m/z=547 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].[I-].[Na+].O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-hydroxybenzoic acid (1.38 g, 0.01 mol), 2-chloro-N,N-diethylacetamide (1.4 g, 0.01 mol) triethylamine (1.44 ml. 0.01 mol) and sodium iodide (150 mg, 0.001 mol) in N,N-dimethylformamide (6 ml) was stirred at room temperature for 18 h. Water (100 ml) was added and the mixture allowed to stand at 4° C. for 5 h. The title compound was isolated by filtration, washed with water and recrystallized from ethanol-water to give 1.8 g. Mp 148°-149° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][CH2:32][CH2:31][N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:17][CH:16]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(-c2cc(-c3ccc(C(=O)O)cc3)[nH]c(=O)n2)ccc1O
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1cc(-c2cc(-c3ccc(C(=O)NCCCN4CCOCC4)cc3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.9 %

Procedure:
4-(6-(4-Hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid (Compound 265, 15.5 mg, 48 umol) and 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 5 mg of product. 1H-NMR (400 MHz, d6-DMSO): δ 8.64-8.69 (m, 1H), 8.19-8.27 (m, 3H), 7.94-8.01 (m, 3H), 7.86-7.91 (d, 1H), 7.50 (s, 1H), 6.88-6.95 (d, 1H), 3.54-3.60 (m, 4H), 3.27-3.36 (m, 4H), 2.29-2.41 (m, 4H), 2.21 (s, 3H), 1.65-1.77 (m, 2H). MS (EI): 449.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl.C(N(CC)CC)C>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(=O)N1
Reaction time: 10 h
Yield: 21 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 65 mg, 0.27 mmol), 3-(trifluoromethyl)phenylboronic acid (101 mg, 0.54 mmol) and cupric acetate (48.5 mg, 0.000267 mol) were placed in a vial, purged with N2, following by methylene chloride (2 mL, 0.03 mol) and triethylamine (0.186 mL, 0.00134 mol) at 23° C. The reaction was allowed to stir for about for 10 hours, and filtrated. The crude material was then purified via chromatography (SiO2, 4 g, 0-35%) to give a pure product (22 mg, 31%). 1H NMR (CHLOROFORM-d) δ: 7.87 (d, J=9.0 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.45-7.52 (m, 2H), 7.37-7.43 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.27-7.31 (m, 2H), 7.22 (d, J=8.3 Hz, 1H), 6.01 (s, 1H), 4.39-4.49 (m, 2H), 1.87 (s, 3H). MS (M+1): 388.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.C1C=CC2N(O)N=[N:28]C=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[OH-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([NH2:28])=[O:21]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.6 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (64.0 mg, 0.16 mmol) in anhydrous THF (3.6 mL) was added HOBt (56.5 mg, 0.42 mmol, 2.6 eq), DIPEA (0.073 mL, 0.42 mmol, 2.6 mmol), and EDCI (67.8 mg, 0.35 mmol, 2.2 eq), and the reaction mixture was stirred at room temperature under N2 for 2 h. Concentrated aqueous ammonium hydroxide solution (0.50 mL) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous solution of ammonium chloride, water and brine. The organic layer was isolated and dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 20% methanol in dichloromethane) to give an oil. Crystallization from DCM—ether—hexane afforded the title compound as a beige solid (9.9 mg, 16.0%). 1H NMR (MeOD, 400 MHz) δ ppm 8.74 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.62 (dd, J=10.4 Hz, 2.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.59 (t, J=8.4 Hz, 1H); LCMS (method D1): RT=0.84 min, [M+H]+=398.
Reaction SMILES: F[C:2]1C=C(OC(CCCCCCCCC)=O)C=C[C:3]=1C(O)=O.C(OC1C=CC(C2C=CC(C([O:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([O:55][CH:56]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[C:57]([F:60])([F:59])[F:58])=[O:54])=[C:49](F)[CH:48]=3)=O)=CC=2)=CC=1)CCCCCCC>O1CCCC1>[OH:46][C:47]1[CH:48]=[CH:49][C:50]([C:53]([O:55][CH:56]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:2][CH3:3])[C:57]([F:58])([F:59])[F:60])=[O:54])=[CH:51][CH:52]=1
Reactant: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)c(F)c3)cc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
To a solution of the 2-fluoro-4-n-nonylcarbonyloxybenzoic acid (0.3 g) obtained in (3) above and the 1,1,1-trifluoro-2-decyl 4-hydroxybenzoate (0.3 g) obtained in (2) above in tetrahydrofuran (about 30 ml) were added dicyclohexylcarbodiimide (0.25 g) and dimethylaminopyridine (0.02 g). The solution was stirred at room temperature for about 20 hours. The solution was distilled to remove the solvent. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrone magnesium sulfate and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer: hexane/ethyl acetate=20/1) to obtain the titled compound (0.21 g).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(C=O)cc2OC)c(C)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(CO)cc2OC)c(C)o1
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of ethyl (2E)-3-{4[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (11.94 g) in tetrahydrofuran (200 mL)-ethanol (20 mL) was gradually added sodium borohydride (650 mg) at 0° C. After stirring the reaction mixture for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals of ethyl (2E)-3-{4[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (11.0 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 96-97° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O.[S-:19][C:20]#[N:21].[K+].II>C(#N)C>[C:13]([C:14]1[S:19][C:20](=[NH:21])[N:1]([CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH:15]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#C[S-]
Reactant: CC(C)(C)CC=O
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCn1cc(C(C)(C)C)sc1=N
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.6 %

