Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:40]=[CH:39][C:26]2/[C:27](=[CH:36]/[C:37]#[N:38])/[C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH2:30][CH2:31][C:25]=2[CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:22][C:23]3[CH:40]=[CH:39][C:26]4/[C:27](=[CH:36]/[C:37]#[N:38])/[C:28]5[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=5[CH2:30][CH2:31][C:25]=4[CH:24]=3)[C:6]=2[CH:13]=1
Reactant: CCCc1nc2cc(Br)cc(C)c2[nH]1
Reactant: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(Br)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
[step 1] Under a nitrogen atmosphere, 6-bromo-4-methyl-2-propylbenzimidazole (WO2004082621; 300 mg, 1.19 mmol) was dissolved in DMF (3 mL), and the mixture was cooled to 0° C. Potassium carbonate (829 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 20 min. To this mixture was added (E)-2-(2-bromomethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (421 mg, 1.30 mmol) obtained in Reference Example B1, and the mixture was stirred at room temperature for 4 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/3) to give (E)-[2-(6-bromo-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (615 mg, 95%).
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH:14]1([CH2:13][C@@H:9]([C:10]([NH:36][C@@H:33]2[C@@H:31]3[C@@H:30]([CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:38])([F:19])[F:37])=[CH:27][CH:26]=4)[CH2:32]3)[CH2:35][CH2:34]2)=[O:12])[NH:8][CH3:18])[CH2:16][CH2:17]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC1CC1)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting 3-cyclopropyl-N-(tert-butoxycarbonyl)-N-methyl-L-alanine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(4-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 716 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.28 (d, J=7.6, 1H), 7.22 (s, 2H), 6.65-6.54 (m, 2H), 4.46-4.36 (m, 1H), 3.55 (dd, J=9.9, 2.7, 1H), 3.35-3.24 (m, 2H), 3.15 (dd, J=9.5, 7.8, 1H), 3.02 (dd, J=9.6, 3.3, 1H), 2.79-2.67 (m, 2H), 2.46 (d, J=9.2, 3H), 2.17-2.05 (m, 1H), 2.02-1.91 (m, 1H), 1.84 (dd, J=30.5, 23.8, 1H), 1.83-1.62 (m, 3H), 1.45-1.35 (m, 1H), 0.99-0.86 (m, 1H), 0.53-0.38 (m, 2H), 0.19-0.07 (m, 2H); MS (ESI+) m/z 412 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=O)[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:22][C:23]4[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)cc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of the hydrochloride salt of 7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.99 g), tert-butyl [3-amino-5-(trifluoromethyl)-benzyl]carbamate (1.98 g, 6.82 mmol), and DMAP (0.834 g, 6.82 mmol) in DMF (60 mL) was added EDCI (1.31 g, 6.82 mmol). The reaction mixture was allowed to stir at rt overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give tert-butyl [3-[({7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)-amino]-5-(trifluoromethyl)benzyl]carbamate (2.45 g, 71%). LCMS: (FA) ES+ 557.9, ES+ 554.6.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([NH:22][CH3:23])[N:19]=[CH:18][N:17]=3)=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].[Cl:29][C:30]1[C:35]([N:36]=[C:37]=[O:38])=[C:34]([Cl:39])[C:33]([O:40][CH3:41])=[CH:32][C:31]=1[O:42][CH3:43].[NH4+].[Cl-]>C1COCC1>[Cl:29][C:30]1[C:31]([O:42][CH3:43])=[CH:32][C:33]([O:40][CH3:41])=[C:34]([Cl:39])[C:35]=1[NH:36][C:37](=[O:38])[N:22]([C:20]1[CH:21]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([N:6]3[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)=[CH:10][C:11]=2[N+:24]([O-:26])=[O:25])[N:17]=[CH:18][N:19]=1)[CH3:23]
Reactant: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)c([N+](=O)[O-])c2)CC1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
To a solution of N4-(4-(4-ethylpiperazin-1-yl)-2-nitrophenyl)-N6-methylpyrimidine-4,6-diamine (870 g, 2.44 mmol) in THF (15 mL) was added NaH (60%, 200 mg, 5 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. A solution of 2,4-dichloro-3-isocyanato-1,5-dimethoxy-benzene (Procedure 2A, steps a-d; 908 g, 3.66 mmol) in THE was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. Saturated aqueous NH4Cl solution (2 mL) was added to quench the reaction. The mixture was concentrated and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (330 mg, yield: 21%) as a red oil. 1H NMR (400 MHz, CDCl3) δ 1.44 (t, 3H), 3.01 (t, 2H), 3.21 (q, 2H), 3.41-3.49 (m, 5H), 3.73-3.80 (m, 4H), 3.92 (s, 6H), 6.27 (s, 1H), 6.55 (s, 1H), 7.25 (d, 1H), 7.69 (s, 1H), 8.32 (d, 1H), 8.52 (s, 1H), 10.28 (br s, 1H), 12.05 (br s, 1H); MS (ESI): 605 [M+H]+.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:46])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])C)C1C=CC=CC=1>CO>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[F:38])[O:31][CH:30]1[CH:24]2[N:23]([C:21]([CH:16]([NH:15][C:14](=[O:46])[CH:12]([NH:10][CH3:9])[CH3:13])[C:17]([CH3:19])([CH3:18])[CH3:20])=[O:22])[CH2:27][CH2:26][CH:25]2[N:28]([CH:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[CH2:29]1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1)C(C)(C)C
Reaction time: 4 h
Yield: 55.8 %

Procedure:
The Cbz-protected intermediate 27 (160 mg, 0.24 mmol) was stirred vigorously with 10% Pd-on-carbon (wet, 100 mg, 0.09 mmol) in MeOH (20 mL) under 1 atm H2. After 4 h, the catalyst was removed by filtration with an Acrodisc® 0.45 μm nylon membrane syringe filter and the solvent was removed in vacuo. The crude product was purified by reverse-phase HPLC (2″ Dynamax® C18, 10-55% ACN/water containing 0.1% HOAc over 20 min; Flow: 40 mL/min) to afford 70 mg of 28 (45%, 3 steps) as a flocculent, white solid following lyophilization.
