Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:26]([O-:28])=[O:27])[CH:2]=C.[O:29]=[O+][O-].O=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[O:29])=[C:5]([N+:26]([O-:28])=[O:27])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(CC=O)c3O2)cc1
Reaction time: 24 h

Procedure:
A solution of 4.2 g (10 mmole) of toluene-4-sulfonic acid (2R)-8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester in 400 mL of methylene chloride was cooled in a dry ice/isopropanol bath and saturated with ozone. It was then purged with oxygen and 2.6 g (20 mmole) of diisopropylethylamine added. The mixture was allowed to come to room temperature and stirred under nitrogen for 24 hours. It was then washed with 300 mL portions of 2 N HCl (aq), water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 3.8 g of the (R)-enantiomer of the title compound as a white solid one-quarter hydrate, m.p. 116-120° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH2:10]([O:12][C:13](=[O:19])[C:14](OCC)=[O:15])[CH3:11].CC[O-].[Na+]>>[CH2:10]([O:12][C:13](=[O:19])[C:14](=[O:15])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:9])[CH3:1])[CH3:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCCC(C)C
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCCC(C)C
Temperature: 25 °C
Yield: 46.8 %

Procedure:
6-Methyl-2-heptanone (0.9981 g, 7.80 mmol) and diethyloxalate (1.06 mL, 7.80 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 2.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 16. The crude material was purified with 1:1 Hexanes: CH2Cl2 to obtain 0.8342 g (46.9%) of 16. 1H (CD3OD, 400 MHz): δ 6.36 (1H, s), 4.30 (2H, q, J=7.1 Hz), 2.50 (2H, t, J=7.3 Hz), 1.68-1.59 (2H, m), 1.61-1.50 (1H, m), 1.33 (3H, t, J=7.1 Hz), 1.25-1.17 (2H, m), 0.89 (6H, d, J=7.0 Hz) ppm. 13C (CD3OD, 100 MHz): δ 204.41, 166.93, 163.28, 102.66, 63.29, 41.89, 39.41, 28.92, 23.65, 22.89, 14.33 ppm.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[F:45]>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:38][C:37]=1[F:45]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-chloro-3-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88-0.99 (m, 6H), 1.58 (dt, J=13.21, 6.60 Hz, 1H), 1.77 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 2.07 (ddd, J=13.57, 7.83, 7.70 Hz, 1H), 3.82 (t, J=7.83 Hz, 1H), 7.33-7.43 (m, 2H), 7.45-7.50 (m, 1H), 7.52-7.58 (m, 2H), 7.61-7.69 (m, 1H), 7.71 (s, 4H); Calcd for C25H21ClF4O2 (M+H) 465.88, Found 465.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:27][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCN
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: Cc1ccccc1
Product: CCCCCCCNC1=C(C(=O)OCC)CN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1-tert-butoxycarbonyl-3-ethoxycarbonyl-piperidin-4-one (prepared from 3-ethoxycarbonyl-piperidin-4-one and di-tert-butyl-dicarbonate in dichloromethane and triethylamine) (8.5 g) and heptylamine (3.61 g) in toluene (100 ml) was heated under reflux in a Dean and Stark apparatus for 18 hours and then evaporated to dryness to give an oil.
Reaction SMILES: Br[C:2]1C=C(Br)C=C(Br)C=1OS(C1C(C)=CC=CC=1)(=O)=O.[C:21]1(C)[C:22]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>>[C:25]1([CH3:2])[CH:26]=[CH:21][C:22]([S:27]([Cl:30])(=[O:28])=[O:29])=[CH:23][CH:24]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1ccccc1S(=O)(=O)Oc1c(Br)cc(Br)cc1Br
Product: Cc1ccc(S(=O)(=O)Cl)cc1

