Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[CH:13][C:8]=2[O:7][C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:4].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].NC1C=CC=CC=1>ClCCl.O>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:14][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:13][C:8]=2[O:7][C:6]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC(C)C)cc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Temperature: 0 °C
Yield: 56 %

Procedure:
6-Amino-2-(4-fluoro-phenyl)-5-isopropoxy-benzofuran-3-carboxylic acid methylamide, prepared according to Example 16 (100 mg, 292 μmol) was dissolved in dry dichloromethane (3 mL) under an argon atmosphere. The reaction was cooled down to 0° C. with an ice bath. Pyridine (16.83 μL, 321 μmol) and methanesulfonyl chloride (22.61 μL, 292 μmol) were mixed together under argon, and then added dropwise to the first aniline solution. The reaction mixture was allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with a 1N HCl solution, water, a saturated aqueous bicarbonate solution and brine and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 20 to 50% ethyl acetate in hexanes gradient) to provide 68 mg (56%) of the product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[S:16][C:15]([CH2:17][CH3:18])=[N:14][C:13]=1[CH3:19])=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[CH2:17]([C:15]1[S:16][C:12]([CH2:10][OH:9])=[C:13]([CH3:19])[N:14]=1)[CH3:18]
Reactant: CCOC(=O)c1sc(CC)nc1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCc1nc(C)c(CO)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
Lithium aluminum hydride (800 mg, 21.2 mmol) was added to a solution of 2-ethyl-4-methylthiazole-5-carboxylic acid ethyl ester (Example 11; 1.63 g, 8.2 mmol) in diethyl ether (100 mL). The solution was allowed to stir at room temperature for 4 h and was then poured carefully into an aqueous potassium sodium tartrate solution (30% w/v; 200 mL). After the mixture was allowed to stir at room temperature for 1 h, the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-ethyl-4-methylthiazole-5-methanol (860 mg, 67% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:26])([CH2:15][N:16]1[CH:25]=[C:19]2[N:20]=[CH:21][C:22]([Br:24])=[CH:23][C:18]2=[N:17]1)[C:13]#[N:14]>C1COCC1>[Br:24][C:22]1[CH:21]=[N:20][C:19]2=[CH:25][N:16]([CH2:15][C:12]([NH:11][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:13]#[N:14])[CH3:26])[N:17]=[C:18]2[CH:23]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(Cl)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-chlorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=418, RT=0.56 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>N1C=CC=CC=1.P(Cl)(Cl)Cl.O>[C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:52](=[O:53])[CH2:51][CH2:50][S:49][CH2:48][CH:47]([O:46][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[CH:12][C:11]=1[F:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1F)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4-amino-2-fiuorobenzoylglutamic acid di-t-butyl ester (181 mg) in pyridine (2.3 ml), phosphorus trichloride (0.020 ml) was added, followed by stirring at room temperature for 2 hours. To this mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 24 (150 mg) was added, followed by stirring at room temperature for 24 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (205 mg, yield 87%) as a wax-like substance.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.C[O:24][B:25](OC)[O:26]C.[OH-].[Na+]>C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:7]([B:25]([OH:26])[OH:24])=[CH:8][C:9]3[O:13][CH2:12][O:11][C:10]=3[CH:14]=2)=[CH:17][CH:18]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(-c2cc3c(cc2Br)OCO3)cc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OB(O)c1cc2c(cc1-c1ccc(F)cc1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
Under nitrogen, 6.3 mL (15.8 mmol) of n-BuLi (2.5M in hexanes) was added to a stirred solution of 3.9 g (13.2 mmol) of 5-bromo-6-(4-fluorophenyl)-1,3-benzodioxole (Step 1) in 30 mL of anhydrous THF at -78° C. After 30 minutes, 4.5 mL (39.4 mmol) of trimethylborate was added. The reaction was warmed to ambient temperature and stirred for 3 hours prior to the addition of 60 mL of 5% NaOH. The reaction was stirred for an additional 60 minutes, the THF removed in vacuo, and the pH adjusted to ca. 4. The residue was dissolved in ethyl acetate; the resulting solution was dried over Na2S04 and concentrated in vacuo to give 1.7 g (50%) of [6 (4-fluorophenyl)-1,3-benzodioxol-5-yl] boronic acid as a pale yellow solid: NMR (CDCl3) δ 4.00 (br s, 2H), 6.06 (s, 2H), 6.75 (s, 1H), 7.08-7.17 (m, 2H), 7.26 (s, 1H), 7.31-7.39 (m, 2H).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:5])C.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C.O>ClCCl.CO>[CH3:5][C:4]1[N:6]=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[N:18]=1
Reactant: CCOC(C)=NC(=O)c1ccc(C)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reaction time: 8 h
Yield: 68 %

