Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[OH:7][C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)CC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of 1,4-cyclohexanedione (6.72 g, 60 mmol) in THF (100 mL) cooled in an ice bath was added a 1 M solution of phenyl magnesium bromide in THF (20 mL, 20 mmol). The mixture was stirred at room temperature for 3 hours and quenched with an NH4Cl solution. The resulting solution was extracted with EtOAc three times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 1:1 EtOAc/hexanes yielded 0.83 g (22%) of the title compound. MS calculated (M+H)+ 190, found 173 (M+H−H2O)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][N:3]=1.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:24][C:22]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:24][CH3:22])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1ncncc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cncnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To the mixture of 4-aminopyrimidine-5-carboxylic acid (0.75 g, 5.39 mmol), methylamine hydrogen chloride (0.44 g, 1.2 eq), EDC (1.67 g, 1.5 eq), HOBt (0.87 g, 1.2 eq) in DMF (20 mL) was added DIEA (3.8 mL, 4.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 4-amino-N-methylpyrimidine-5-carboxamide (0.701 g, isolated yield 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:47]=[CH:46][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][N:34]4C(=O)C5=CC=CC=C5C4=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN.CO>C(O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][NH2:34])=[O:22])=[CH:46][CH:47]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCN)cc2)cc1
Yield: 98.5 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-phthalimidopropyloxy)phenyl]benzamide (545 mg) and hydrazine hydrate (0.212 ml) in ethanol (20 ml) was refluxed for 4 hours. After removal of insoluble material, the filtrate was evaporated in vacuo to give an oil and the oil was subjected to a silica gel column (5% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-aminopropyloxy)phenyl]benzamide (425 mg).
Reaction SMILES: [C:1]([N:8](C)[CH2:9][C:10]([C:12]1[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:14][CH:13]=1)=[O:11])(OC(C)(C)C)=O.[ClH:31]>O1CCOCC1>[ClH:31].[CH3:1][NH:8][CH2:9][C:10]([C:12]1[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:14][CH:13]=1)=[O:11]
Reactant: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate (7.26 g, 17.57 mmol) and 4 M HCl in 1,4-dioxane (150 mL) was stirred for 1 h at RT. Evaporation on the rotavap and trituration with Et2O afforded the title compound as a white powder (5.93 g, 97%): 1H NMR (250 MHz, CD3OD) δ 7.05-8.00 (m, 9 H), 5.23 (s, 2H), 4.88 (s, 2H), 4.65 (s, 2H), 2.80 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][C:22]3[CH:21]=[C:20]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:42])[O:33][CH2:34][C@H:35]5[CH2:39][O:38]C(C)(C)[O:36]5)[CH:26]=4)[CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][C:22]3[CH:21]=[C:20]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:42])[O:33][CH2:34][C@@H:35]([OH:36])[CH2:39][OH:38])[CH:26]=4)[CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC[C@H](COC(=O)Nc2cc(Oc3ccc4c(c3)CC(C(=O)Nc3cccc(C(C)(C)C)c3)CC4)ccn2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)OC[C@@H](O)CO)c4)cc3C2)c1
Temperature: 70 °C
Yield: 56.2 %

Procedure:
A mixture of [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl {4-[(7-{[(3-tert-butylphenyl)amino]carbonyl}-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]pyridin-2-yl}carbamate (290 mg, 0.50 mmol) and pTSA (87 mg, 0.50 mmol) in MeOH (10 mL) and water (1 mL) were heated at 70° C. for 56 h. The reaction mixture was concentrated; diluted with water, and extracted with EtOAc. The organic solutions were combined, washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (2S)-2,3-dihydroxypropyl {4-[(7-{[(3-tert-butylphenyl)amino]carbonyl}-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]pyridin-2-yl}carbamate (I-272) (150 mg, 55%) as a white solid. 1H NMR (400 MHz, CD3OD, HCl salt) δ: 9.86 (s, 1H), 8.21 (d, 1H), 7.65-7.62 (m; 1H), 7.43-7.38 (m, 1H), 7.31-7.20 (m, 2H), 7.17-7.14 (m, 1H), 7.11-7.06 (m, 1H), 7.04-6.97 (m, 2H), 6.70-6.67 (m, 1H), 4.40-4.25 (qq, 2H), 3.91-3.85 (m, 1H), 3.60-3.56 (m, 2H), 3.15-2.79 (m, 5H), 2.24-2.16 (m, 1H), 1.99-1.88 (m, 1H), and 1.31 (s, 9H). LCMS: (FA) ES+534.3, ES−532.6.