Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.[CH:12]([N-]C1CCCCC1)(C)C.[Li+].CI>>[CH3:12][CH:11]1[CH:2]([CH3:1])[CH2:3][CH2:4][C:5](=[C:6]([CH3:7])[CH3:8])[C:9]1=[O:10]
Reactant: CC(C)[N-]C1CCCCC1
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Agent: [Li+]
Solvent: CI
Product: CC(C)=C1CCC(C)C(C)C1=O
Yield: 72 %

Procedure:
The regioisomeric problem upon fragmentation of the tosylhydrazone (i.e., production of mix 74/75) was overcome by increased substitution for increased selectivity. Therefore 3R-pulegone was used as a starting material for synthesis (Scheme VIII). The enolate of pulegone was generated with lithium isopropylcyclohexylamide (LICA) and alkylated with methyl iodide to furnish mainly 2,3-dimethyl-6-isopropylidene cyclohexanone 78 along with by-product 79, ##STR51## which was previously observed by Reusch et al., (Lee, R. A., McAndrews, C., Patel, K. M., and Reusch, W. Tetrahedron Lett. 965 (1973)) but 79 did not react in the following conversion of crude material. When the mixture containing the isopropylidene 78 was placed in acid and submitted to prolonged heating, acetone distilled prior to the water azeotrope of the epimeric mix of 80:81 (1:1.96, as determined by NMR) in 72% yield. The corresponding tosylhydrazone mix 82 from the mix of 80:81 was made as before and underwent n-butyllithium-effected fragmentation in TMEDA to a regioisomerically pure cyclohexenyl anion, which was capped with dimethylformamide to afford isomeric aldehydes 83 in 76% yield. The mix was treated with tris(trimethylsilyl)aluminum (III) etherate (L. Rosch and G. Altman, J. Organomet. Chem., 195, 47 (1980).It should be noted that this procedure has failed to work in our hands, as well as others: See B. Trost, J. Yoshida, and M. Lautens, J. Amer. Chem. Soc., 105, 4494 (1983). However, a procedure which works is provided in the experimental. The reagent can be titrated as described or by reaction with peperonal: L. Rosch, G. Altman, and W. Otto, Angew. Chem. Int. Ed. Engl., 20 581 (1981)) and followed by acetylation to provide a mixture of all possible diastereomers of 84. The lack of selectivity was surprising in contrast to the total synthesis of QHS, in which a synthetic intermediate substrate differs in the presence of a 6'-methyl instead of a larger alkyl chain. Regardless, the mixture 84 upon exposure to lithium diethylamide rearranged to a mixture of diastereomeric cyclohexylacetic acids, which upon rigorous chromatographic separation furnished geometric isomers of acid 85 in a 1:1 ratio by NMR, in 28% yield. The acid 85 was submitted to single-pot exposure to ozone and acidification to give trioxane 30 in 22% yield. Alternatively the acid 85 was methylated via the corresponding LDA-generated dianion to the propionic acid 86, which was subsequently reacted with ozone and acidified to provide trioxane 31. The two optically active trioxanes 30 and 31 have been assessed for their antimalarial activity. In addition, all three optically active trioxanes, 29, 30 and 31, display temperature-dependent NMR behavior. ##STR52##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3cc(F)ccc3s2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2sc(-c3ccc(CBr)cc3)nc2c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
31.6 g of 2-(4-methylphenyl)-5-fluorobenzothiazole was dissolved in 660 ml of carbon tetrachloride, and 23.1 g of N-bromosuccinimide and 700 mg of benzoyl peroxide were added. The mixture was refluxed for 6 hours. The reaction mixture was cooled to room temperature, and the insoluble materials were separated by filtration. The filtrate was concentrated to a volume of 100 ml under reduced pressure. The precipitated crystals were collected by filtration to give 31.0 g of the captioned compound as crude crystals. Recrystallization from carbon tetrachloride gave the captioned compound as colorless platelike crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[N:30]([C:31]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)=[O:32])[CH2:29][CH2:28][N:10]2[C:11](=[O:27])[C:12]2[N:13]([CH:15]=[C:16]([N:18]4[CH:22]=[C:21]([Si](C)(C)C)[N:20]=[N:19]4)[CH:17]=2)[CH2:14]3)=[CH:5][CH:4]=1.O.C([O-])(O)=O.[Na+]>C(O)(=O)C.O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[N:30]([C:31]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)=[O:32])[CH2:29][CH2:28][N:10]2[C:11](=[O:27])[C:12]2[N:13]([CH:15]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[N:19]4)[CH:17]=2)[CH2:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(C23Cn4cc(-n5cc([Si](C)(C)C)nn5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C23Cn4cc(-n5ccnn5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 60 °C
Yield: 41.4 %

