Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([N+:11]([O-])=O)[N:10]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:20][N:21]1[CH:25]=[C:24]([NH:26][C:27]([O:29][CH2:30][CH2:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:28])[N:23]=[C:22]1[C:45](O)=[O:46].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC(=O)OCC.CN(C=O)C.C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([NH:11][C:45]([C:22]2[N:21]([CH3:20])[CH:25]=[C:24]([NH:26][C:27]([O:29][CH2:30][CH2:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=3)(=[O:33])=[O:34])=[O:28])[N:23]=2)=[O:46])[N:10]=1)=[O:5])[CH3:2]
Reactant: Cn1cc(NC(=O)OCCS(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1C(=O)O
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Agent: [Pd]
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(NC(=O)c2nc(NC(=O)OCCS(=O)(=O)c3ccc(C(F)(F)F)cc3)cn2C)cn1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 54.4 %

Procedure:
1-Methyl-4-nitroimidazole-2-carboxylic acid ethyl ester (71.05 mg, 0.3567 mmol) was dissolved in EA (10 ml) and 10% Pd/C (10 mg, catalytic weight) was added thereto. The reaction solution was stirred for 10 hours at room temperature under hydrogen atmosphere to reduce a nitro group (NO2) into an amino group (NH2), whereby an imidazole-type amino acid was obtained. 10% Pd/C was filtered out by celite 545 and the filtrate was washed with EA and methanol. 1-Methyl-4-[2-(4-trifluoromethyl-benzenesulfonyl)-ethoxycarbonylamino]-1H-imidazole-2-carboxylic acid (50.10 mg, 0.1187 mmol) dissolved in a solvent mixture of anhydrous DMF (6 ml) and DCM (2 ml) was added thereto, TFFH (94.21 mg, 0.3567 mmol), HOBt (64.74 mg, 0.4748 mmol) and DIEA (82.85 ml, 0.4748 mmol) were also added thereto, and the reaction solution was reacted according to the same procedure as Step (4-1) of Example 2 to give 1-methyl-4-({1-methyl-4-[2-(4-trifluoromethyl-benzenesulfonyl)-ethoxycarbonylamino]-1H-imidazole-2-carbonyl}-amino)-1H-imidazole-2-carboxylic acid ethyl ester (37.00 mg, 54.45%) of a pale yellow solid.
Reaction SMILES: C([N:8]([CH2:51][C@@H:52]([C:61]1[CH:70]=[CH:69][C:68]([O:71]CC2C=CC=CC=2)=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:79])[NH:66]2)[O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([CH2:20][CH2:21][CH2:22][N:23]([CH3:50])[C:24]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([O:34][C:35](=[O:49])[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:30][CH2:29]2)=[O:25])=[O:19])[CH:14]=[CH:15][CH:16]=1)C1C=CC=CC=1.C(O)(=O)C.O>CO.[OH-].[Pd+2].[OH-]>[Si:54]([O:53][C@H:52]([C:61]1[CH:70]=[CH:69][C:68]([OH:71])=[C:67]2[C:62]=1[CH:63]=[CH:64][C:65](=[O:79])[NH:66]2)[CH2:51][NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([CH2:20][CH2:21][CH2:22][N:23]([CH3:50])[C:24]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([O:34][C:35](=[O:49])[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:30][CH2:29]2)=[O:25])=[O:19])[CH:14]=[CH:15][CH:16]=1)([C:57]([CH3:60])([CH3:58])[CH3:59])([CH3:55])[CH3:56]
Reactant: CN(CCCC(=O)Nc1cccc(CCN(Cc2ccccc2)C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CN(CCCC(=O)Nc1cccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)c1)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-[2-({3-[3-(2-{benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethyl]-amino}ethyl)phenylcarbamoyl]propyl}methylcarbamoyl)ethyl]piperidin-4-yl ester (258 mg, 0.238 mmol) in MeOH (3 mL) at room temperature was added a solution of acetic acid in water (17.4 M, 41.4 μL, 0.720 mmol). The resulting solution was purged with nitrogen (3 cycles of vacuum following by dry nitrogen) and then palladium hydroxide (47 mg, 0.34 mmol) was added. This mixture was again purged with nitrogen and then with hydrogen (5×) and then stirred at room temperature under hydrogen (balloon with submerged needle) for 6 h. LC-MS (Method 2-90) showed product was present (Rt 3.71 min; m/z 903.6 [M+H]+). The reaction mixture was filtered through a membrane filter and the filtrate was concentrated under reduced pressure to give the title compound, which was used in the next reaction without further purification.
Reaction SMILES: CI.[C:3](=O)(O)[O-].[Na+].[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][NH:19][C@H:18]([C:21](=[O:24])[NH:22][CH3:23])[CH2:17]2)=[CH:12][CH:11]=1.[Cl-].[Na+]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][S:15][C@@H:16]2[CH2:20][N:19]([CH3:3])[C@H:18]([C:21](=[O:24])[NH:22][CH3:23])[CH2:17]2)=[CH:25][CH:26]=1
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
244 μl of methyl iodide and 300 mg of sodium bicarbonate were added, whilst ice-cooling, to a solution of 1.00 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine [prepared as described in step (4) above] dissolved in 6 ml of dry dimethylformamide. The mixture was then stirred at 0° to 5° C. for 1 hour and allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 10:1 by volume mixture of ethyl acetate and methanol), to afford 222 mg of the title compound as colorless crystals, melting at 82°-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][N:34]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:35](=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:42][CH2:43][CH:38]([N:34]([CH3:33])[C:35](=[O:37])[CH3:36])[CH2:39][CH2:40]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(=O)N(C)C1CCNCC1
Product: CC(=O)N(C)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N-(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-N-methyl-acetamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and N-Methyl-N-piperidin-4-yl-acetamide following General Procedure B.
Reaction SMILES: [NH2:1][C:2](=[S:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:1]=[C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:9][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(N)=S
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cs1
Yield: 83 %