Procedure:
In the same manner the o-toluenesulfonic acid-2,4,6-tribromophenyl ester can be obtained by using o-toluenesulfonyl chloride in the same molar amount instead of the para compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[Li+].[OH-:16]>C1COCC1.CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]=[CH:7][C:5]([O:6][CH2:2][CH3:1])=[O:16]
Reactant: Cc1oc(-c2ccccc2)nc1C=O
Reactant: [OH-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
5-Methyl-2-phenyloxazole-4-carbaldehyde [Hulin, et al., J. Med. Chem. (1992) 35(10), 1853-64] (5.62 g, 30 mmol), triethylphosphonoacetate (6.55 mL, 33 mmol), and LiOH (1.38 g, 33 mmol) were dissolved in anhydrous THF (150 mL) and stirred for 18 h at ambient temperature under an atmosphere of nitrogen. The reaction mixture was then diluted with ether (100 mL) and washed with saturated NH4Cl solution (100 mL), then water (100 mL). The aqueous layers were back-extracted with ether (100 mL) and the combined organic layers were again washed with water (100 mL). The ether layer was dried over MgSO4 and concentrated. The resultant residual solids were purified by column chromatography (250 mg silica, 100% hexanes to 10% EtOAc/hexanes) to provide a white crystalline solid (3.46 g, 45%): Rf=0.55 (50% hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.97-8.05 (m, 2H), 7.50 (d, 1H), 7.40-7.44 (m, 3H), 6.63 (d, 2H) 4.26 (q, 2H), 2.43 (s, 3H), 1.33 (t, 3H); MS(EI): 258 (M+1).
Reaction SMILES: CCN(CC)CC.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].[Cl:13][C:14]1[N:22]=[C:21](I)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:24]>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[N:22]=[C:21]([C:11]#[C:10][CH2:9][CH2:8][OH:12])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH3:24]
Reactant: C#CCCO
Reactant: Cn1cnc2c(Cl)nc(I)nc21
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1cnc2c(Cl)nc(C#CCCO)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NEt3 (4.9 ml, 34.5 mmol) and but-3-yn-1-ol (1.1 ml, 25.63 mmol) were added to a solution of 6-chloro-2-iodo-9-methyl-9H-purine (6.8 g, 23.3 mmol), CuI (454 mg, 2.23 mmol) and bis-triphenylphosphine palladium dichloride (811 mg, 1.15 mmol) in dioxane (93 ml). The reaction mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. Water (50 ml) was added to the dark residue obtained. The aqueous phase was extracted with DCM (3×100 ml). The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH: 94/6) to give an off-white precipitate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38](=O)[O:39]C(C)=C)[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1>O1CCOCC1.CN1CCCC1.CS(C)=O>[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38]([NH:6][C:5]4[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH2:9][N:10]5[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]5)[CH:4]=4)=[O:39])[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N)cc3n(CC)c2=O)c(C)cc1F
Reactant: CN1CCN(Cc2cc(N)ccc2F)CC1
Agent: CN1CCCC1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCN(C)CC4)c3)c(F)cc2C)cc2cnc(N)cc21
Temperature: 80 °C
Yield: 21.9 %

Procedure:
A mixture of Example D2 (0.100 g, 0.448 mmol) and prop-1-en-2-yl (5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.142 g, 0.358 mmol) in dioxane (3 mL) was treated with 1-methylpyrrolidine (3 drops) and heated at 80° C. overnight. The mixture was treated with DMSO (2 drops) and heated at 80° C. for an additional 24 h. The mixture was cooled to RT, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (44 mg, 22% yield). 1H NMR (400 MHz, pyridine-d5): δ 9.87 (s, 1H), 8.89 (s, 1H), 8.71 (m, 1H), 8.60 (s, 1H), 7.97 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (dt, J=8.7, 3.6 Hz, 1H), 7.64 (s, 1H), 7.26 (s, 2H), 7.15 (t, J=9.2 Hz, 1H), 7.07 (d, J=12.0 Hz, 1H), 6.56 (s, 1H), 4.17 (q, J 7.1 Hz, 2H), 3.58 (s, 2H), 2.53 (s, 4H), 2.30 (m, 7H), 2.13 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 562.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-isoleucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.15 in 97:3 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[C:15]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=2)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccccc1)N1CCNCC1
Product: CC(=O)Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Yield: 98.7 %

