Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:3].CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:16]2[C@@H:2]([CH3:3])[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)(=[O:18])=[O:19])=[CH:25][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2-c2ccccc2[C@@H](C)O)cc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@@H]2C)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
N-[(R)-2′-(1-Hydroxy-ethyl)-biphenyl-2-yl]-4-methoxy-benzenesulfonamide (0.04 g, 0.10 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0° C. Di-tert-butylazodicarboxylate (0.05 g, 0.21 mmol) and triphenylphosphine (0.06 g, 0.21 mmol) were added. After four hours, additional di-tert-butylazodicarboxylate (0.05 g, 0.21 mmol) and triphenylphosphine (0.06 g, 0.21 mmol) were added. The mixture was warmed to room temperature and stirred for 36 hours. Trifluoroacetic acid (2.5 mnL) was added and the mixture was stirred for two hours. A solution of saturated, aqueous sodium bicarbonate was added (100 niL) and the resulting mixture was extracted with diethyl ether (5×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield an oil. The resulting oil solidified upon standing. The title compound was evaluated by chiral stationary phase HPLC (Chiralpak AD-25×0.46 cm column) on a Rainin Auto-Prep System using 90:10 hexane:isopropanol as the eluding solvent with a 0.8 mL/min flow rate. HPLC analysis showed the product to be a 95:5 mixture of enantiorners where the S enantiomer was the major product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH2:8]2)[CH2:4][CH2:3]1.CCN(CC)CC.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32](Cl)=[O:33])=[CH:26][CH:25]=1>C(Cl)Cl>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:32]([O:31][CH2:30][C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)=[O:33])[CH2:3][CH2:4]2)[CH2:8]1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution spiro[indene-1,4′-piperidin]-3(2H)-one hydrochloride (5.0 g, 24.84 mmol) and Et3N (7.54 g, 74.53 mol) in CH2Cl2 (50 mL) was added drop-wise Cbz-Cl (4.66 g, 27.33 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The precipitate was filtered, washed with Et2O and dried to furnish benzyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (6.1 g, yield 99%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)cc1
Yield: 84.2 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 0.33 g of 4'-hydroxyacetophenone and 0.70 g of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 0.74 g of the title compound, melting at 157°-159° C., was obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:55][NH:56][CH3:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:31])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:56]([CH3:57])[CH3:55])=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CO)cn2)cc1
Reactant: CNC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(CN(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.2 %

Procedure:
To N-cyclopropyl-3-[(4-{[5-(hydroxymethyl)pyridin-2-yl]methoxy}benzoyl)amino]-4-methylbenzamide (100 mg, 0.232 mmol) in DCM (10 mL) was added Dess-Martin periodinane (197 mg, 0.464 mmol) and the reaction was stirred at room temperature for 3 h. The reaction was diluted with DCM (40 mL), washed with 2N NaOH (3×15 mL) and then a saturated brine solution (20 mL). The DCM solution of the aldehyde was dried with magnesium sulphate and then concentrated under reduced pressure to approximately 10 mL. To this solution was added dimethylamine (2M in THF, 0.13 mL, 0.260 mmol), acetic acid (2 drops) and titanium iso-propoxide (132 mg, 0.464 mmol). The mixture was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (123 mg, 0.580 mmol) was added. The reaction was stirred for 18 h at room temperature. Water (4 drops) was added and the reaction was evaporated to dryness. The residue was purified by basic preparative HPLC to give the title compound as a white solid (30 mg, 28%); NMR Spectrum: (DMSOd6) 0.62 (m, 2H), 0.75 (m, 2H), 2.21 (s, 6H), 2.31 (s, 3H), 2.90 (m, 1H), 3.48 (s, 2H), 5.83 (s, 2H), 7.22 (d, 2H), 7.38 (d, 1H), 7.57 (d, 1H), 7.68 (dd, 1H), 7.81 (m, 1H), 7.85 (d, 1H), 8.04 (d, 2H), 8.42 (d, 1H), 8.57 (s, 1H), 9.88 (s, 1H); Mass Spectrum: M+H+ 459.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[CH:37]>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.[Cu]I>[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[C:37][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(C#CC(C)(C)C)c4ccccc34)cc2)n1
Temperature: 90 °C

Procedure:
A resealable pressure tube, purged with argon, was charged with 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (150 mg, 0.329 mmol), bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.020 mmol), copper(I) iodide (3.8 mg, 0.020 mmol), and 3,3-dimethyl-1-butyne (0.101 mL, 0.823 mmol). This mixture was purged with argon for 10 minutes, followed by addition of acetonitrile (3.3 ml, 0.1 M). The pressure tube was sealed and the mixture inside heated to 90° C. for 16 hrs. The next day, the reaction was stopped, cooled to RT, diluted with dichloromethane and filtered over a plug of celite. Filtrate was concentrated to afford a brown residue, which was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(3,3-dimethylbut-1-ynyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine as a yellow solid. MS m/z=502 [M+H]+. Calc'd for C30H27N7O: 501.58.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([Cl:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:22][C:4]1[CH:3]=[C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:7]=[CH:6][C:5]=1[C:8](=[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2Cl)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Temperature: 140 °C
Yield: 59.8 %