Procedure:
To a stirred solution of ethyl 3-amino-3-thioxopropanoate (20.00 g, 135.9 mmol) in ethanol (120 mL) was added 2-bromo-4′-fluoroacetophenone (29.49 g, 135.9 mmol). The mixture was refluxed for 1 hour, concentrated and partitioned between ethyl acetate (300 mL) and aqueous NaHCO3 (400 mL). The organic layer was combined with a backextract of the aqueous layer (ethyl acetate, 1×100 mL), dried (Na2SO4) and concentrated. The resulting light brown solid was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 2-(4-(4-fluorophenyl)thiazol-2-yl)acetate as an off-white solid (29.92 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[CH3:26][CH2:27][C:28](=O)[CH2:29][CH3:30].C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: CCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(C)cn2)CC1
Temperature: 50 °C
Reaction time: 96 h
Yield: 39.2 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess 3-pentanone (1.32 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol furnished 0.21 g (39%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A mixture of Example 135B (260.0 mg, 0.561 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (191 mg, 0.618 mmol), Pd(Ph3P)4 (32.4 mg, 0.028 mmol), and saturated sodium bicarbonate solution (2 mL, 0.561 mmol) in N,N-dimethylformamide (8 mL) was purged with nitrogen and heated at 80° C. for 4 hours. The mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 306 (M+1).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[CH2:8][O:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[C:1]([O:6][CH2:8][O:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: ClCOC1Cc2ccccc2C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCOC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Into a mixture of 103 g of methacrylic acid, 183 g of chloromethyl(2-indanyl)ether, and 1500 g of toluene was added 111 g of triethylamine under ice-cooling with agitation, and then the reaction mixture was agitated at room temperature for 16 hours. After a usual aqueous work-up, the solvent was removed by distillation to obtain a crude product. It was purified by a column chromatography to obtain 209 g of an objective product, (indane-2-yloxy)methyl methacrylate (yield 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>>[CH3:1][O:2][C:3]1[C:4]([CH:5]=[CH:24][N+:21]([O-:23])=[O:22])=[C:7]([CH3:15])[C:8]([O:13][CH3:14])=[C:9]([CH3:12])[C:10]=1[CH3:11]
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1c(C)c(C)c(OC)c(C=C[N+](=O)[O-])c1C
Temperature: 80 °C