Procedure:
A solution of 5-bromo-2-nitrobenzenamine (0.5 g, 2.3 mmol), acetyl chloride (0.18 ml, 2.5 mmol) and potassium carbonate (0.64 g, 4.6 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. Crude N-(5-bromo-2-nitrophenyl)acetamide (0.40 g, 70%) was obtained after removing of the solvents. A solution of N-(5-bromo-2-nitrophenyl)acetamide (0.3 g, 1.1 mmol) and benzoyl piperazine (0.44 g, 2.3 mml) was stirred at 105° C. under argon atmosphere for 16 hours. The reaction was quenched with 500 ml water and extracted with ethyl acetate (2×10 ml). N-(5-(4-benzoylpiperazin-1-yl)-2-nitrophenyl)acetamide (0.4 g, 93%) was obtained after flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.31 (s, 3H), 3.40-3.57 (m, 8H), 6.56 (dd, J=2.8, 9.7 Hz, 1H), 7.48 (m, 5H), 8.21 (d, J=9.7 Hz, 1H), 8.38 (d, J=9.7 Hz, 1H), 11.0 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 26.4, 47.1, 47.3, 61.4, 103.8, 108.5, 127.2, 127.6, 129.0, 129.1, 130.7, 135.5, 138.3, 155.7, 170.1, 171.1
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36]C)=[O:35]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][CH2:33][C:34]([OH:36])=[O:35])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Product: O=C(O)COc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and methyl bromoacetate, in substantially the same manner, as described in Example 2 step g , and was obtained as an off-white solid, mp 183-185° C.; MS m/e 606 (M+);
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:26]([C:32](Cl)=[O:33])=[C:25]([CH3:35])[C:24]([N+:36]([O-:38])=[O:37])=[CH:23][C:22]=2[N:21]=1>O1CCCC1>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:32]([C:26]1[C:27]2[N:28]=[C:29]([O:30][CH3:31])[C:20]([O:19][CH3:18])=[N:21][C:22]=2[CH:23]=[C:24]([N+:36]([O-:38])=[O:37])[C:25]=1[CH3:35])=[O:33])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCC(=O)OC(C)(C)C)c2nc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of glycine tert-butyl ester hydrochloride 104 mg (0.67 mmol) and triethylamine in 3 mL anhydrous tetrahydrofuran 0.26 mL (1.69 mmol) under an atmosphere of nitrogen was added dropwise a solution of 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) in 7 mL anhydrous tetrahydrofuran at 0° C. After the addition was complete (approximately 5 minutes), the reaction mixture was stirred at room temperature for 24 hours, filtered, and concentrated. The residue was taken up in ethyl acetate and the organic solution was washed with water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude product was purified by elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes/ethyl acetate) to give a yellow oil which crystallized on standing, 200 mg (77%), mp 125-126° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H, 8-H), 6.32 (br s, 1H, amide NH), 4.14 (d, 2H, J=5.1 Hz), 4.09 (s, 3H), 3.99 (s, 3H), 2.54 (s, 3H), 1.47 (s, 9H, tert-butyl protons); MS (APCI): m/z 407 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[I:23]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([I:23])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)ccc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(I)c1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(3-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (27 mL) and methanol (3 mL), and N-iodosuccinimide (1.79 g) and trifluoromethanesulfonic acid (5 droplets) was added to the solution, and then the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (1.30 g) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:15][CH2:14]1>CC1C=CC=CC=1>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCC(Nc2nc3ccccc3o2)CC1)c1ccc(F)cc1
Yield: 34 %

