Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[F:12][C:13]([F:31])([F:30])[C:14]1[CH:29]=[CH:28][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>C(#N)C.O>[F:12][C:13]([F:30])([F:31])[C:14]1[CH:29]=[CH:28][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:11])[CH2:6][CH2:5]4)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: FC(F)(F)c1ccc(COc2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: O=C1CCc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 305.5 %

Procedure:
5-Hydroxyindanone (1.0 g, 1.1 mmol) was dissolved in acetonitrile (40 mL) with 5E (1.8 g, 1.0 mmol) and Cs2CO3 (4.4 g, 2.2 mmol). The reaction mixture was stirred at RT for 3 h. Ether (25 mL) and water were added and the stirring was continued for another 5 min. The layers were separated and the aqueous layer was extracted with ether (2×20 mL). The combined organics was dried over MgSO4 and concentrated to a tan solid. The crude product was purified by column chromatography eluted with EtOAc and hexanes to give the desired product, compound 52A as a tan solid (1.26 g, 50%). MS m/z 413 (M+1). Step 2. Preparation of {5-[4-(4-Trifluoromethyl-benzyloxy)-benzyloxy]-indan-1-yl}-acetic acid ethyl ester (Compound 52B).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1.ClS([N:30]=[C:31]=[O:32])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]([C:31](=[O:32])[NH2:30])[CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C(N)=O)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 30.8 %