Procedure:
10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (10.6 mg, 0.012 mmol) was dissolved in a mixture of acetic acid/water/THF (3:1:1; 1 mL). The mixture was stirred at 60° C. When the reaction was complete (48 hours; monitored by LCMS) water was added followed by a saturated aqueous solution of NaHCO3. The mixture was then extracted with EtOAc (3 times) and the organics washed with brine, dried (Na2SO4), filtrated and concentrated in vacuo. The resulting material was purified by flash chromatography (Silica gel, EtOAc/Hex 3:1 followed by 100% EtOAc) to give compound 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-(1H-1,2,3-triazol-1-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (113) as a white solid (2.28 mg, yield 25%).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][C:10]1([CH2:16][OH:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C>[OH:17][CH2:16][C:10]1([CH2:9][NH:8][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: NCC1(CO)CCOCC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCC2(CO)CCOCC2)CS1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (898 mg) in ethanol (15 mL) was added a solution (5 mL) of [4-(aminomethyl)tetrahydro-2H-pyran-4-yl]methanol (1.00 g) in ethanol, and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, the precipitate was collected by filtration, and the obtained powder was washed with ethyl acetate to give the title compound (1.44 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.Cl>O1CCOCC1>[NH2:24][CH2:23][CH2:22][CH2:21][N:10]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][S:12][C:11]1=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2csc(=Nc3ccccc3)n2CCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2csc(=Nc3ccccc3)n2CCCN)cc1
Yield: 122.7 %

Procedure:
A mixture of t-butyl 3-[4-(4-methoxyphenyl)-2-(phenylimino)-thiazol-3(2H)-yl]propylcarbamate (400 mg) and a 4N solution of hydrogen chloride in dioxane (8 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the residue was added diethyl ether. The insoluble salt was collected by filtration to give the title compound (379 mg) as hydrochloride.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=1>C(O)C>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=[C:22]([O:21][CH3:20])[C:27]=1/[N:15]=[N:14]/[C:11]1[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: COc1cc(OC)cc(OC)c1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COc1cc(OC)c(/N=N/c2ccc(S(F)(F)(F)(F)F)cc2)c(OC)c1
Reaction time: 0.1 h
Yield: 75.2 %

Procedure:
Diazonium salt 1 (11.9 mg, 0.0374 mmol) and 1,3,5-trimethoxybenzene (6.6 mg, 0.039 mmol) were dissolved in 0.18 g of 95% aqueous ethanol. After 0.1 h, a red solid precipitated which was filtered. The red precipitate was purified by SiO2 column chromatography (7:3 hexane/ethyl acetate) to afford 27b as a red oil (11.2 mg, 75%): IR (ATR): {tilde over (v)}=2943, 1599, 1456, 1335, 1207, 1151, 1126, 837 cm−1. MS (GC, EI): m/z=398 [M+], 271 [M+-SF5], 195, 152. 1H NMR (500 MHz, CDCl3): δ=7.91 (d, J=9.3 Hz, 2H), 7.85 (d, J=9.3 Hz, 2H), 6.23 (s, 2H), 3.93 (s, 6H), 3.92 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=164.4 (C), 156.4 (2 C), 154.6 (C), 153.9 (C), 127.1 (C), 126.9 (2CH), 122.0 (2CH), 91.4 (2CH), 56.6 (2CH3), 55.7 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=84.5 (quint, J=150 Hz, 1 F), 63.3 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C@H:23]2[CH2:25][O:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(#N)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:25][C@@H:23]([OH:24])[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=1
Reactant: CNCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)cc1
Solvent: CC#N
Product: CN(Cc1ccc2ccccc2n1)C[C@@H](O)COc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-(Methylaminomethyl)quinoline (5.57 g, 32.41 mmol) in acetonitrile (30 mL) was added to a stirring solution of (R)-(-)-2-[(4-nitrophenoxy)methyl]oxirane (6.32 g, 32.41 mmol) in acetonitrile (90 mL) and the mixture was stirred 18 hours at 60° C., then 48 hours at 20° C. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate/brine. The organic layer was dried, decolorized, and concentrated to afford crude product which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[C:14]3=[O:21])[C:9](=[O:22])[C:8]=12)([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:1][C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[C:14]3=[O:21])[C:9](=[O:22])[C:8]=12
Reactant: CN1C(=O)CCC(N2C(=O)c3csc([N+](=O)[O-])c3C2=O)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN1C(=O)CCC(N2C(=O)c3csc(N)c3C2=O)C1=O
Yield: 52.3 %