Procedure:
A mixture of 72 (459 mg, 1.22 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 310 mg (60%) of 73. 1H NMR (400 MHz, CDCl3): δ1.52 (s, 9H), 1.58 (m, 6H), 1.99 (m, 2H), 2.28 (m, 2H), 4.71 (s, 1H), 6.31 (d, J=16.0 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 7.17 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.9 Hz, 1.5 Hz, 1H), 7.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([C:21](=O)[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=C(CCc1ccccc1)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(CCc1ccccc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1,3-diphenyl-propan-1-one.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[F:53]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[F:53])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(N)c(F)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-fluoro-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=398.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([SH:20])[CH2:17][CH2:18][SH:19]>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[S:20][CH2:16][CH2:17][CH2:18][S:19]2)=[CH:4][CH:3]=1
Reactant: SCCCS
Reactant: O=Cc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Oc1ccc(C2SCCCS2)cc1
Temperature: 0 °C

Procedure:
4-Hydroxybenzaldehyde (46 g, 0.377 mol), recrystallized from benzene, and 1,3-propanedithiol (45 ml, 0.449 mol) were added to dry chloroform. The reaction mixture was stirred at 0° C. and HCl gas was bubbled through the solution for 10 minutes. After the exothermic reaction stopped the solution was refluxed for 10 hours. A white precipitate formed. This was filtered off and the chloroform solution was washed with water three times, dried (MgSo4) and evaporated under reduced pressure to yield a light yellow solid. White needles were obtained after recrystallization from chloroform, MP=151°-152° C. The white precipitate was also recrystallized from chloroform to yield white needles that melted at 151°-152° C. IR and NMR confirmed the two compounds to be identical. Total yield after recrystallization: 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][CH:9]2[NH2:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:11][CH2:10][C@H:9]2[NH:12][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:31])[F:32])=[CH:6][CH:7]=1
Reactant: NC1CCC1c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CC[C@@H]1c1ccc(Cl)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of 2-(4-chlorophenyl)cyclobutanamine (105 mg, 0.55 mmol) and triethylamine (140 mg 2.5 eq.) in THF was added 2-trifluoromethyl-benzoylchloride (127.46 mg, 1.1 eq.) at 0° C. The RM was stirred at rt for 2 h. Et3N.HCl was filtered off and the THF was evaporated. The residue—mixture of two isomers cis and trans (2:1) was purified and separated with chromatography on silica gel, eluent i-Hx:diethylether 1:1, (KMnO4 stain). N-[cis-2-(4-chlorophenyl)cyclobutyl]-2-(trifluoromethyl)benzamide (cis) (33 mg, m.p. 147-9° C.) and its trans isomer (17 mg, m.p. 117-9° C.) were isolated as crystalline products.
Reaction SMILES: [F:1][C:2]1([F:41])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24](O)=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1.[F:42][C:43]([F:53])([F:52])[C@H:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>C(OCC)(=O)C.ClCCl.O>[F:41][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([NH:51][C@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:43]([F:42])([F:52])[F:53])=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCC(F)(F)C4)CC3)c(C(=O)O)c2c1
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCC(F)(F)C4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A suspension of 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.167 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.046 g, 0.218 mmol), N,N-diisopropylethylamine (0.088 mL, 0.502 mmol), and propylphosphonic anhydride (0.128 mL of a 50% solution in ethyl acetate, 0.218 mmol) in dichloromethane (2.57 mL) was stirred at room temperature for 30 min. Water (2 mL) was added, and the mixture was poured into a hydrophobic frit to separate the layers. The organic phase was concentrated in vacuo, and the residue was loaded onto florisil and purified via column chromatography (ISCO, 4 g silica, 0-10% methanol/methylene chloride) to afford 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.110 g, 83% yield). MS (m/z) 755.2 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg]>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: c1csc(-c2cccs2)c1
Temperature: 25 °C