Procedure:
N-(1-ethoxy-ethylidene)-4-methyl-benzamide 429 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-(3-methyl-5-p-toly-[1,2,4]triazole-1-yl)-benzenesulfonamide (467 mg, yield: 68%) was obtained as a solid phase.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:24][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C:14]3=O)=[C:9]2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2].[Cl-:26].O>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[O:24][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[C:14]3[Cl:26])=[C:9]2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2]
Reactant: [Cl-]
Reactant: CCOC(=O)c1cc(=O)c2c3c(ccc2o1)C(=O)CC(C(=O)OC)=N3
Solvent: O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2c(ccc3c(Cl)cc(C(=O)OC)nc32)o1
Yield: 66 %

Procedure:
The product of step (b) (1.3 g, 3.79 mmole) and phosporyl chloride (0.69 ml) in dry dichloroethane (80 ml) were heated to reflux for 15 minutes. The reaction mixture was then cooled and treated with water. The mixture was extracted with dichloroethane, the organic layer was washed with water, dried, and evaporated to give a brown solid. This was dried in vacuo over P2O5 at 50° C. to give the sub-title compound (0.9 g; 66%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:17]=[C:16]4[N:18]([CH2:22]C5CCOCC5)[C:19](=[O:21])[NH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C[Sn](C)(C)C1C=CC(N2C=CC=N2)=CC=1.BrC1N=C2N([CH2:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)C(=O)NC2=NC=1>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:17]=[C:16]4[N:18]([CH2:22][CH2:55][CH:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)[C:19](=[O:21])[NH:20][C:15]4=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CC1CCOCC1
Reactant: O=c1[nH]c2ncc(-c3ccc(-n4cccn4)cc3)nc2n1CC1CCOCC1
Agent: C[Sn](C)(C)c1ccc(-n2cccn2)cc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(-c3ccc(-n4cccn4)cc3)nc2n1CCC1CCOCC1
Yield: 4 %

Procedure:
6-(4-(1H-Pyrazol-1-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 1-(4-(Trimethylstannyl)phenyl)-1H-pyrazole (300 mg, 0.97 mmol), 6-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 101.B) (304 mg, 0.97 mmol), dichlorobis(triphenylphosphine) palladium(II) (68 mg, 0.097 mmol) in DMF (15 mL) were reacted for 1.5 h at 90° C. The product was purified by reverse-phase semi-preparatory HPLC (10-60% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The desired fractions were concentrated and treated with aqueous 6N ammonium hydroxide (few drops). The volatiles were removed under reduced pressure, and the residue was taken up in water (2 mL), and the solid was filtered and rinsed with water to provide the title compound (14.5 mg, 4% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.57(s, 1H), 8.32 (d, J=8.8, 2H), 8.01 (d, J=8.8, 2H), 7.68 (s, 2H), 2.27-2.33 (m, 2H), 1.66-1.63 (m, 2H), 1.51-1.49 (m, 2H), 1.27 (m, 2H), 0.88-0.84 (m, 2H); MS (ESI) m/z 377.3 [M+1]+; mp 294-296° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:47])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]([O:36]CC4C=CC(OC)=CC=4)=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=3)=[CH:23][C:22]=2[F:46])=[CH:14][C:13]=1[C:48]([F:51])([F:50])[F:49])C1C=CC=CC=1>CO.[Pd]>[CH2:34]([O:33][C:31]1[C:30](=[O:36])[NH:29][CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([C:48]([F:50])([F:51])[F:49])[CH:14]=3)=[O:47])=[C:22]([F:46])[CH:23]=2)[CH:32]=1)[CH3:35]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCO)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A suspension of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.071 mmol) in MeOH (10 mL) was added to a solution of Pd/C (15.10 mg, 0.142 mmol) in MeOH (10 mL). The mixture was hydrogenated under a H2 atmosphere at 26° C. for 2 h. Then the solution was filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, basic condition) to yield a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide (26.17 mg, 0.053 mmol, 74.6% yield). TLC (DCM/MeOH=10/1, Rf=0.4): 1H NMR (400 MHz, CD3OD) δ 7.84-7.83 (m, 1H), 7.72-7.70 (d, J=8.8 Hz, 1H), 7.43-7.41 (m, 1H), 7.39-7.29 (m, 3H), 7.23-7.22 (d, J=2.0 Hz, 1H), 7.17-7.15 (d, J=9.2 Hz, 1H), 4.14-4.11 (m, 4H), 3.88-3.86 (m, 2H), 3.76 (s, 2H), 1.47-1.44 (t, J=7.0 Hz, 3H); ES-LCMS m/z 495.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[H][H]>C(O)C.[Pd]>[NH2:12][C:4]1[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]c(=O)oc12
Temperature: 45 °C
Yield: 94 %