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38](=N)[NH:39][NH2:40])[N:33]=1>ClCCl.C(O)CCC>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:38]([C:34]3[N:33]=[C:32]([CH3:31])[CH:37]=[CH:36][N:35]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1ccnc(C(=N)NN)n1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1ccnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(0.250 g, 0.859 mmol) was dissolved in dichloromethane (DCM) (2.147 ml) and triethyloxonium tetrafluoroborate (0.196 g, 1.031 mmol) was added. The solution was left to stir at room temperature under argon for 18 hours. 4-Methyl-2-pyrimidine carboximidohydrazide (I99) (0.156 g, 1.031 mmol) was dissolved in 1-butanol (2.147 ml) and this was added to the reaction mixture and this was left to stir under argon for a further 60 minutes. The dichloromethane was removed under reduced pressure and the reaction mixture was left at reflux for 4 hours. The solvent was removed under reduced pressure to afford a crude product of 0.690 g. The crude material was purified by flash chromatography (Biotage Isolera 4, 50 g cartridge) with a gradient of methanol 0-10% in Dichloromethane. The solvent was removed under reduced pressure to afford 0.223 g of material which was further purified using MDAP. The solvent was removed under reduced pressure to afford 0.090 g of crude material that was dissolved in methanol and loaded onto a 5 g SCX column. The column was washed with methanol and the desired compound was eluted off using 2M ammonia in methanol. The solvent was removed under reduced pressure to afford the purified product in 0.075 g.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH:20][CH:21]=[O:22])=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH:21]([NH:20][NH:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:1]([CH2:4][N:5]2[C:9](=[O:10])[CH2:8][S:7][C:6]2=[S:11])=[O:3])=[CH:14][CH:15]=1)=[O:22]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: Nc1ccc(NNC=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=CNNc1ccc(NC(=O)CN2C(=O)CSC2=S)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 1.91 g (10 millimole) of 3-carboxymethylrhodanine, 1.51 g (10 millimole) of 2-(4-aminophenyl)-1-formylhydrazine and 2.06 g (10 millimole) of N,N'-dicyclohexylcarbodiimide was added 50 ml of tetrahydrofuran. The resulting mixture was stirred for 5 hours at room temperature to precipitate crystals. These were filtered off, and dissolved in 50 ml of N,N-dimethylformamide (DMF). The matter remaining insoluble was removed from the solution. 100 ml of water was added to the filtrate, and allowed to stand for one night to precipitate crystals. These were filtered off, and washed with water and methanol. Thus, the intended compound was obtained. Yield, 2.98 g (92%). Melting Point, 260° C. (decomposed).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:5]=1[NH:6][CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:15])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1cc(OC)ccc1N
Product: CCOC(=O)c1c[nH]c2c(OCC)cc(OC)cc2c1=O
Yield: 75.7 %

Procedure:
2-Ethoxy-4-methoxyaniline (2.2 g) and diethyl ethoxymethylenemalonate (2.9 g) were reacted in the same manner as in Experimental Example 1 to give 8-ethoxy-3-ethoxycarbonyl-6-methoxy-4(1H)-quinolone (2.9 g). The compound (1.5 g) was N-ethylated with potassium carbonate (2.1 g) and ethyl iodide (4.0 g) in the same manner as in Experimental Example 9 to give 8-ethoxy-3-ethoxycarbonyl-1-ethyl-6-methoxy-4(1H)-quinolone (compound 78, 1.3 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=3[F:20])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:1][CH2:2][CH2:3][O:4]3)[CH2:6][CH2:7]2)=[C:12]([F:20])[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCC3(CC2)OCCO3)c(F)c1

Procedure:
4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)-3-fluoronitrobenzene (24.48 g, 0.087 M) was dissolved in ethyl acetate (500 ml) treated with palladium catalyst (10% on carbon, 5 g) and hydrogenated at atmospheric pressure until the theoretical uptake of gas. After filtration through celite and evaporation, the required product was obtained as a pink solid of sufficient quality for use without purification (19.3 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:31])[N:19]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[CH2:20][C@H:13]12.C(N(CC)CC)C>C(Cl)Cl>[O:31]=[C:18]1[N:14]2[CH2:15][CH2:16][CH2:17][C:12](=[O:11])[C@H:13]2[CH2:20][N:19]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=1[CH3:30]
Reactant: Cc1c(N2C[C@@H]3[C@H](O)CCCN3C2=O)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(N2C[C@@H]3C(=O)CCCN3C2=O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