Procedure:
Gringard reagent 2-thiophenylmanesium bromide was prepared from 60 g of 2-bromothiophene (0.368 mole) and magnesium (9.7 g, 0.404 mole). Magnesium was slowly added to a mixture of 2-bromothiophene (50 g, 0.307 mole), Ni(dppp)Cl2 (1.66 g, 3 mmol) in 150 mL dry ether at 0° C. The mixture was warmed to RT for 20 h before being quenched by diluted HCl. The aqueous layer was extracted with ether and all organic layers were combined. The solvent was evaporated after drying over MgSO4. The crude liquid product was redistilled under reduced pressure to afford 40 g (80%) of a low melting solid of the tilled compound. Mp 32-33° C. 1H-NMR (300 MHz, CDCl3) δ 7.19 (dd, 4H), 7.04 (t, 2H).
Reaction SMILES: [B:1]#B.[BH4-].[Na+].[CH2:5]([S:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:6][CH:7]([CH3:9])[CH3:8]>COCCOCCOC>[BH3:1].[CH2:11]([S:10][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: B#B
Agent: CC(C)CCSCCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: B
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Diborane generated as described in Example 6 was passed through a bubbler containing sodium borohydride (0.1 g) in diglyme (5 ml) and a trap cooled to -78° C. was absorbed in neat diisoamyl sulfide (8.67 g, 50 mmol) at 0° C. Excess diborane was absorbed in the next bubbler containing tetrahydrofuran (10 ml) over mercury and cooled in ice water. A mercury bubbler was connected to the exit. Diborane was passed into the sulfide until the concentration of borane in THF reached 1M. Borane-diisoamyl sulfide, a colorless liquid, was stirred overnight at room temperature prior to disconnecting the bubblers and then analyzed for active hydride by a standard procedure using a water-glycerol-methanol 1:1:1 hydrolyzing mixture. Concentration 4.2M, 11B NMR, δ, -22.5 ppm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][C@:9]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:10]1[CH:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:32])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C@@H:18]([OH:31])[CH2:17][CH2:16]3)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[CH3:27][C@:24]12[C@@:23]3([CH3:28])[C@@H:14]([C@:15]4([CH3:32])[C@@H:20]([CH2:21][CH2:22]3)[C:19]([CH3:29])([CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]4)[CH2:13][CH2:12][CH:11]1[C@H:10]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:9]1([CH:8]=[O:7])[CH2:26][CH2:25]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
To a 2M solution of oxalyl chloride (47.0 mL, 94 mmol) in CH2Cl2, was added a solution of DMSO (13.7 mL, 192 mmol) in CH2Cl2 (20 mL) dropwise at −15° C. After 5 min, a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (4.43 g, 10.01 mmol) in a mixture of DMSO (30 mL) and CH2Cl2 (50 mL) was added at −15° C. Triethylamine (56 mL) was added 15 minutes later and the stirring was continued for another 10 min. The reaction mixture was allowed to warm up to RT. The reaction was quenched by addition of water (100 mL), and the reaction mixture was extracted with CH2Cl2 (70 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over MgSO4, filtered and concentrated. The crude material was purified using silica gel chromatography eluted with a mixture of ethyl acetate and hexanes, to give the product as a solid (3.3 g 75%). LCMS: m/e 461.15 (M+Na)+, 2.91 min (method 2).
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:2]([C:6]([N:8]([CH3:41])[C@H:9]([C:27]([NH:29][CH2:30][C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:28])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:26])[NH:15][S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.[Pd]>[NH:1]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C@@H:2]([C:6]([N:8]([CH3:41])[C@H:9]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:26])[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)O)N(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Yield: 78 %

Procedure:
A solution of Boc-D-Val-NMeArg(Tos)-Gly-OBzl (4.50 g, 6.53 mmol) in 80 ml of methanol was purged with nitrogen gas, 1.30 g of 10% Pd/C was added, and hydrogen gas was passed over the reaction. After 1 hour the catalyst was removed by filtration through a bed of celite, and the solvent removed under reduced pressure. The resulting solid was triturated with ether, filtered, and washed with petroleum ether to provide Boc-D-Val-NMeArg(Tos)-Gly (3.05 g, 78%); 1H NMR (D6 -DMSO) d 7.90 (br t, 1H), 7.65 (d, 2H), 7.30 (d, 2H), 7.00 (d, 1H), 6.85 (br d, 1H), 6.60 (br s, 1H), 5.00 (dd, 1H), 4.15 (t, 1H), 3.70 (m, 2H), 3.05 (m, 2H), 2.90 (s, 3H), 2.35 (s, 3H), 1.90 (m, 2H), 1.55 (m, 1H), 1.35 (s, 9H), 1.25 (m, 2H), 0.80 (br t, 6H); FAB-MS: [M+H]=599.45.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH:40]=[N:39][CH:38]=[CH:37]3)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][N:39]([CH3:44])[CH2:38][CH2:37]3)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cnccc3c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4)cc3)ccc2C1

Procedure:
In an analogous manner to that previously described, by alkylating tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate with methyl iodide in chloroform and subsequently reducing with sodium borohydride in methanol there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ylmethoxy)-piperidine-1-carboxylate, which was used in the next step as the crude product without further characterization.