Reaction SMILES: C(O[C:6](=O)[NH:7]C1(C2C=CC(C3C(=O)C4C(=CC=C(C#N)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[C:59](Br)[C:60]([O:66][CH3:67])=[CH:61][CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[C:59]([C:6]#[N:7])[C:60]([O:66][CH3:67])=[CH:61][CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1C#N
Yield: 33 %

Procedure:
Following the procedure used to prepare {1-[4-(6-cyano-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(8-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (150 mg, 0.0867 mmol) was reacted to give the title compound (15 mg, 33%). LCMS (Method B): RT=4.79 min, [M+H]+=523.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22](=O)[NH2:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]#[N:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(N)=O)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C#N)c12
Temperature: 5 °C
Yield: 84.5 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carbamoyl-5-fluoro-1,2-benzisoxazole (0.25 g) in dimethylformamide (2.0 ml) was added phosphorus oxychloride (0.12 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.20 g, 87% yield) as a colorless powder.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[CH2:10][CH2:11][N:6]([CH3:4])[CH2:7][CH2:8]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid ethyl ester (0.28 g, 0.66 mmol) and lithium aluminum hydride (0.051 g) were suspended in tetrahydrofuran (5 ml) and stirred for 2 hours. The reaction mixture was quenched with addition of water, solvent removed under reduced pressure, the residue was partitioned between ethyl acetate and 2N NaOH. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to afford the desired product (0.241 g, 99% yield). LC/MS: (PS-B3) Rt 3.78 [M+H]+ 363.95, 365.73.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:11][CH:10]([O:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:13][O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 77.4 %

Procedure:
To a solution of 2-{[1-(diphenylmethyl)azetidin-3-yl]oxy}-1H-isoindole-1,3(2H)-dione (600 mg, 1.56 mmol; which may be prepared as described in Step 2) in ethanol (13.3 mL) was added hydrazine hydrate (100 μL, 2.06 mmol). The resulting mixture was heated to reflux for 2 h then concentrated under reduced pressure. The residue was taken up in dichloromethane/methanol mixture then filtered. The filtrate was concentrated and the residue purified on column chromatography (eluent: Dichloromethane/NH3 7N in MeOH, 2% to 5%) to give the title compound (307 mg, 77%) as a clear oil.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Br:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>ClCCl>[C:2]([O:19][C:17]([C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:6][Br:5])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)=[O:18])([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: O=C(O)c1cccc2ccc(CBr)cc12
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc2ccc(CBr)cc12
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Isobutylene was passed through a suspension of 7-bromomethylnaphthalene-1-carboxylic acid (10.4 g, 39.2 mmol) in dichloromethane (150 mL) in the presence of concentrated sulfuric acid (1 mL) for 3 hours, and then the mixture was stirred overnight. The resulting deep green solution was washed with a saturated solution of sodium hydrogen carbonate, dried (magnesium sulfate) and the solvent was removed under reduced pressure to give crude 7-bromomethylnaphthalene-1-carboxylic acid tert-butyl ester (11.2 g, 88.8%) as a deep green oil. This compound was directly used for the subsequent Michaelis-Becker alkylation without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3]1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38])/[C:29](=[N:31]/O)/[NH2:30]>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([C:29]2[N:31]=[C:7]([CH:4]3[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]3)[O:9][N:30]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2noc(C3CCC(=O)C3)n2)cc1Cl
Temperature: 140 °C
Yield: 55.6 %

Procedure:
To a slurry of 3-oxocyclopentanecarboxylic acid (0.123 g, 0.962 mmol) in DMF (1.0 ml) was added EDC (0.184 g, 0.962 mmol) followed by HOBT hydrate (0.130 g, 0.962 mmol). After about 1 h a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.2 g, 0.875 mmol) in DMF (0.5 ml) was added and the reaction mixture was heated to about 140° C. for about 45 min. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentanone (0.156 g, 56%) as a yellow oil. LCMS (Table 1, Method c) Rt=2.75 min, m/z 321 (M+H)+.