Procedure:
In a 500 mL round bottom flask was placed 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (2.5 g, 12 mmol) and ammonium acetate (1.3 g, 17 mmol). The solids were taken up in nitromethane (240 mL), and the mixture warmed to 80° C. for 90 min. After the reaction was complete, volatiles were removed in vacuo, the residue was dissolved in ethyl acetate (200 mL), washed with water and brine (50 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3.3 g 1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene as a yellow solid. Further purification was performed by digesting the solid product in cyclohexane for 3 hrs, after which the 2.5 g pure compound 1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene was obtained. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H), 7.95 (d, 1H), 3.65 (s, 3H), 3.63 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H) ppm.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=CC=C[CH:4]=1.C([Li])(CC)C.[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1C=C)=[CH2:15]>>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:8].[CH2:15]=[CH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccccc1C=C
Agent: [Li]C(C)CC
Solvent: C=Cc1ccccc1
Product: C=CC(=C)C
Reaction time: 0.5 h

Procedure:
The polymerization was continued for 30 minutes at 70°C. Upon addition of styrene, it appeared that the reaction product of the secondary butyl lithium and divinyl benzen separated out in gel-form and did not go into solution. With the aid of the initiator gelated in this way an A-B-(A)n block copolymer was obtained by successive polymerization isoprene (50 ml) and styrene (10 ml). The properties of the resulting block copolymer are given below:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][N:9]=[C:8]([CH3:29])[C:7]=1[OH:30].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][N:13]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][N:9]=[C:8]([CH3:29])[C:7]=1[O:30][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: COC(=O)CCc1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(C)c1O
Product: COC(=O)CCc1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(C)c1OCc1cccc(C#N)c1
Yield: 68 %

Procedure:
The coupling of 3-(5-{[tert-butoxycarbonyl-(4-cyano-phenyl)-amino]-methyl}-3-hydroxy-2-methyl-pyridin-4-yl)-propionic acid methyl ester (121) and α-bromo-m-tolunitrile (102 mg, 0.5 mmol), as described in Example 1, gave 3-[5-{[tert-butoxycarbonyl-(4-cyano-phenyl)-amino]-methyl}-3-(3-cyano-benzyloxy)-2-methyl-pyridin-4-yl]-propionic acid methyl ester (122) (162 mg, 68% yield for 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.O.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)cc1
Yield: 40.9 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylate (3.44 g, 9.38 mmol) in THF (53 mL) was added water (26 mL) and 1 N LiOH (28.2 mL, 28.2 mmol) and the resulting mixture was heated to 40 degrees overnight. The reaction was cooled, acidified with 1 N HCl, and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers were dried over MgSO4, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (methanol/DCM=0/100→20/80). Recrystallization from ethyl acetate/hexanes gave 1.3 g of the title compound as a white solid. (41% yield). LC/MS (FA) ES+ 339. 1H NMR (400 MHz, DMSO-d6) δ: 12.74 (s, 1H), 7.33-7.30 (m, 2H), 7.26-7.23 (m, 2H), 4.21 (s, 2H), 3.67-3.64 (m, 4H), 3.42-3.40 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([F:33])[CH:35]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1cccc(F)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCc1cccc(F)c1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 73.4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-fluorobenzylamine (available from Aldrich Chemical Company, Inc.; 78 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-fluoro-benzylcarbamoyl)-biphenyl-2-carboxylic acid (89 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 9.14 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.35-7.43 (m, 1H), 7.13-7.23 (m, 2H), 7.04-7.11 (m, 1H), 4.53 (d, J=6.0 Hz, 8H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:8])[CH2:5][CH2:6]Br.[CH:9]([CH:11]=[CH2:12])=[O:10]>>[CH3:8][CH:4]([CH2:5][CH2:6][CH:9]([OH:10])[CH:11]=[CH2:12])[CH2:3][CH2:2][CH:9]([OH:10])[CH:11]=[CH2:12]
Reactant: CC(CCBr)CCBr
Reactant: C=CC=O
Product: C=CC(O)CCC(C)CCC(O)C=C
Yield: 77.9 %

