Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br>CN(C=O)C>[CH3:17][O:18][C:19](=[O:22])[CH2:20][N:10]1[CH:9]=[C:8]([C:7]([CH3:14])([CH3:13])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[N:11]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn[nH]c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(C)(C)O[SiH2]C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1H-pyrazole (348 mg) was dissolved in DMF (12 mL) and cooled to 0° C. To this solution was added NaH (60% in mineral oil, 111 mg). The mixture was stirred at 0° C. for 30 minutes and then methylbromoacetate (0.23 mL) was added dropwise. The mixture was stirred at r.t. overnight. The reaction mixture was poured into ice/water and extracted with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=100:0 to 0:100) to give the title compound as a yellow oil (484 mg, 98%). MS (m/e)=285.0 [MH+].
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].O1CCCC1.CS(Cl)(=O)=O.Cl.[NH2:26][C:27]([CH3:35])([CH2:33][CH3:34])[C:28](=[O:32])[CH:29]([Cl:31])[Cl:30]>C(OCC)(=O)C.O.C(N(CC)CC)C>[Cl:30][CH:29]([Cl:31])[C:28](=[O:32])[C:27]([NH:26][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])=[CH:12][CH:11]=1)([CH2:33][CH3:34])[CH3:35]
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Reactant: CCC(C)(N)C(=O)C(Cl)Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(C(=O)NC(C)(CC)C(=O)C(Cl)Cl)cc1
Yield: 7.4 %

Procedure:
In a 250 mL three-necked, round-bottomed flask fitted with a mechanical stirrer nitrogen inlet and thermometer were placed 3 g of 4-diethylaminobenzoic acid, 60 mL of tetrahydrofuran and 6.4 g of triethylamine. To the resulting well-stirred mixture was added 1.3 mL methane sulfonyl chloride dropwise while keeping the reaction temperature at -30° C. The resulting suspension was stirred at -30° C. for 15 minutes, after which 3.76 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride were added slowly over a 60 minute period. After the addition was completed, the reaction mixture was stirred at -30° C. for an additional 45 minutes. The reaction mixture was poured into a mixture of 200 mL of water and 100 mL of ethyl acetate. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×60 mL). The combined organic phases were washed sequentially with water (1×60 mL), 3% aqueous hydrochloric acid (2×100 mL), brine (1×100 mL) and 3% aqueous sodium hydroxide (2×100 mL), and then dried over anhydrous magnesium sulfate. The solvent then was removed using a rotary evaporator, yielding 410 mg N-(3,3-dichloro-1-ethyl-1-methyl-2-oxopropyl)-4-diethylaminobenzamide.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:20])[CH3:18])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:30]([O:32]C)=O)[CH2:5]1)=[N+:2]=[N-:3].[Li+].[OH-].[C@H:36]1([NH2:46])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1>>[N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:20])[C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:18])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:30](=[O:32])[NH:46][C@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][CH2:38][CH2:37]2)[CH2:5]1)=[N+:2]=[N-:3]
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound of Example 2 was treated with LiOH using the general procedure C to hydrolyze the methyl ester. The resulting acid was coupled to (R)-tetrahydro-1-naphthylamine using the general procedure D to prepare the title compound of Example 3. 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: Cl[CH:2]([CH2:10][C:11]([Cl:17])([Cl:16])[C:12]([F:15])([F:14])[F:13])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[CH3:18]C(C)([O-])C.[Na+]>C(O)(C)(C)C.CN(C=O)C>[Cl:16][C:11]([Cl:17])([C:12]([F:15])([F:14])[F:13])[CH2:10][CH:2]1[CH:4]([C:5]([O:7][CH3:18])=[O:6])[C:3]1([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(CC(=O)O)C(Cl)CC(Cl)(Cl)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: COC(=O)C1C(CC(Cl)(Cl)C(F)(F)F)C1(C)C

