Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH2:14])=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(c2ccc(C(N)=O)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(CN)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To an ice cold solution of 4-(1-methylpiperidin-4-yl)benzamide (190 mg, 0.87 mmol) in tetrahydrofuran (5 mL) was added 1.0M lithium aluminum hydride in tetrahydrofuran (1.79 mL, 1.79 mmol) and stirring continued overnight at room temperature. The reaction mixture was quenched by adding sodium sulfate decahydrate until gas evolution ceased. The suspension was filtered through Celite and the filter cake washed with a mixture of ethyl acetate and chloroform (2:1, 50 mL). The filtrate was concentrated to give 4-(1-methylpiperidin-4-yl)benzylamine (130 mg, 71%) as an oil. 1H NMR (400 MHz, CDCl3): 7.23 (dd, 4H), 3.86 (s, 3H), 2.98 (m, 2H), 2.49 (m, 1H), 2.11 (m, 2H), 1.83 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41]O)[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:41][CH:37]2[CH2:38][CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:36]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(COc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
4-Fluorophenol (520 mg, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64 mmol) were added to a solution of N-boc-piperidine-3-methanol (500 mg, 2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixture was cooled to 0° C. and DEAD (673 μL, 3.71 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N, dried over Na2SO4 and concentrated. The residue was purified on column chromatography (eluent: pentane/EtOAc 95/5) to give the title compound (300 mg, 42%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.C(O)C.O>[CH3:23][O:22][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:20][C:19]=1[CH3:21]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: COc1ccc(Cl)nc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(-c2ccc(C(F)(F)F)nc2)nc1C
Temperature: 120 °C
Yield: 186.1 %

Procedure:
A 20 mL microwave vial was charged with 6-(trifluoromethyl)pyridin-3-ylboronic acid (666 mg, 3.49 mmol), 6-chloro-3-methoxy-2-methylpyridine (500 mg, 3.17 mmol), bis(triphenylphosphine)palladium(II) chloride (111 mg, 0.159 mmol), and K2CO3 (877 mg, 6.35 mmol), followed by the addition of DME (9.0 mL), water (3.86 mL) and ethanol (2.57 mL). The mixture was heated on the microwave at 120° C. for 10 minutes. To the reaction mixture was added 200 mL EtOAc, and washed with 200 mL water and 200 mL brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 40 g column, eluted with 0-40% EtOAc in Hexanes (25 mL/min) to provide the title compound (1.583 g, 5.90 mmol, 62.0% yield) as a white solid. MS (ESI+) m/z 269.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.37 (d, J=1.8, 1H), 8.64 (dd, J=8.3, 1.9, 1H), 8.03 (d, J=8.6, 1H), 7.97 (d, J=8.3, 1H), 7.50 (d, J=8.6, 1H), 3.90 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([CH:22]1[CH2:23][CH2:24][N:25]([C:28]([C:30]2[CH:31]=[C:32]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:5]([F:16])=[CH:4][N:3]=3)[CH:34]=[CH:35][CH:36]=2)=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc(N)c2)CC1
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)c2)CC1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted to provide N2-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.92 (d, 1H, J=3.6 Hz), 7.82 (s, 1H), 7.62 (td, 1H, J=1.2 and 8.4 Hz), 7.30 (t, 1H, J=8.4 Hz), 7.19–7.09 (m, 3H), 6.93 (d, 1H, J=7.5 Hz), 6.55 (td, 1H, J=1.2 and 7.5 Hz), 4.43 (bd, 1H, J=12.3 Hz), 4.13 (q, 2H, J=6.9 Hz), 3.7 (bd, 1H, J=11.7 Hz), 3.10–2.92 (m, 2H), 2.67–2.55 (m, 1H), 2.06–1.50 (m, 4H), 1.24 (t, H, J=6.9 Hz); 19F NMR (282 MHz, CD3OD): −47299; LCMS: purity: 99%; MS (m/e): 480(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[C:14]([O:24]CC)(=[O:23])[CH2:15][C:16]([C:18](OCC)=O)=O.[Na].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH3:13])[C:18]3=[CH:16][C:15]([C:14]([OH:24])=[O:23])=[N:10][N:9]3[C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CNc1ccc(N)cc1C(=O)NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: Cn1c2ccc(N)cc2c(=O)n2nc(C(=O)O)cc12