Procedure:
Preparation ofthe di-Grignard reagent from 1,5-dibromo-3-methylpentane (46 g, 189 mmole) and treatment with acrolein (23.3 g, 415 mmole), as described in Example 6 (Step 2/Method A), gave 6-methylundeca-1,10-diene-3,9-diol (29.2 g, 78% yield). C12H22O2 (198.31 g/mole). bp: 115° C., 0.4 mm Hg. 1HNMR (500 MHz, CDCl3): 0.86 (d, 3H), 1.08-1.58 (m, 9H), 1.95 (bs, 2H), 4.02 (m, 2H), 5.06 (d, 2H), 5.18 (m, 2H), 5.79-5.87 (m, 2H) ppm. 13CNMR (125 MHz, CDCl3): 19.66, 32.38, 32.66, 32.77, 34.47, 73.50, 73.67, 114.62, 114.70, 141.32, 141.38. IR (νmax(cm−1)): 3360(bs), 3080(w), 2925(s), 2860(s), 1645(w), 1430(w), 995(s), 920(s). MS (m/z): 165(M-33), 151, 147, 109, 95, 81, 67, 57, 41.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15](=[O:17])(=[O:16])[C:6]=2[C:5]([Cl:18])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20])[O:12][CH2:11][CH2:10][O:9]3.C(Cl)(=O)C(Cl)=O.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH2:29]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15](=[O:17])(=[O:16])[C:6]=2[C:5]([Cl:18])=[CH:4][C:3]=1[C:19]([O:21][C:28]1[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH:29]=1)=[O:20])[O:9][CH2:10][CH2:11][O:12]3
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)c1cc(Cl)c2c(c1Cl)C1(CCS2(=O)=O)OCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2cc(Cl)c3c(c2Cl)C2(CCS3(=O)=O)OCCO2)CCC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 27.9 %

Procedure:
1.75 g (4.97 mmol) of the title compound of Step F, 1.30 mL (0.015 mol) of oxalyl chloride (purchased from Janssen), and 2 drops of N,N-dimethylformamide were added to 50 mL of methylene chloride. The mixture was refluxed under nitrogen for 2 h and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and the resulting mixture was evaporated to dryness. Another 50 mL of methylene chloride was added to the residue, and the solution was cooled to about 0° C. 0.61 g (5.5 mmol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.15 mL (0.0154 mol) of triethylamine, and the mixture was stirred over 2 days while warming to room temperature. The mixture was evaporated to dryness and the crude product was chromatographed over silica gel eluting with a mixture of ethyl acetate:hexane (6:4) to yield 0.62 g of the title compound of Step G as a solid melting at 168° C. (dec). 1H NMR (CDCl3): δ2.1 (m,2H), 2.5 (t,2H), 2.7 (t,4H), 3.6 (m,2H), 4.2 (m,2H), 4.4 (m,2H), 6.1 (s,1H), 7.8 (s,1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>C(#N)C.O>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(NCc2ccccc2)cc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(NCc2ccccc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-(benzylamino)benzoic acid (200 mg, 0.88 mmol) in acetonitrile (2 ml) was added piperidine (0.174 ml, 1.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (184 mg, 0.97 mmol), hydroxybenzotriazole hydrate (10 mg, catalytic) followed by triethylamine (0.31 ml, 2.2 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 ml) and extracted with dichloromethane (2×2 ml). The organic phases were combined, washed with brine, dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2) eluting with ethyl acetate/dichloromethane (1:4) to afford the title compound as an off white solid (122 mg, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:16]=[C:17]([N:23]4[CH2:28][CH2:27][S:26][CH2:25][CH2:24]4)[CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(F)n1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(N2CCSCC2)n1

Procedure:
The title compound, MS: m/e=395.1, 397.1 (M+H+), was prepared in accordance with the general method of example 27 from 2-[4-(3-chloro-phenylethynyl)-2-methylimidazol-1-yl]-6-fluoro-pyridine and thiomorpholine.