A mixture of oxalyl chloride (94 μL, 0.19 mmol) in DCM (50 μL) was cooled to −78° C. and a solution of DMSO (26 μL, 0.37 mmol) in DCM (0.7 mL) was added. The resulting mixture was stirred at −78° C. for 15 min. A solution of 4-[(8R,8aR)-8-hydroxy-3-oxohexahydroimidazo[1,5-a]pyridin-2-yl]-2-chloro-3-methylbenzonitrile (77J) (16 mg, 0.052 mmol) in DCM (0.5 mL) was followed by DCM (0.5 mL) and stirred at −78° C. for 30 min. Triethylamine (120 μL, 0.86 mmol) was added and gradually warmed to rt over 1 h. The solvent was removed and the residue was purified by flash chromatography (silica gel, 30-50% EtOAc/hexane) to give the title compound 78A (12.9 mg) as a white solid: Chiral analytical HPLC (ChiralPak AD OD 4.6×250 mm, 35% IPA/hexane isocratic) retention time 13.8 min (100% ee); MS (ES) m/z 304.1 [M+1]+; HRMS calcd for C15H13ClN3O2 302.0696, Found 302.0681.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:34][C@H:33]([CH2:35][N:36]=[N+]=[N-])[O:32][C:31]3=[O:39])=[CH:26][C:25]=2[F:40])C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41](OCC)(=[O:43])[CH3:42]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:34][C@H:33]([CH2:35][NH:36][C:41](=[O:43])[CH3:42])[O:32][C:31]3=[O:39])=[CH:26][C:25]=2[F:40])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CC(=O)NC[C@H]1CN(c2ccc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(F)c2)C(=O)O1

Procedure:
To a stirred solution of 4.2 g of (3R)-3-{[4-{(5R)-5-azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-benzyl-oxycarbonyl-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (7.3 mmol) in 50 ml ethyl acetate were added 400 mg of Pd/C 10% and the mixture was stirred under hydrogen over night. The reaction was controlled by TLC. The Pd/C was filtered, the filtrate evaporated to dryness. The residue was dissolved in 5 ml acetic acid and 2 ml acetic anhydride was added. The reaction was stirred at rt for 2 hrs and monitored by TLC. The solvents were evaporated, the residue dissolved in ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated to dryness.
Reaction SMILES: CNC[C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.BrC1C=CC=CC=1CBr.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:6]1[C:5]2[C:10](=[CH:11][C:12]3[C:17]([CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1
Reactant: CNCc1c2ccccc2cc2ccccc12
Agent: BrCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2cc3ccccc3cc2c1
Yield: 95 %

Procedure:
A solution of 9-((methylamino)methyl)anthracene (1.00 g, 4.5 mmol), 2-bromobenzyl bromide (1.13 g, 4.5 mmol) and K2CO3 (0.691 g, 5.0 mmol) in 50 mL of acetonitrile was refluxed under nitrogen for 18 hr. The solution was filtered on a sintered-glass filter and solvent was removed from the filtrate under reduced pressure to yield 9-(N-Methyl-N-(o-bromobenzyl)amino)methyl)anthracene (95% by NMR). The resulting solid was taken up in diethyl ether (50 mL), and treated at 0° C. with 1 equiv of butyllithium. The mixture was stirred at 0° C. for 2 h at which time 5 equiv of trimethyborate was added via a cannula. After warming the mixture to room temperature, 50 mL of water was added to quench the reaction. The ether layer was separated, washed with 3×10 mL water, and dried over sodium sulfate. Removal of the solvent under reduced pressure provided a solid identical to that obtained in (A) in 52% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][NH2:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].[F:14][C:15]([F:33])([F:32])[C:16]([N:18]([CH2:25][P:26]([O:30]Cl)([O:28]Cl)=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17]>O1CCCC1>[F:14][C:15]([F:33])([F:32])[C:16]([N:18]([CH2:25][P:26]([O:30][NH:9][NH:8][C:7]1[C:6]([F:10])=[C:5]([F:11])[C:4]([F:12])=[C:3]([F:13])[C:2]=1[F:1])([O:28][NH:9][NH:8][C:7]1[C:2]([F:1])=[C:3]([F:13])[C:4]([F:12])=[C:5]([F:11])[C:6]=1[F:10])=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17]
Reactant: NNc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CN(CP(=O)(ONNc1c(F)c(F)c(F)c(F)c1F)ONNc1c(F)c(F)c(F)c(F)c1F)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of pentafluorophenylhydrazine (3.96 g, 0.02 mole) in 40 ml. of tetrahydrofuran at 0° C. was added over 1/2 hour ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (1.65 g, 0.005 mole) in 40 ml. of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stir for 2 hours, then filtered. The filtrate was washed with water, dried, and concentrated in vacuo to yield a dark red-brown solid. This solid was washed several times with 70% ether in petroleum ether to yield ethyl N-trifluoroacetyl-N-(bis(pentafluorophenylhydrazino)phosphonomethyl)glycinate, m.p. 100°-110° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:6]=1)=[O:4].[OH-].[Na+].Cl>O>[Cl:20][C:16]1[CH:15]=[C:14]([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=2[CH:11]2[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