Procedure:
0.097 g of 1-nitro-5-(1-methyl-2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of acetone; and a solution obtained by dissolving 0.239 g of Na2S2O4 in 10 mL of water was added. The reaction mixture was refluxed for 2 h, cooled, and 10 mL of water were added. The aqueous phase was extracted with ethyl acetate (3×30 mL), the organic phases were combined, washed with 40 mL of water and 40 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness to remove the solvent. The remaining residue was purified on silica gel column chromatography to yield a solid (0.046 g). MS (m/z): 292 (M−1)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH2:49])[CH:44]=1.[CH3:50][O:51][C:52]([C:54]1[N:55]=[C:56]([CH3:60])[S:57][C:58]=1Br)=[O:53].C(=O)([O-])[O-].[Cs+].[Cs+]>F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>[CH3:50][O:51][C:52]([C:54]1[N:55]=[C:56]([CH3:60])[S:57][C:58]=1[NH:49][C:45]1[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=1)=[O:53]
Reactant: COC(=O)c1nc(C)sc1Br
Reactant: Nc1cccnc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1nc(C)sc1Nc1cccnc1
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
Dry dioxane (10.00 ml) was degassed by bubbling with argon in an ultrasonic bath, then added to a sealed microwave vial containing a mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.38 g, 0.66 mmol), palladium dibenzylideneacetone chloroform complex (0.21 g, 0.20 mmol), pyridin-3-ylamine (0.19 g, 2.00 mmol), 5-bromo-2-methyl-thiazole-4-carboxylic acid methyl ester (0.47 g, 2.00 mmol) and cesium carbonate (1.16 g, 6.00 mmol). The mixture was stirred for 10 min, then a few drops of 1-butyl-3-methylimidazolium hexafluorophosphate were added and the vial was irradiated in a microwave oven at 150° C. for 15 min. The volatiles were then removed under vacuum, and the residue was purified by flash chromatography (heptane/ethyl acetate), yielding 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid methyl ester (0.47 g, 94%), as a yellow solid, MS (ISP): m/e=250.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22](O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCc2ccccc2)c1

Procedure:
Mitsunobu reaction of phenol 58 with phenethyl alcohol gave 2-(3-(3-phenethoxyphenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.360 g, 30%): 1H NMR (400 MHz, CDCl3) δ 7.77-7.81 (m, 2H), 7.66-7.71 (m, 2H), 7.22-7.34 (m, 6H), 6.71-6.78 (m, 2H), 6.65 (dd, J=7.2, 2.0 Hz, 1H), 3.87 (t, J=6.8, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.88 (t, J=6.4 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.98-2.06 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O.CN1CCN(C)C1=O.O1CCCC1.[ClH:36]>CO>[ClH:36].[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][NH:5][CH2:3][C@@H:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:1])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=C(NCCc1ccc([N+](=O)[O-])cc1)[C@H](O)c1ccccc1
Agent: Cl
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCNC[C@H](O)c2ccccc2)cc1
Temperature: -18 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
A mixture of 7.51 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, 23 liters of 1,3-dimethyl-2-imidazolidinone and 23 liters of tetrahydrofuran was cooled at −18° C. and 49.4 kg of 1M boran-tetrahydrofuran solution was dropped there into at not higher than −7° C. After that, temperature of the mixture was raised to 70° C. followed by stirring for 5 hours. The reaction mixture was cooled at −12° C. and 2.9 kg of methanol and 5.9 kg of concentrated hydrochloric acid were added thereto at not higher than 5° C. After stirring at 68° C. for 1 hour, the mixture was concentrated in vacuo until the amount became 50 liters. A 30% aqueous solution (60 kg) of K2CO3 and 6 liters of water were added thereto followed by extracting with 75 liters of ethyl acetate. The organic layer was washed with 75 liters of water and concentrated in vacuo. Isopropanol (75 liters) was added to the residue, the mixture was dissolved at 40° C. and 2.46 kg of concentrated hydrochloric acid was added to crystallize followed by stirring at 23° C. throughout one night. The crystals were filtered and washed with 38 liters of isopropanol. They were dried in vacuo to give 7.29 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol monohydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C@@H]2[C@H](C(N)=O)C[C@@:9]1(C1C=CC=CC=1)[C@H](OCC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CC2)C1C=CC=CC=1.CNC.[CH2:44]([N:51]1[C@@H:56]2[C@H:57]([C:59]3[N:60]=[N:61][N:62]([CH2:64][C:65]([OH:67])=O)[N:63]=3)[CH2:58][C@@:52]1([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C@H:53]([O:68][CH2:69][C:70]1[CH:75]=[C:74]([C:76]([F:79])([F:78])[F:77])[CH:73]=[C:72]([C:80]([F:83])([F:82])[F:81])[CH:71]=1)[CH2:54][CH2:55]2)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([N:51]1[C@@H:56]2[C@H:57]([C:59]3[N:60]=[N:61][N:62]([CH2:64][C:65](=[O:67])[N:8]([CH3:9])[CH3:1])[N:63]=3)[CH2:58][C@@:52]1([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C@H:53]([O:68][CH2:69][C:70]1[CH:75]=[C:74]([C:76]([F:79])([F:77])[F:78])[CH:73]=[C:72]([C:80]([F:83])([F:82])[F:81])[CH:71]=1)[CH2:54][CH2:55]2)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Reactant: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: CNC
Product: CN(C)C(=O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1