Temperature: 25 °C
Yield: 59 %

Procedure:
The procedure of Sircar, et al., (J. Med. Chem., 24:735-742 (1981)) was followed. A mixture of 5-amino-2-methylaminobenzoic acid hydrazide (35.05 g, 0.194 mol) and 95% diethyl oxalacetate, sodium salt (47.33 g, 0.214 mol, Aldrich Chemical Co.) in 1 L of water was refluxed for 2 hours. The dark solution was cooled to room temperature and sodium carbonate (22.68 g, 0.214 mol) was added. The solution was refluxed for 1 hour, then allowed to cool to room temperature overnight. A small amount of solid formed. The mixture was filtered through a pad of Celite, the filtrate was cooled and acidified by dropwise addition of 10% hydrochloric acid. At a pH of about 4, a solid formed, the mixture was filtered, and the yellow-green solid was washed with water and vacuum-dried to give 29.65 g (59%) of the title compound, mp 249°-252° C., dec.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>B(F)(F)F>[CH:2]1[C:6]2[C:6](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Agent: FB(F)F
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 400° C. in the presence of a HF.BF3 catalyst to obtain a pitch which had an optical anisotropy of 100%, a Mettler softening point of 250° C. and an elemental composition as analyzed of C: 94.8 wt % and H: 5.2 wt %. This pitch was finely pulverized. Then, pyridine (solubility parameter: 10.6) was added in an amount of 200 ml to 5 g of this pitch, and extraction was conducted at 100° C., followed by filtration with a 0.5 μm membrane filter to remove a pyridine-insoluble matter. Then, a solvent mixture of toluene/hexane=40 volume %/60 volume % (solubility parameter: 7.9) was added in an amount of 150 ml to 3 g of the soluble matter, and extraction was conducted at about 70° C., followed by filtration with a 0.5 μm membrane filter to remove a soluble matter. From the insoluble matter, the solvent was removed to obtain a spinning pitch. The pitch had ΔTg of 27° C. and Qi of not more than 1% by weight.
Reaction SMILES: [CH2:1]1O[CH:2]1[CH3:3].O[CH2:6][CH:7]([CH2:9]O)O>>[CH2:2]([C:1]1[CH:6]=[CH:7][C:1]([CH2:2][CH3:3])=[CH:6][C:7]=1[CH2:9][CH3:9])[CH3:3]
Reactant: CC1CO1
Reactant: OCC(O)CO
Product: CCc1ccc(CC)c(CC)c1

Procedure:
30 grams of the reaction product of glycerine with propylene oxide to a molecular weight of about 260.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
Following the procedure of N. I. Carruthers et al. (J. Med. Chem. 2005, 48, 1857-1872), to a −78° C. solution of 2-bromobenzotrifluoride (12.9 g, 7.8 mL, 57 mmol) in THF (225 mL) was added dropwise a solution of n-BuLi (2.5 M in hexanes, 26 mL, 65 mmol) over 10 min. After 1 h, the reaction mixture was stirred at 0° C. for 10 min, recooled to −78° C., and a solution of N-benzyl-4-piperidone (10.7 g, 57 mmol) in THF (40 mL) was added dropwise via addition funnel over 10 min. After 2 h at −78° C., sat. NH4Cl solution (200 mL) was added and the mixture was warmed to room temperature. The aqueous phase was extracted with EtOAc (2×200 mL). The organic phase washed with H2O (200 mL) and brine (150 mL), dried (MgSO4), and concentrated. Flash chromatography afforded the alcohol (2.7 g), a yellow oil, slightly contaminated with piperidone starting material, in ˜15% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5]>[Ru]>[CH3:1][CH:2]1[CH2:8][CH:7]([CH3:9])[CH2:6][CH:4]([NH2:5])[CH2:3]1
Reactant: Cc1cc(C)cc(N)c1
Agent: [Ru]
Product: CC1CC(C)CC(N)C1

Procedure:
N-cis, cis-3,5-Dimethylcyclohexyl-N-cyclopentyl amine is synthesized as shown in Scheme M. 3,5-Dimethylcyclohexyl amine is synthesized by catalytic hydrogenation of 3,5-dimethyl aniline for 7 to 24 hours. A suitable catalyst is 5% ruthenium on carbon. Hydrogenation pressure may change from 500 to 1500 psi and temperatures may range from 80° to 150°. N-cis cis-3,5-Dimethylcyclohexyl-N-cyclopentyl amine is formed by reductive amination of cyclpentanone with 3,5-dimethylcyclohexyl amine. The reductive amination may be carried out by hydrogenation using palladium on carbon as catalyst at pressures ranging from 15 to 90 psi. The temperature may range from room temperature to 50°. The reaction time is from 7 to 48 hours.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:43]=[CH:44][CH:45]=1