Procedure:
A mixture of 1.65 parts of 1-(4-fluorobenzoyl)aziridine (solution in benzene 1.2M), 2.1 parts of N-(4-piperidinyl)-2-benzoxazolamine and 90 parts of methylbenzene was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and recrystallized from 2-propanone, yielding 1.3 parts (34%) of N-[2-[4-[(2-benzoxazolyl)-amino]-1-piperidinyl]ethyl]-4-fluorobenzamide; mp. 173.3° C. (448).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(OCCN2CCCC2)c2ncccc12
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c4ncccc34)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-8-(2-pyrrolidin-1-yl-ethoxy)-quinoline (200 mg, 0.54 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (116 mg, 0.54 mmol).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=3[F:31])=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[F:31][C:22]1[C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:15]([N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2cccc(C(F)(F)F)c2F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1c(-c2nccnc2N2CCNCC2)cccc1C(F)(F)F
Reaction time: 19 h

Procedure:
Add 4 M HCl in 1,4-dioxane (5 mL) to a solution of 3′-(2-fluoro-3-trifluoromethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.101 g, 0.237 mmol) in DCM (10 mL) and stir for 19 hr. Concentrate, dissolve the residue in methanol (20 mL) and purify by SCX chromatography (pre-wash column with methanol), load material, elute with 2 M ammonia in methanol, and concentrate to give the title preparation as a yellow solid (0.0985 g). MS (ES): m/z=327 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)[S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Product: CN([C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1)S(C)(=O)=O

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 26, Step H in Step A and methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9](=S)[NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[F:22][C:23]([F:31])([F:30])[C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1.CN(C)CCCN=C=NCC>CC(OC)(C)C.[Cl-].[Na+]>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]=[C:9]([NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)[NH:29][C:26]2[CH:25]=[C:24]([C:23]([F:31])([F:30])[F:22])[NH:28][N:27]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)Nc1cc(F)cc(Cl)c1)c1ccc(Cl)cc1
Reactant: Nc1cc(C(F)(F)F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(N=C(Nc1cc(F)cc(Cl)c1)Nc1cc(C(F)(F)F)[nH]n1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A suspension of 4-chloro-N-((3-chloro-5-fluorophenyl)carbamothioyl)benzamide (20.5 g, 59.7 mmol) in TBME (500 mL) was heated to 50° C. 5-(Trifluoromethyl)-1H-pyrazol-3-amine (10.8 g, 71.7 mmol, 1.20 equiv) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) (17.6 g, 89.6 mmol, 1.50 equiv) were added. The resulting reaction mixture was stirred at 40° C. for 3 hr and then diluted with a saturated aqueous sodium chloride solution (0.5 L). The organic layer of the resulting mixture was isolated, dried (Na2SO4), filtered, and concentrated. The resulting residue was diluted with EtOAc (20 mL), and this mixture was warmed to 50° C., then diluted with heptane (20 mL). Next, the heat source was removed and the mixture was allowed to cool to room temperature, then an ice/water bath was applied to the reaction vessel to affect precipitation. The resulting solids were collected by filtration, rinsed with EtOAc/heptane (1/1 mixture by volume, 20 mL) and air dried at room temperature. Then, the solids were dissolved in EtOH (80 mL) and the resulting mixture warmed to 40° C. EtOH/water (1/1 mixture by volume, 80 mL) was added to the mixture slowly over 40 minutes. Then, the heat source was removed from the reaction vessel and the reaction mixture was allowed to stir at room temperature for 2 days. Then, the reaction mixture was filtered, collected solids were rinsed with EtOH/water (1/1 mixture by volume, 15 mL), and dried (60° C./10 Torr) to afford the title compound (15.2. g, 57% yield). 1H NMR (DMSO-d6) of the title compound: δ 13.3 (s, 1H), 10.7 (s, 1H), 10.0 (s, 1H), 7.90 (s, 1H), 7.90 (d, 2H, J=8.4), 7.72 (d, 1H, J=11.5), 7.63 (m, 3H), 7.07 (d, 1H, J=8.5), 6.00 (s, 1H). HPLC: 98.6% purity at 26.02 min.