Procedure:
tert-Butyl 2-aminoethylcarbamate (5.9 g, 37 mmol) and 3,3-dimethylbutanal (4.9 mL 95%, 37 mmol) were mixed in dry acetonitrile (30 mL) with 4 g of 4 Å (8-12 mesh beads) molecular sieves and stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite and washed with acetonitrile (5 mL). Potassium thiocyanate (4.8 g, 49 mmol) was added and the mixture warmed to 50° C. for 10 minutes. Iodine (9.3 g, 37 mmol) was added and the reaction mixture was stirred at 50° C. for 6 hours. Acetonitrile (30 mL) was added followed by 10 mL of 20% Na2S2O5. The layers were separated and the organic layer was dried with Na2SO4, filtered, and concentrated. The concentrate was purified by flash chromatography on SiO2, equilibrating the column with CH2Cl2, loading the sample, and eluting with 5% methanol in CH2Cl2 (0.1% NH4OH) isocratically to provide the title compound (3.5 g, 11.7 mmol, 32% yield). MS (DCI/NH3) m/z 300.2 (M+H)+. 1H NMR (300 MHz, CDCl3) δ ppm 1.31 (s, 9 H) 1.42 (s, 9 H) 3.57 (q, J=6.78 Hz, 2 H) 4.26 (t, J=6.95 Hz, 2 H) 5.63 (t, J=5.76 Hz, 1 H) 6.58 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.[Br:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[S:26][C:27]=1[Cl:28]>>[Br:22][C:23]1[CH:24]=[C:25]([S:29]([NH:21][C:18]2[S:19][CH:20]=[C:16]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=4)=[CH:7][C:2]=3[Cl:1])[N:17]=2)(=[O:31])=[O:30])[S:26][C:27]=1[Cl:28]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1)c1cc(Br)c(Cl)s1

Procedure:
The title compound 4-[2-chloro-4-(4 -chlorophenoxy)phenyl]-1,3-thiazol-2-amine (91 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (44.4 mg) with purity >90%: MS (pos) m/z 595.3, 597.3, 599.3; MS (neg) m/z 593.2, 595.2, 597.2.
Reaction SMILES: CO.O=[C:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.[C:18]([BH3-])#[N:19].[Na+].C(N(CC)CC)C>Cl>[CH3:18][NH:19][CH:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)Cc1ccc(CC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNC(C)Cc1ccc(CC(=O)OC)cc1
Reaction time: 3 h

Procedure:
To 25 mL of methanol 0.59 g of methyl 4-(2-oxopropyl)phenylacetate, prepared above, was added and dissolved. Then with stirring the following were added: 2.0 g-methylamine hydrochloride, 0.3 g sodium cyanoborohydride, and 0.3 mL of triethylamine. After approximately 12 hours an additional 0.1 g of sodium cyanoborohydride was added to the mixture. After 3 hours more, the reaction was diluted with 100 mL of 0.1 M hydrochloric acid, washed with diethylether, and the resulting aqueous phase was basified to a pH of 12 by addition of 5 mL portions of 1 N sodium hydroxide solution. This was extracted three times with 100 mL portions of diethylether, combined extracts washed with brine and dried. The solvents were removed in vacuo to yield 0.44 g of a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:12])([O:3][CH3:4])=[O:2].[CH3:25]CO>>[C:1]([C:5]1[S:6][C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[O:12])([O:3][CH2:4][CH3:25])=[O:2]
Reactant: CCO
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Product: CCOC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 36 h
Yield: 59 %

Procedure:
A solution of Ti(OEt)4 (0.10 mL, 0.476 mmol, 11.8 equiv), N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.014 g, 0.040 mmol), and EtOH (10 mL) was heated at the reflux temp. for 36 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in EtOAc and purified by flash chromatography (gradient from 10% EtOAc/hexane to 20% EtOAc/hexane) to afford N-(2-carboethoxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.0086 g, 59%): 1H NMR (CDCl3) δ1.30 (d, J=7.4 Hz, 3H), 1.35 (s, 9H), 2.30 (s, 3H), 4.24 (q, J=7.4 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.30 (br s, 1H), 7.86 (s, 1H), 9.68 (s, 1H); 13C NMR (CDCl3) δ14.3, 20.8, 31.8 (3C), 35.2, 60.6, 105.1, 117.2, 121.0 (2C), 129.7 (2C), 133.8, 135.2, 145.9, 152.1, 164.2, 164.8.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC(OC)=CC=1B(O)O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([NH:30][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NCc1ccccc1
Agent: COc1ccc(I)c(B(O)O)c1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NCc1ccccc1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Into a 25 mL round bottom flask equipped with a stir bar was added phenyl acetic acid (0.075 g, 0.55 mmol, 1.1 equiv), (2-iodo-5-methoxyphenyl)boronic acid (13.9 mg, 0.05 mmol, 10 mol %) and 1 g of activated 4 Å Molecular Sieves. Dichloromethane (7 mL) was added and the mixture was stirred for 10 min. Then, benzylamine (55 pit, 0.5 mmol, 1 equiv) was added (in order to get reproducible results, it is necessary to use a gas tight 100 μL syringe). The resulting mixture was stirred for 2 h at room temperature (24-25° C.). The reaction mixture was filtered through a pad of Celite® 545, the filtrate was washed with aqueous acidic solution (pH=4), aqueous basic solution (pH=10-11) and brine. The organic layer was collected, dried over anhydrous Na2SO4 and evaporated to yield the title compound (71% using 1, 98% using 2) as a pure product. The catalyst can be recuperated in up to 80% yield by acidification of the aqueous basic solution to pH 7 and extraction with EtOAc.