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 15 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 164B (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.033 g, 15%). 1H NMR (300 MHz, CDCl3) δ 9.5 (br, 1H), 8.63 (s, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.32-7.43 (m, 4H), 7.00 (dd, 1H), 6.31 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.91 (s and t, 5H), 3.50 (s, 3H); LC-MS (ESI) m/z 533 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1.[Cl-].N>CN(C)C=O>[CH3:17][S:16][C:12]1[N:13]=[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:15]=[CH:10][N:11]=1
Reactant: OCC(F)(F)F
Reactant: CSc1nccc(Cl)n1
Agent: N
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CSc1nccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
2,2,2-Trifluoroethanol (3.74 g) was dissolved in N,N-dimethylformamide (50 mL), sodium hydride (about 60% in oil) (1.37 g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 min. After ice-cooling again, 4-chloro-2-(methylthio)pyrimidine (5.0 g) was added, and the mixture was stirred at 0° C. for 1 hr. Saturated aqueous ammonia chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.1 g) as a slightly yellow oil.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]([O:13][CH3:14])[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=2[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:33]([NH2:35])=[O:34])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:11]([C:10]1[C:5]2[N:4]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:3]=[C:2]([C:28]3[CH:29]=[C:30]([C:33]([NH2:35])=[O:34])[S:31][CH:32]=3)[C:6]=2[C:7]([O:13][CH3:14])=[N:8][CH:9]=1)#[N:12]
Reactant: CC1(C)OB(c2csc(C(N)=O)c2)OC1(C)C
Reactant: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)cn2C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A mixture of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (400 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (553 mg) obtained in Step B of Example 33, (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (102 mg), 2M aqueous sodium carbonate solution (1.24 mL) and DME (3.5 mL) was stirred under microwave irradiation at 120° C. for 1 hr 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (310 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Zn](CC)CC.[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[CH:19]=[CH:18][C:17]=1I>CN1C(=O)N(C)CCC1.C1COCC1.Cl[Cu]>[CH3:25][C:20]1[C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=1[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1ccc(I)c(C)c1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: CC[Zn]CC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1ccc(C)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
A three-necked flask equipped with a thermometer, a gas inlet, and a magnetic stirring bar was charged under argon with MnBr2 (320 mg, 1.5 mmol) in DMPU (25 ml). CuCl (85 mg, 1 mmol), ethyl 4-bromobutyrate (5.85 g, 30 mmol) and Et2Zn (2.7 ml, 27 mmol) were successively added. The reaction mixture turned dark red and was stirred for 4 h at 25° C. After cooling to −30° C., a solution of Cl2Pd(dppf) (0.925 g, 10 mmol) and 2,4-dimethyl-3-nitroiodobenzene (6.93 g, 25 mmol) in anhydrous THF (25 ml) was slowly added. The reaction mixture was warmed to 25° C. for 30 min and was then stirred at 65° C. overnight and quenched with an aqueous 2N HCl solution (100 ml). This mixture was extracted with CH2Cl2 three times, and the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the crude residue obtained was purified by Biotage (hexane/EtOAc, 0-30%, 40 min) to give 4.5 g of yellow oily products (68%). 1H-NMR δ (CDCl3, 300 MHz): 7.13 (d, J=7.8 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.34 (t, J=7.8 Hz, 2H), 2.23 (s, 3H), 2.20 (s, 3H), 1.86 (m, J=7.8 Hz, 2H), 1.24 (t, J=7.8 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2].[SH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O.CO>[C:1]([NH:4][C:5]1[S:6][C:7]([S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ccncc1