Procedure:
To a solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (5.04 grams, 14.80 mmol) in methylene chloride (150 mL) was added chlorosulfonylisocyanate (1.3 mL, 14.80 mmol) and the resulting solution was stirred for 5 days at room temperature. The solution was then concentrated in vacuo, and the crude product dissolved in a 6:1 ratio of acetone:water (180 mL). The pH of this solution was adjusted to approx. 8 by the addition of 2 M sodium hydroxide (aq). The resulting mixture was stirred, at room temperature, for 45 minutes. The reaction was diluted with water (300 mL) and the resulting suspension was stirred for 30 minutes. Filtration, followed by trituration of the solid in methanol gave 4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.75 grams). The filtrate was concentrated, and the crude chromatographed on silica gel (2.5% methanol/methylene chloride) to give additional 4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.36 grams, 37% yield overall).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1.C[OH:32]>O>[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:15][CH2:16][S:17](=[O:32])[CH2:18][CH2:19]1
Reactant: CO
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium metaperiodate (42 mg, 0.196 mmol) was dissolved in water (1 mL) and then cooled to 0° C. (ice bath). Next, the N-[[3-[3-fluoro-4-(4-thiomorpholinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (66 mg, 0.187 mmol) was added. Methanol (3 mL) was added to increase solubility. The reaction was stirred at 0° C. for an additional 4 hours under N2 before being stoppered and stored in the freezer (65 hours). The reaction was filtered through a medium-porosity sintered glass funnel, rinsing the flask and filter cake with CHCl3 (5 mL). The filtrate was transferred to a separatory funnel, the layers separated, and the water layer further extracted with more CHCl3 (3×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure to yield 80 mg of a gummy solid. The material was chromatographed on silica gel (10 g silica, packed with 10% CH3CN/CHCl3), eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3 to give 49 mg (71%) of the title compound as an off-white solid with a mp of 159°-161° C. and a HRMS (M+) calculated for C16H20N3O4FS 369.1158, found 369.1182.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1O)([CH2:18][OH:19])[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].OC1C=C2C(CCC2)=CC=1C1(CO)C2C(=CC=CC=2)N(CC(OCC)=O)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCC3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 1.45, and making non-critical variations using ethyl [4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace ethyl [3-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (41%): mp 133-134° C.; 1H NMR (300 MHz, CDCl3) δ 7.26-7.15 (m, 3 H), 6.78-6.58 (m, 2H), 5.08 (d, 1H), 4.91 (d, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 4.24 (q, 2H), 1.29 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.5, 166.8, 157.1, 143.7, 130.7, 129.0, 127.8, 120.0, 111.8, 111.6, 107.5, 99.8, 99.5, 62.2, 59.1, 41.7, 14.1; MS (ES+) m/z 438 (M+1), 440 (M+1), 460 (M+23), 462 (M+23).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:13][NH:14][C:15]([O:17][CH2:18]C)=[O:16])CO)=[CH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:18][O:17][C:15](=[O:16])[NH:14][N:13]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)NN=C(CO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NN=C(c2ccc(Cl)cc2)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in oil, 16 mmoles) is added, in small portions and at ambient temperature, to a solution of the compound obtained in Step B (100.5 mmoles) in ethanol (800 ml). After reacting for 2 hours, the reaction mixture is cooled to 0° C. and stirring is continued for 30 minutes. The precipitate formed is filtered off, washed with cold ethanol and then dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=c1ccc(O)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1ccc(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 5-hydroxypyridin-2(1H)-one (4.44 g, 40.0 mmol) in methanol (50 mL) was added potassium hydroxide (2.64 g, 40.0 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature, followed by the addition of benzyl bromide (5.2 mL, 44 mmol). The reaction mixture was kept stirring at ambient temperature for 2 hours and then heated at 45-50° C. for 1 hour. The solvent was removed in vacuo, and the residue was washed with water, dichloromethane and then recrystallized from methanol to afford the title compound (5.39 g, 67%): 1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.42-7.26 (m, 6H), 7.09 (d, J=3.0 Hz, 1H), 6.30 (d, J=9.6 Hz, 1H), 4.89 (s, 2H); MS (ES+) m/z 202.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[CH:22]=[CH2:23].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:23][CH:22]=[CH2:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCBr
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.150 g, 0.426 mmol) in dichloromethane (5 mL) was treated with allyl bromide (0.155 g, 1.28 mmol) and DBU (0.195 g, 1.28 mmol) and then stirred 2 hours at 20° C. The product mixture was diluted with EtOAc (50 mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.149 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.34 (s, 1H), 6.65 (m, 1H), 6.04 (m, 1H), 5.47 (d, J=17 Hz, 1H), 5.30 (d, J=9 Hz, 1H), 4.59 (s, 2H), 3.80 (m, 1H), 3.6-3.3 (m, 3H), 3.2-2.8 (m, 4H), 1.31 (m, 3H). MS calculated for C16H17BrF3NO2+H: 392, observed: 392.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:6]=12.CO.C1COCC1.[Cl-].[NH4+]>CCOC(C)=O.[Zn]>[NH2:22][C:20]1[CH:19]=[CH:18][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:11][CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:6]=23)=[C:2]([F:1])[CH:21]=1
Reactant: COC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of methyl 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (230 mg, 0.69 mmol) in a mixed solvent (10 mL of MeOH and 10 mL of THF) were added ammonium chloride (185 mg, 3.45 mmol) and zinc dust (226 mg, 3.45 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (50 ml), and filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give the desired product (207 mg, 100%) as a yellow solid. MS(ESI+) m/z 302.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:25]([C:24]([OH:27])=[O:26])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 0 °C

Procedure:
To 1.0 g of 3-(4-fluorophenyl)-1H-5-indazolecarbonitrile were added 5 ml of water, 4 ml of concentrated sulfuric acid and 4 ml of glacial acetic acid, and the mixture was heated under reflux for 3 hours. After standing to cool, 25 ml of ice-cooled water was added. The resulting crystals were collected by filtration. The collected crystals were dissolved in 250 ml of ethyl acetate, sequentially washed with water and brine, and dried over anhydrous magnesium sulfate. After filtrating the organic layer through a silica gel pat, the solvent was evaporated, to give 968 mg of the title compound as bright yellow crystals.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:34])[N:11]([CH3:33])[C:12]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:13][C:14]=1[C:15]1[O:19][N:18]=[C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:16]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH:28]1([C:12]2[N:11]([CH3:33])[C:10](=[O:34])[C:9]([OH:8])=[C:14]([C:15]3[O:19][N:18]=[C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[N:16]=3)[N:13]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cn1c(C2CCCC2)nc(-c2nc(Cc3ccc(F)cc3)no2)c(OCc2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C2CCCC2)nc(-c2nc(Cc3ccc(F)cc3)no2)c(O)c1=O
Yield: 92 %