Procedure:
Prepared in analogous manner to (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75) using dimethylamine (2.0M solution in THF) and (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2-carboxymethyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 145).
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:18])[C@@H:8]([NH:11]C(=O)C(F)(F)F)[CH2:9][CH3:10])[CH2:2][CH2:3][C:4]#[CH:5].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C.C1COCC1.CO.O.[I].[Cu].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>[NH2:11][C@@H:8]([CH2:9][CH3:10])[C:7]([NH:6][CH2:1][CH2:2][CH2:3][C:4]#[C:5][C:26]1[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=1)=[O:18]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: C#CCCCNC(=O)[C@H](CC)NC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [I]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](N)C(=O)NCCCC#Cc1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(S)—N-(pent-4-ynyl)-2-(2,2,2-trifluoroacetamido)butanamide (0.246 g, 0.93 mmol), 4-bromophenyl methyl sulfone (0.200 g, 0.85 mmol), triethylamine (5 ml), copper iodine (0.032 g, 0.17 mmol) and Pd(PPh3)2Cl2 (0.175 g, 0.25 mmol) were combined in anhydrous DMF (5 ml) and heated to 70° C. in a sealed tube overnight. The resulting mixture was then concentrated in vacuo and ethyl acetate (46 ml) was added to the remaining residue. The resulting mixture was washed with 1N HCl (2×23 ml), water (23 ml), brine (23 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue was chromatographed eluting with ethyl acetate/heptanes (30:70) to yield a residue. The residue was dissolved in THF (0.5 ml)/MeOH (0.13 ml) and cooled to 0° C. 3N NaOH (0.10 ml, 0.30 mmol) was added, the resulting mixture was warmed to room temperature and stirred overnight. The resulting mixture was then diluted with water (0.25 ml) and concentrated in vacuo. The aqueous layer was extracted with methylene chloride (3×5 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue was chromatographed eluting with methylene chloride/methanol (95:5) followed by elution with methylene chloride/methanol/ammonium hydroxide (95:5:0.4) to yield (S)-2-amino-N-(5-(4-(methylsulfonyl)phenyl)pent-4-ynyl)butanamide. ES-MS m/z 323 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[C:23]2[CH:24]=[C:25]([I:27])[S:26][C:22]=2[C:21]([C:28]#[N:29])=[CH:20][N:19]=1>CN1C(=O)CCC1>[I:27][C:25]1[S:26][C:22]2[C:21]([C:28]#[N:29])=[CH:20][N:19]=[C:18]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:23]=2[CH:24]=1
Reactant: N#Cc1cnc(Cl)c2cc(I)sc12
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2ncc(C#N)c3sc(I)cc23)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
To NMP (41.3 mL) and 4-methoxybenzylamine (3.66 mL, 28.1 mmol) was added K2CO3 (7.76 g, 56.2 mmol) and 4-chloro-2-iodo-thieno[3,2-c]pyridine-7-carbonitrile 26 (7.52 g, 23.4 mmol). The reaction was heated to 80° C. After 1.5 h, NMP was distilled away under reduced pressure. The resulting solids were suspended in H2O (500 mL) and filtered. The product was recrystallized from 350 mL of toluene to obtain 7.75 g of 27. 1H NMR (400 MHz, d6-DMSO) δ 8.58 (t, J=6 Hz, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.28 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.68 (d, J=6 Hz, 2H), 3.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2([OH:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CCOc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-ethoxy-pyridin-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.