6-(3-Chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester (80 mg, 0.28 mmol) and sodium hydroxide (CAN 1310-73-2, 30 mg,) was added into water (10 mL). The mixture was stirred for 2 h at ambient temperature. Subsequently the pH was adjusted to 3 with 1M hydrochloric acid, the mixture extracted with ethyl acetate (3×10 mL), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give product (60 mg, 78%); MS (EI): m/e 274.1 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]1[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=3)=[CH:18][N:19]=1)[CH:9]=[CH:8]2)(=O)C.[OH-].[K+].Cl>C(O)C>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]1[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=3)=[CH:18][N:19]=1)[CH:9]=[CH:8]2
Reactant: CCCCCCc1ccc(-c2cnc(-c3ccc4cc(OC(C)=O)ccc4c3)s2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCc1ccc(-c2cnc(-c3ccc4cc(O)ccc4c3)s2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Then, in a 300 ml-reaction vessel, 10.4 g (2.42×10-2M) of 2-(6-acetoxy-2-naphthyl)-5-(4-hexylphenyl)-thiazole and 170 ml of 0.5N-solution of potassium hydroxide in ethanol, followed by stirring for 0.5 hour at 60° C. After cooling, the reaction mixture was poured into 400 ml of ice water and acidified with 6N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in ethanol, followed by treatment with activated carbon. The activated carbon was removed from the above mixture by filtration and the filtrate was condensed, followed by drying to provide a residue. The residue was recrystallized from ethanol to obtain 7.73 g of 2-(6-hydroxy-2-naphthyl)-5-(4-hexylphenyl)thiazole (Yield: 82.6%).
Reaction SMILES: [CH2:1]([O:3][Si:4]([CH:11]([Li])[Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[Br:23]Br>>[CH2:1]([O:3][Si:4]([CH:11]([Br:23])[Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: [Li]C([Si](OCC)(OCC)OCC)[Si](OCC)(OCC)OCC
Reactant: BrBr
Product: CCO[Si](OCC)(OCC)C(Br)[Si](OCC)(OCC)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To the lithiated carbanion solution prepared in Example 1 above, a slight excess of bromine (1.5 g, 9.4 mmol) at −78° C. was added. The solution was stirred at −78° C. for 30 minutes and then at RT for 2 hrs. The solvent was pumped off and the product was further extracted with dry pentane. The residue was distilled under vacuum resulting in bis(triethoxysilyl)methylbromide (86% yield): boiling point 144–148° C. at 0.04 mm Hg; 1H NMR (300 MHz, CDCl3) δ 0.55–0.58 (t, 1 H, CHSi), δ 1.18–1.23 (q,18H, CH3) δ 2.89–2.92 (d, 2H, CH2Ph), δ 3.78–3.82 (t, 12H, CH2O), δ 7.17–7.20 (d, 2H, ArH), δ 7.36–7.39 (d, 2H, ArH); 13C NMR (75.48 MHz, CDCl3) δ 10.80 (CHSi), δ 18.46 (CH3), δ 29.47 (CHPh), δ 58.66 (CH2O), δ 130.84, 131.10 (CH aromatic); EI-MS (m/z) 508 (5%, M+), 464 (100%, [M+−44]).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1>CCO.CO.[Pd]>[CH3:16][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccncn2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.7 %

Procedure:
To a solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (100 mg, 0.186 mmol) and TEA (52 μL, 0.371 mmol) in EtOH (5 mL) and MeOH (1 mL) was added 10% (w/w) palladium on carbon (50 mg, 0.048 mmol). The suspension was transferred to a hydrogenation bottle, and installed in a Fisher-Porter hydrogenation apparatus. The bottle was charged with H2 (50 psi) and stirred at rt for 72 h. The reaction mixture was filtered through Celite and concentrated to generate 90 mg (0.178 mmol, 96%) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.10 (s, 1H), 8.60 (d, J=5.3 Hz, 1H), 7.53-7.57 (m, 1H), 7.40-7.50 (m, 4H), 7.30 (t, J=7.6 Hz, 1H), 6.89 (d, J=5.3 Hz, 1H), 1.43 (s, 9H). MS (ESI): 504.6 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=2[N:25]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:30][C:27]2[CH:28]=[CH:29][C:23]3[S:22][C:21]([CH3:20])=[N:25][C:24]=3[CH:26]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Cc1nc2cc(O)ccc2s1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3sc(C)nc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-methyl-benzothiazol-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a yellow oil.