Procedure:
The (−) enantiomer of the methyl ester of 4,6,6-trichloro-7,7,7-trifluoro-3,3-dimethylheptanoic acid (14.43 gm) was cyclised with sodium t-butoxide base (6.3 gm 100%) in t-butanol/DMF solvent at <0° C. to produce methyl 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl-cyclopropane carboxylate which was isolated by quenching with water and extracting into dichloromethane. After washing with water and brine the product was obtained as a yellow/orange oil (10.1 gm) by topping off the dichloromethane solvent. The product obtained was analysed by GLC, GCMS and NMR to confirm the material was consistent with that of methyl 3-(2,2-dichloro-3,3,3-trifluoropropyl)-2,2-dimethyl-cyclopropane carboxylate and it had a 80/20 cis:trans ratio.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([NH:30][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: NC1CCCCC1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)NC3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and cyclohexanamine. MS (ESI): mass calcd. for C23H23FN4O, 390.19; m/z found, 391.4 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.60-8.53 (m, 1H), 8.11 (d, J=1.5, 1H), 8.03-7.93 (m, 1H), 7.74-7.62 (m, 1H), 7.54-7.37 (m, 3H), 7.32 (dd, J=8.0, 1.7, 1H), 7.30-7.20 (m, 1H), 5.24 (d, J=8.3, 1H), 4.72 (s, 2H), 3.93-3.73 (m, 1H), 1.78-1.67 (m, 2H), 1.61-1.44 (m, 3H), 1.39-1.27 (m, 2H), 1.14-0.98 (m, 1H), 0.97-0.81 (m, 2H).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].C(OC(=O)[NH:18][C:19](=[NH:53])[C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(C)(C)C>>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[C:19]([C:20]1[S:21][C:22]([S:51][CH3:52])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)(=[NH:18])[NH2:53]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of dichloromethane/trifluoroacetic acid (1/1) [1 mL] was added to (imino-{4-[2′-(4-methanesulfonyl-butyrylamino)-6′-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (0.011 g, 0.017 mmol) [example 209, step b] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to give the title compound (0.004 g, 36%) as a solid. 1H-NMR (MeOD): δ 8.29 (s, 1H), 8.04 (md, 1H, J=6.4 Hz), 7.87 (t, 1H, J=2.0 Hz), 7.69 (t, 1H, J=7.6 Hz), 7.54 (md, 1H, J=7.6 Hz), 7.34 (t, 1H, J=7.6 Hz), 7.28 (d, 1H, J=7.2 Hz), 7.18 (d, 1H J=7.2 Hz), 2.91 (s, 3H), 2.78 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 2.18 (t, 2H, J=7.6 Hz), 2.07 (s, 3H), 1.74 (m, 2H). ESI-MS (m/z): Calcd. for C24H27N3O5S4: 566.1; found: 566.8.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1c(-c2cccc3sc(C(C)=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1c(-c2cccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:27]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30]>CN(C=O)C.CCOC(C)=O>[N:27]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)N[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O

Procedure:
Next, 1.34 g (2.5 m moles) of H-Phe-Arg(NO2)-CHA was dissolved in 10 ml of 0.75N-NEM/DMF, to this solution was added 0.84 g (2.5 m moles) of BOC-D-Pro-SDP at 0° to 5° C. and reacted at room temperature for 18 hours. After the reaction was completed, the reaction mixture was diluted with 150 ml of AcOEt, and washed 4 times with 50 ml of cold 5% hydrochloric acid, and washed twice with 50 ml of an aqueous solution saturated with sodium chloride, then decolored and dried with activated carbon and anhydrous magnesium sulfate. After drying, magnesium sulfate and activated carbon were removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure to obtain crude product of BOC-D-Pro-Phe-Arg(NO2)-CHA, recrystallized from AcOEt to obtain 1.2 g (85.9%) of BOC-D-Pro-Phe-Arg(NO2)-CHA.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([NH:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:10])=O)[CH3:2].N1C=CC=CC=1.S(Cl)(Cl)=O.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[N:8][N:7]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a solution of {N′-[3-(2-Fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-hydrazino}-oxo-acetic acid ethyl ester (1.27 g, 2.69 mmol, 1.0 eq.) in DCM (20 mL) containing pyridine (0.55 g, 6.99 mmol. 2.66 eq.) thionyl dichloride (0.26 mL, 3.5 mmol; 1.30 eq) was added at 0° C. The reaction mixture were stirred at 0° C. for 2 hrs. The solvent was evaporated, toluene was added and the reaction mixture was stirred at 110° C. for 6 hrs. Removal of the solvent resulted in a residue that was subjected to silica gel column chromatography (EtOAc:Hex=1:2) to afford the desired product (0.50 g). [5.32 min; 455 (M+1)]
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1>Cl.CC(C)=O>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1nccnc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(c2nccnc2F)CC1
Yield: 70.1 %