Procedure:
A solution of 5-(benzyloxy)-2-cyclopentyl-6-(3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)-3-methylpyrimidin-4(3H)-one (0.248 g, 0.54 mmol) in TFA (5 mL) was stirred 4 h at room temperature. The resulting yellow reaction mixture was then concentrated and the residue was crystallized from EtOH/H2O to afford the title (0.184 g, 92% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ: 9.74 (1H, s), 7.30 (2H, dd, J=8.2, 5.5 Hz), 7.01 (2H, t, J=8.6 Hz), 4.15 (2H, s), 3.64 (3H, s), 3.21-3.15 (1H, m), 2.04-2.00 (4H, m), 1.89-1.82 (2H, m), 1.72-1.64 (2H, m). HRMS (M+H) calcd for C19H20N4O3F: 371.1520. found: 371.1535. Anal calcd for C19H19N4O3F: C, 61.61; H, 5.17; N, 15.12; F, 5.13. found: C, 61.92; H, 5.54; N, 14.87; F, 5.10.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31]([N:34]=[C:35]=[O:36])([CH3:33])[CH3:32]>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:35]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:36])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)N=C=O
Reactant: OCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: ClCCl
Product: CC(C)NC(=O)N(CCCCCO)CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 0 °C

Procedure:
Part D. A solution of the amine prepared in Part C above (2.92 g, 6.89 mmol) in methylene chloride (50 mL) was cooled to 0° C., and a solution of isopropylisocyanate (0.70 mL, 7.1 mmol) in methylene chloride (20 mL) was added dropwise. The mixture was allowed to stir and slowly warm over 18 hours, then was evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane) to afford the product, 1-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-(5-hydroxypentyl)-3-(1-methylethyl)-urea, as a low-melting solid (3.00 g, 5.90 mmol, 86%). 1H NMR (CDCl3): 11.34 (1H, br s); 7.60 (2H, br d, J=7 Hz); 7.48 (2H, br d, J =7 Hz); 7.38-7.20 (6H, m); 4.21 (1H, br d, J=6.6 Hz); 4.02 (1H, br s); 3.82 (1H, octet, J=6.6 Hz); 3.65 (2H, br t, J=7 Hz); 3.32 (2H, t, J=6.4 Hz); 3.12 (2H, t, J=7.5 Hz); 3.01 (2H, t, J=6.6 Hz); 1.81-1.36 (12H, m); 1.06 (6H, d, J=6.6 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[F:10][C:11]([F:20])([F:21])[O:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([O:12][C:11]([F:10])([F:20])[F:21])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2cccc(OC(F)(F)F)c2)nc1Nc1cccc(OC(F)(F)F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-trifluoromethoxyaniline were reacted to yield N2,N4-bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.03 (bd, 1H), 7.62 (bs, 2H), 7.48 (bd, 1H), 7.39 (t, 1H, J=8.1 Hz), 7.34 (m, 1H), 7.29 (t, 1H, J=7.5 Hz), 7.01 (m, 2H), 6.88 (m, 2H); 19F NMR (CDCl3): −16447 (s, 3F), −16459 (s, 3F), −46738 (s, IF); LCMS: ret. time: 33.77 min.; purity: 93%; MS (m/e): 449 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH2:15])[CH2:9]1)=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2N)C1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1C[C@@H](N)C[C@@H](F)C1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-bisfluorophenyl)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (50 mg). 1H NMR (500 MHz, DMSO) δ 9.25 (s, 1H), 8.18 (t, J=20.9 Hz, 1H), 7.64 (s, 2H), 7.53 (ddd, J=14.8, 8.4, 6.4 Hz, 2H), 7.26 (t, J=8.7 Hz, 2H), 7.12 (d, J=5.3 Hz, 1H), 4.94 (d, J=46.1 Hz, 1H), 3.05 (dd, J=32.9, 12.7 Hz, 2H), 2.66-2.34 (m, 3H), 2.07 (s, 1H), 1.53 (dt, J=23.8, 11.5 Hz, 1H). ESIMS m/z=449.1 (M+1).
Reaction SMILES: [OH-].[CH3:2][N+:3]1[N:4]([CH3:20])[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[C:24]([CH3:33])[CH:23]=1>O>[Cl:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([O-:30])=[O:29])=[C:24]([CH3:33])[CH:23]=1.[CH3:20][N+:4]1[N:3]([CH3:2])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(Cl)ccc1OCC(=O)O
Agent: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)ccc1OCC(=O)[O-]
Reaction time: 48 h