Reactant: CC(=O)Nc1nc(CO)c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CO)c(Sc2ccncc2)s1
Temperature: 110 °C
Yield: 66.1 %

Procedure:
A mixture of 2-acetylamino-5-chloro-4-hydroxymethylthiazole (1 g), 4-mercaptopyridine (0.6 g) and potassium carbonate (1 g) in N,N-dimethylformamide (20 ml) was heated at 110° C. for 8 hours with stirring. The reaction mixture was poured into ice water and filtered by suction. The filtrate was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1) and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 75 g) and eluded with a mixture of chloroform and methanol (10:1l). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-4-hydroxymethyl-5-(4-pyridylthio)thiazole (0.90 g, yield: 64.3%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][F:32])[CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][F:32])[CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)NC(CC(=O)O)C(=O)CF
Yield: 72.2 %

Procedure:
A solution of N-[(1-methylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (19 mg, 0.041 mmol) and anisole (0.1 mL) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature. After 30 min the reaction mixture was concentrated and chased with methylene chloride. The crude residue was triturated with diethyl ether and the solid filtered to afford the title compound as a light brown solid (12 mg, 72% yield). TLC(AcOH:MeOH:CH2Cl2, 1:1:20): Rf=0.59. Mass Spectrum for C20H24FN3O5: [MH]+ 406, [MH]− 404.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:25][CH2:24][CH:19]([OH:20])[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: Clc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-6,7-dihydro-4H-spiro[1,3-benzoxazole-5,2′-[1,3]dioxolane] (12.5 g) in a mixed solvent of THF (60 mL)-methanol (30 mL)-water (30 mL) was added 6 M hydrochloric acid (34.5 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (1.31 g), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.63 g).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[CH:23]=2)=[O:20])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:30][N:28]([CH3:29])[C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:36][CH:35]=3)[CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
Using an analogous procedure to that described in the last paragraph of the portion of Example 1 which is concerned with the preparation of starting materials, a mixture of 3-(4-benzyloxybenzamido)-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.227 g), 10% palladium-on-carbon (0.028 g), ammonium formate (0.37 g) and methanol (20 ml) was stirred and heated to reflux for 1.5 hours. The mixture was cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was evaporated and the residue was triturated under water. The resultant solid was washed with a 100:1:0.12 mixture of methylene chloride, methanol and a saturated aqueous ammonium hydroxide solution and dried under vacuum at 55° C. There was thus obtained the title compound as a solid (0.104 g); NMR Spectrum: (DMSOd6) 2.26 (s, 3H), 2.84 (s, 6H), 6.44 (d, 1H), 6.84 (d, 2H), 7.13 (m, 3H), 7.39 (d, 1H), 7.76 (d, 1H), 7.86 (d, 2H), 7.92 (s, 1H), 9.73 (s, 1H), 9.91 (s, 1H); Mass Spectrum: M+H+ 391.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Combine 4-fluorophenylacetic acid (10.6 g, 68.8 mmol) and anhydrous methanol (100 mL). Add concentrated sulfuric acid (3 drops). Heat at 50° C. After 12 hours, cool to ambient temperature and evaporate most of the solvent in vacuo. Dilute the evaporated reaction mixture with ether, extract with aqueous saturated sodium bicarbonate solution and brine. Dry over MgSO4 filter and allow to stand until a solid forms. Collect the solid by filtration to give methyl 4-fluorophenylacetate which may be used without further purification.