Procedure:
A solution of 2-fluoro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazine (91 g, 0.382 mol, 1.0 eq.) in 1N aqueous HCl (573 mL) and acetone (4 L) was heated to 37° C. overnight. The reaction mixture was cooled to room temperature and most of acetone was removed under reduced pressure. The crude material was diluted with EtOAc (4 L) and the solution was washed with aqueous saturated NaHCO3 (500 mL×2), water (500 mL), brine (500 mL), dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (100% hexanes to 50% EtOAc in hexanes, Rf=0.3 in 30% EtOAc in hexanes) to give 52 g (70% yield) of 4-(3-fluoropyrazin-2-yl)cyclohexanone. GC-MS: 195 (M+1); calcd for C10H11FN2O: 194.21
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[Br:13]NC(=O)CCC(N)=O>CN(C)C=O>[Br:13][C:11]1[C:2]([F:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2
Reactant: O=C1CCc2c(F)cccc2N1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Product: O=C1CCc2c(ccc(Br)c2F)N1
Reaction time: 8 h

Procedure:
To a stirred solution of 5-fluoro-3,4-dihydroquinolin-2(1H)-one (146-4; 0.45 g, 0.00272 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinamide (0.53 g, 0.0029 mol). Reaction mass was allowed to stir for overnight. Ice cold water was added to reaction mass. The solid separated was filtered and dried thoroughly to obtain the title compound. MS (M+1): 246.0.
Reaction SMILES: [O-:1]Cl=O.[Na+].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([CH2:21][CH3:22])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CS(C)=O>[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:1])=[O:18])=[C:15]([CH2:21][CH3:22])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCc1cc(OCc2ccccc2)ccc1C=O
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(OCc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous solution (750 ml) of 85 g of NaClO2 and 90 g of NaH2PO4 is added dropwise with cooling and stirring to 120 g of 4-benzyloxy-2-ethylbenzaldehyde, dissolved in 1 l of DMSO, during which the temperature should not rise above 35° C. The mixture is stirred at RT for a further 3 h, and the precipitate formed is filtered off with suction. The solid is then dissolved in 600 ml of EtOAc, dried and re-evaporated. The residue is crystallised from (Me2CH)2O, giving 4-benzyloxy-2-ethylbenzoic acid; yield 96.2 g (75%); m.p. 132-133°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].[OH-].[Na+].Cl>CO>[Br:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: COC(=O)/C=C/c1c(Br)nc(C)n1Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(Br)c(/C=C/C(=O)O)n1Cc1ccc(Cl)cc1Cl
Yield: 98.7 %

Procedure:
Methyl (E)-3-(4-bromo-1-(2,4-dichlorobenzyl)-2-methyl-imidazol-5-yl)-2-propenoate (800 mg) was dissolved in 20 ml of methanol, and then 20 ml of 1N sodium hydroxide was added to the solution. After being heated under reflux for 30 minutes, the solution was adjusted to an acidic pH with 1N hydrochloric acid under cooling with ice, and extracted with dichloromethane. The organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to yield 762 mg of white crystals of (E)-3-(4-bromo-1-(2,4-dichlorobenzyl)-2-methylimidazol-5-yl)-2-propenoic acid.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CC#N>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCC[C@H](O)CNc1ccc2c(c1)NC(=O)CS2
Temperature: 60 °C
Yield: 16 %