Procedure:
1,2-Dimethyl-3,5-diphenylpyrazolium hydroxide in a H2O solution was titrated with 4-chloro-2-methylphenoxyacetic acid (MCPA), a known herbicide until pH 7 was obtained and retained for 48 hours. MCPA was added as a solid and slowly dissolved. ##STR7## The H2O solution was evaporated to a low volume (oil) and toluene/acetone azeotroped several times. Hexane (5% acetone) was added and the oil solidified to a light yellow solid and was filtered, washed with hexane and dried. 6.5 Grams, melting point 138° C. to 140° C. of a light yellow solid was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]([CH3:25])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:14]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:30]1[CH:40]=[CH:39][C:33](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:26])[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:36](=[O:37])[CH:35]=[CH:34][C:33]3[CH:39]=[CH:40][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:20]2)[CH:14]=1)([CH3:11])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(/C=C/C(=O)O)cc1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1ccc(C=CC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 99 mg, 0.28 mmol) in 2 mL methylene chloride was added 4-isopropyl-trans-cinnamic acid (59 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) and allowed to stir 18 h at ambient temperature. The reaction was concentrated under reduced pressure and the resultant oil flash chromatographed with 30% ethyl acetate/hexanes to yield 89 mg (60%) of 2-(3-{1-[3-(4-Isopropyl-phenyl)-acryloyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester as a clear oil.
Reaction SMILES: [C:1](/[C:3](/[C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)#[N:2]>ClCCCl>[C:1](/[C:3](/[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:10]=1)#[N:2]
Reactant: COC(=O)c1ccc(/C=C(\C#N)c2ccc(OC)cc2)cc1
Solvent: ClCCCl
Product: COC(=O)c1ccc(/C=C(\C#N)c2ccc(O)cc2)cc1
Yield: 37.6 %

Procedure:
The procedure of Preparation Example 2 was repeated, except that 1.465 g of methyl 4-[(1Z)-2-cyano-2-(4-methoxyphenyl)vinyl]phenyl-carboxylate was used in place of 4′-methoxy-2-biphenylacetonitrile, and 1,2-dichloroethane was used in place of methylene chloride. The resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and tetrahydrofuran as the developing solvent) to obtain 524 mg of methyl 4-[(1Z)-2-cyano-2-(4-hydroxyphenyl)vinyl]phenylcarboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:15][C:16]1[CH:21]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (24 g, 112 mmol), 3-fluorophenol (5.6 g, 59 mmol) and triphenylphosphine (31.4 g, 118 mmol) in THF (100 ml) was added di-isopropylazodicarboxylate (23.3 ml, 118 mmol). The reaction was stirred at room temperature for 3 days and then the solvent removed in vacuo. The residue was diluted with DCM, hexane was added and the resultant white precipitate filtered off. The filtrate was concentrated in vacuo and purified by chromatography. Elution with DCM gave the title compound (16.4 g, 87% pure). δH (CDCl3, 250 MHz) 1.47 (9H, s), 1.76 (2H, m), 1.92 (2H, m), 3.35 (2H, ddd), 3.69 (2H, ddd), 4.44 (1H, m), 6.65 (3H, m), 7.20 (1H, m).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43]([OH:45])=O)=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29]([O:31]CC)=O)[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:45])[N:51]([C:50]3[CH:52]=[CH:53][C:47]([F:46])=[CH:48][CH:49]=3)[C:29](=[O:31])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(F)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 88 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (2.87 g, 4.49 mmol) and 4-fluoroaniline (0.64 ml, 6.735 mmol) gave the title compound (2.71 g, 88%) as pale yellow powders.