Procedure:
107.5 g (1 mole) of 5-chloro-7-nitro-2(3H)-benzoxazolone prepared according to Example 1d was suspended in 1000 ml of ethanol. 9.25 g of Pd/C 5% and 50 ml of ethanol were added and the mixture was hydrogenated at 4 bar hydrogen pressure for four to six hours at 60-65° C. while vigorously stirring. When the hydrogenation was complete, the mixture was cooled to 45° C. and filtered over Hyflo®. The Hyflo® was washed twice with 175 ml of methanol. 500 ml of solvent was distilled off under reduced pressure at 50° C., followed by addition of 250 ml of water and removal of 300 ml of solvent was by distillation under reduced pressure at 50° C. The last procedure was repeated twice and finally 250 ml of water was added and 400 ml of solvent was distilled off. The resulting mixture was cooled to 0-5° C. in about one hour. The solid was filtered off, washed three times with 125 ml of cold water, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 94%.
Reaction SMILES: I[CH2:2][CH:3]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH2:4]1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[C:3]1([CH2:2][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: O=C(O)C1CCNCC1
Reactant: ICC1Cc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(CC2=Cc3ccccc32)CC1
Reaction time: 6 h

Procedure:
0.028 mole of 1-(iodomethyl)benzocyclobutene (Process 1, stage G}, 0.028 mole of 4-piperidinecarboxylic acid and 0.028 mole of triethylamine are mixed in 95 ml of dimethylformamide. The mixture is brought to 60° C. for 6 hours. It is evaporated to dryness, the residue is taken up with ethyl acetate and water and settling is allowed to take place.
Reaction SMILES: ClC1C=C(C=CC=1I)N.[C:10]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[C:20]([Cl:25])[CH:19]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].[Na+].Br[CH:29]([CH3:37])[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>CN(C=O)C.ClCCl>[CH2:33]([O:32][C:30](=[O:31])[C@H:29]([CH3:37])[N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][C:21]([I:24])=[C:20]([Cl:25])[CH:19]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(Cl)c1
Reactant: CC(C)COC(=O)C(C)Br
Agent: Nc1ccc(I)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)COC(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccc(I)c(Cl)c1
Temperature: 100 °C

Procedure:
Following General Procedure AR above and using 3-chloro-4-iodoaniline (Aldrich), N-BOC-3-chloro-4-iodoaniline was prepared. To a stirred slurry of 5.0 equivalents of sodium hydride in DMF was added 1.0 equivalent of N-BOC-3-chloro-4-iodoaniline and then 1.1 equivalents of iso-butyl 2-bromopropionate (from Example AD above) were slowly added. The reaction was heated to 100° C. for 10 hours, cooled, diluted with dichloromethane and washed with cold 1N HCl, water and brine. The solvents were removed at reduced pressure and the residue was chromatographed to provide N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester as a clear oil. Following General Procedure AN above, the BOC group was removed from N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester to provide the title compound. The BOC-removal reaction was monitored by tlc on silica gel (Rf=0.58 in 30% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 30% EtOAc/hexanes as the eluant). The compound was further purified by chromatography on an HPLC chiral column (Chiralcel OD).
Reaction SMILES: C([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]2)=[CH:11][CH:10]=1)=[O:7])(C)(C)C.[CH3:24]C(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>N1C=CC=CC=1.CCOC(C)=O>[CH3:24][N:8]([C:9]1[CH:14]=[CH:13][C:12]([B:15]2[O:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[O:19]2)=[CH:11][CH:10]=1)[C:6](=[O:7])[CH3:5]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(C)(C)CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 77 %