Procedure:
A mixture of (S)-tert-butyl-dimethyl-(3-oxiranyl-propoxy)-silane (28.3 g, prepared according to Org. Lett. (2005), 7, 3997) and 6-amino-4H-benzo[1,4]thiazin-3-one (23.6 g) in MeCN (390 mL) was treated with LiClO4 (41.8 g) and heated at 60° C. for 4 h. The volatiles were removed under reduced pressure and the residue partitioned between EA and brine. The org. phase was dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 1:1, EA) to give the desired intermediate as a yellowish foam (8.4 g; 16% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[CH3:32][NH:33][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:15]=2[O:14]1
Reactant: COc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Reactant: CN
Product: CNCC1Cc2cccc(-c3ccc(OC)cc3OC)c2O1

Procedure:
The title compound was prepared (0.272 g, 82%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.435 g, 0.987 mmol) and methylamine (0.306 g, 9.87 mmol). mp 185-188° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47]>O.ClCCl.C(N(CC)CC)C>[OH:49][C:42]1[C:41]([CH2:40][NH:39][C:14](=[O:16])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][N:12]=2)=[C:46]([CH3:47])[CH:45]=[C:44]([CH3:48])[N:43]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cn1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cn2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
A mixture of 5-phenoxypicolinic acid (83 mg, 0.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1 mmol), N-hydroxybenzotriazole (135 mg, 1 mmol), triethylamine (0.2 mL) and dichloromethane (5 mL) was stirred at 25° C. for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added to the mixture. The resultant mixture was stirred at 25° C. for 12 hours. Then water (20 ml) was added to the mixture and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-5-phenoxypicolinamide (Compound I-21) as a white solid (50 mg, 37%). LRMS (M+H+) m/z: calcd 349.15. found 349. HPLC purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.53 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 8.37-8.36 (m, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.48-7.42 (m, 3H), 7.26-7.16 (m, 3H), 5.86 (s, 1H), 4.32 (d, J=6.0 Hz, 2H), 2.22 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [OH-].[K+].C(O)(C)(C)C.[CH2:8]1[O:16][C:15]2[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=2[O:9]1.[Br:18][CH2:19][CH2:20][CH2:21]Br>O>[Br:18][CH2:19][CH2:20][CH2:21][O:17][C:12]1[CH:13]=[CH:14][C:15]2[O:16][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: BrCCCOc1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution prepared by dissolving 7.3 g of potassium hydroxide in 7 ml of water and then adding 120 ml of t-butanol are added 15 g of 3,4-methylenedioxyphenol and 88 g of 1,3-dibromopropane and the mixture is stirred for 3 hours under heating at reflux. After completion of the reaction, the solvent is distilled off and benzene is added and washed with water. The benzene layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is subjected to vacuum distillation to give 23 g of 5-(3-bromopropoxy)-1,3-benzodioxole boiling at 120° C./1 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:23]=[CH2:24].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:16]1([CH2:15][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2](/[CH:24]=[CH:23]/[CH2:22][NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:3]=2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(N(CC1CCCCC1)c1cccc(Br)c1)C(F)(F)F
Reactant: C=CCNC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC/C=C/c1cccc(N(CC2CCCCC2)C(=O)C(F)(F)F)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
N-(3-Bromophenyl)-N-(cyclohexylmethyl)-2,2,2-trifluoroacetamide (1.0 g, 2.74 mmol), N-allyl-2,2,2-trifluoroacetamide (0.5 g, 3.29 mmol), tri-O-tolylphosphine (0.08 g, 0.27 mmol) and triethylamine (2 mL, 13.7 mmol) was added to DMF and the mixture was flushed with argon for 15 min. Pd(OAc)2 (0.06 g, 0.27 mmol) was charged to the reaction mixture which was stirred at 90° C. for 2 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. Organic layer was washed thoroughly with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 5% to 10% EtOAc in hexane) gave (E)-N-(cyclohexylmethyl)-2,2,2-trifluoro-N-(3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)phenyl)acetamide 5 as a colorless semi solid. Yield (0.4 g, 33%); 1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (m, 2H), 7.18 (s, 1H), 7.13 (d, J=6.8 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.48 (bs, 1H), 6.24-6.16 (m, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.62 (bs, 2H), 1.73-1.65 (m, 5H), 1.56-1.48 (m, 1H), 1.21-1.14 (m, 3H), 1.07-0.99 (m, 2H).