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@@H:12]2[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]2[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[N:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])C=CC=CC=1.CSC>C(Cl)Cl>[CH:11]([C@@H:12]1[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]1[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[N:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:1]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ozone was passed through a -78° C. methylene chloride (100 mL) solution of compound 34 (8.2 g, 12 mmol) until the solution retained a blue color. Dimethyl sulfide (10 mL) was added. The solution was warmed to room temperature and allowed to stand for 16 h. The solution was concentrated to afford the title product which was not purified but used directly in Step B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][C:4]=1[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]1([C:36](O)=[O:37])[CH2:35][CH2:34]1.ON1C2C=CC=CC=2N=N1.N>O1CCCC1.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:36]([C:33]2([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)[CH2:35][CH2:34]2)=[O:37])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(CCN)cc1C
Reactant: O=C(O)C1(c2cccs2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CCNC(=O)C2(c3cccs3)CC2)cc1C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
A mixture of 2-(4-methoxy-3-methylphenyl)ethylamine (16 g), triethylamine (1.74 ml), 1,3-dicyclohexylcarbodiimide (8.75 g), 1-(2-thienyl)cyclopropanecarboxylic acid (7 g) and 1-hydroxybenzotriazole (5.6 g) in tetrahydrofuran (95 ml) was stirred for 16 hours. The mixture was poured into water, basified with aqueous ammonia solution and filtered. The filtrate was extracted with ethyl acetate (3×50 ml) and the combined extracts washed with 1M hydrochloric acid and brine then dried and the solvent removed in vacuo. The resulting gum was treated with acetonitrile and insoluble matter filtered off. Evaporation of the filtrate gave crude N-(2-(4-methoxy-3-methylphenyl)ethyl)-1-(2-thienyl)cyclopropanecarboxamide as a solid (10.7 g), which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]([CH:34]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]1)([C:11]1[S:12][C:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[N:17]=2)=[CH:14][N:15]=1)[CH3:10]>ClCCl>[CH3:22][C:20]1[CH:19]=[C:18]([NH:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=2)[N:17]=[C:16]([C:13]2[S:12][C:11]([C:9]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)([OH:8])[CH3:10])=[N:15][CH:14]=2)[CH:21]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCN(C(=O)OC(C)(C)C)C3)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCNC3)s2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (0.4 mL, 5.19 mmol) was added to a solution of tert-butyl 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate (100 mg, 0.182 mmol) in dichloromethane (0.8 mL). The mixture was stirred at room temperature for 16 hours then concentrated under reduced pressure. The residue was purified on reverse phase HPLC (Sunfire prep C18 OBD 5 uM, acetonitrile/water+0.1% TFA) to afford 1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol as a 1:1 mix of diastereomers. MS ESI calc'd. for C21H22F3N5OS [M+H]+ 450. found 450. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=5.6 Hz, 1H), 8.37 (d, 11-1, two singlets from two diastereomers), 8.12 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=5.5 Hz, 1H), 7.05 (s, 1H), 3.58-2.95 (m, 5H, two sets of peaks from two diastereomers), 2.45 (s, 3H), 2.30-1.79 (m, 2H, two sets of peaks from two diastereomers), 1.69 (d, 3H, two singlets from two diastereomers). rhSyk activity=+++.
Reaction SMILES: [I-].[CH:2]1([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH2:50][CH3:51])=[CH:45][CH:44]=1)=O)[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:52])[C:41]([C:43]1[CH:48]=[CH:47][C:46]([S:49][CH2:50][CH3:51])=[CH:45][CH:44]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:38]
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(SCC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(SCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphonium iodide (24.48 g, 51.82 mmol) in dry tetrahydrofuran (100 mL) was cooled to 0° C. and then treated dropwise with a 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (52 mL, 51.82 mmol). The bright orange reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then treated with (4-ethylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (9.50 g, 39.87 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 20 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then diluted with water (300 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2-(4-ethylsulfanyl-phenyl)-acrylic acid ethyl ester (6.08 g, 50%) as a yellow oil containing a 1.82:1 mixture of (E):(Z) isomers: FAB-LRMS m/e calcd for C18H24O2S (M+H)+ integer mass 304, found 305. The isomeric mixture was used without further separation in subsequent reactions.