Procedure:
A mixture of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (100 mg, 0.429 mmol) in pyridine (1 mL) was added acetic anhydrate (1 mL) and stirred at room temperature for 23 hours. The mixture was diluted with AcOEt, washed with 1N HCl, brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated to afford the desired product (91 mg, 77%) as a dark brown solid. 1HNMR (CDCl3) 400 MHz δ: 7.85 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 3.27 (s, 3H), 1.88 (s, 3H), 1.35 (s, 12H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@@H:15]([O:32][CH2:33][CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[CH:19][C:18]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@@H:15]([O:32][CH2:33][CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd]
Product: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 1 d], (S)-4-benzyl-3-[(2S)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-propionyl]-oxazolidin-2-one was hydrogenated over 10% palladium on charcoal to give the title compound as yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[F:14][C:15]([F:35])([F:34])[C:16]1[C:25]([C:26](Cl)=[O:27])=[C:24]([OH:29])[C:23]2[C:18](=[CH:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][CH:22]=2)[N:17]=1>C(OCC)(=O)C>[F:34][C:15]([F:14])([F:35])[C:16]1[C:25]([C:26]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:27])=[C:24]([OH:29])[C:23]2[C:18](=[CH:19][C:20]([C:30]([F:33])([F:31])[F:32])=[CH:21][CH:22]=2)[N:17]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Yield: 37.6 %

Procedure:
A solution of 5.37 g of 2-amino-thiazole, 16.27 g of triethylamine and 214 ml of ethyl acetate were added with stirring over 25 minutes at 7° C. to a solution of 18.62 g of the product of Step F in 320 ml of ethyl acetate, and after the temperature returned to room temperature, the mixture was refluxed for one hour and cooled. The mixture was vacuum filtered and the filtrate was washed with water, dried and evaporated to dryness under reduced pressure at 40° C. The 19.22 gm of residue which was the triethylamine salt of the acid was taken up in 180 ml of 2 N sodium hydroxide solution and the mixture was refluxed for 3-4 minutes and was cooled. The mixture was vacuum filtered and the pH of the filtrate was adjusted to 1 by addition of 20% hydrochloric acid. The mixture was vacuum filtered and the recovered product was crystallized from acetic acid to obtain 8.22 g of 2,7-bis-(trifluoromethyl)-4-hydroxy-N-(2-thiazolyl)-3-quinolinecarboxamide melting at 270° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([B:19]4[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].C1(C)C=CC=CC=1.C(NC(C)C)(C)C.[Cl:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:52]=1[C:53](Cl)=[O:54]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:52]=1[C:53]([N:12]1[C:13]2=[N:14][CH:15]=[C:16]([B:19]3[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:24])([CH3:25])[O:23]3)[CH:17]=[C:18]2[C:10]([C:8]([C:7]2[C:2]([F:1])=[C:3]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32])[CH:4]=[CH:5][C:6]=2[F:28])=[O:9])=[CH:11]1)=[O:54]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (30, 2.1 g, 4.16 mmol), 21 mL of toluene, diisopropylamine (1.5 mL, 8.31 mmol), 4-dimethylaminopyridine (101 mg, 0.83 mmol) and 2,6-dichloro-benzoyl chloride (10, 0.7 mL, 4.78 mmol) are combined in a reaction flask under nitrogen. The reaction is stirred at room temperature for 17 hours, then diluted with 100 mL of ethyl acetate and extracted. The organic layer is washed sequentially with 40 mL of saturated aqueous sodium bicarbonate, 40 mL of water, and 40 mL of brine, then dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum and the resulting material is triturated with diethyl ether to provide the desired compound.