Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](O)=[O:23])=[CH:16][CH:15]=1>CO>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:22](=[O:23])[CH:21]=[CH:20][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:25])([F:26])[F:12])=[CH:19][CH:18]=3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12
Temperature: 175 °C

Procedure:
5-Aminoisoquinoline (0.50 g, 3.47 mmol) and 3-[4-(trifluoromethyl)phenyl]acrylic acid (3.47 mmol) were combined in a sealed tube and heated at 175° C. for 16 hours with stirring. The mixture was cooled to room temperature, diluted with MeOH, transferred to a flask, and concentrated under reduced pressure. The residue was triturated with ethyl acetate and filtered to provide the title compound. MS (ESI+) m/z 343 (M+H)+; MS (ESI−) m/z 341 (M−H)−; 1H NMR (DMSO, 300 MHz) rotamers δ 6.68 (d, J 15.9, 1H), 7.29 (d, J 15.9, 1H), 7.60 (d, J 15.9, 1H), 7.80 (m, 1H), 8.25 (d, J 6.8, 1H), 8.57 (d, J 5.8, 1H), 9.35 (s, 1H), 10.36 (s, 1H); Anal. Calcd for C19H13F3N2O+2 HCl+0.3 H2O: C, 54.25; H, 3.74; N, 6.66. Found: C, 53.90; H, 3.94; N, 7.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH2:18]([N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[N:21]1)[CH3:19]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:22]3[N:23]=[N:24][N:20]([CH2:18][CH3:19])[N:21]=3)=[CH:26][CH:27]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: CCn1nnc(-c2ccc(C(=O)Cl)cc2)n1
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1nnc(-c2ccc(C(=O)N[C@@H]3CCCC[C@@H]3c3ccc(OC)c(OC)c3)cc2)n1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
3.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound C2) are dissolved in 100 ml of methylene chloride and 3.0 ml of triethylamine. A solution of 3.0 g of 4-(2-ethyl-2-H-tetrazol-5-yl)benzoyl chloride in 50 ml of methylene chloride is added dropwise at RT and the mixture is extracted, after stirring for 2 h, with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulphate and concentrated. The residue is taken up in petroleum ether (low)/ethyl acetate in the ratio 2/1, filtered off with suction and dried. 5.2 g of the title compound of m.p. 188-192° C. are obtained.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[NH2:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2.[F:25][C@@H:26]1[CH2:30][N:29]([C:31](=[O:43])[CH2:32]OS(C2C=CC=CC=2)(=O)=O)[C@H:28]([C:44]#[N:45])[CH2:27]1>>[CH2:23]([O:22][C:20]([C:15]12[CH2:14][CH2:13][C:12]([NH:11][CH2:32][C:31]([N:29]3[CH2:30][C@@H:26]([F:25])[CH2:27][C@H:28]3[C:44]#[N:45])=[O:43])([CH2:19][CH2:18]1)[CH2:17][CH2:16]2)=[O:21])[CH3:24]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Agent: O=S(=O)(O)c1ccccc1
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 101.1 %

Procedure:
Using ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate benzenesulfonate (609 mg) and (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (783 mg), the same procedure was followed as in Example 7 to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile (609 mg, 87% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C@H:5]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]([OH:14])[C@H:6]1[OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:16]([O:15][C@@H:6]1[C@@H:7]([O:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:8]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]([CH2:11][O:12][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][C@@H:5]1[O:4][CH3:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of NaH (5.19 g of a 60% dispersion in oil, 130 mmol) in DMF (150 mL) was added portionwise methyl-α-D-glucopyranoside (4.2 g, 21.6 mmol). The resulting mixture was stirred at rt for 2 hr, to which tetrabutyl ammonium bromide (800 mg, 2.16 mmol) was and followed by dropwise addition of benzyl bromide (11.58 mL, 97 mmol). After stirring at rt overnight, the mixture was concentrated and the residue was suspended in water and extracted with ether (3×150 mL). The combined ether layers were washed with brine (200 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (330 g), eluting with 0-30% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 3.44 (s, 3H), 3.62 (dd, J=9.6, 3.5, 1H), 3.66-3.72 (m, 2H), 3.75-3.82 (m, 2H), 4.04 (t, J=9.3, 1H), 4.51-4.55 (m, 2H), 4.66 (d, J=12.1, 1H), 4.69 (d, J=3.5, 1H), 4.72 (d, J=12.1, 1H), 4.83-4.90 (m, 3H), 5.04 (d, J=11.0, 1H), 7.19 (m, 2H), 7.30-7.43 (m, 18H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[N:24]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[O:32][CH2:31][CH2:30][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: OCCN1CCOCC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(OCCN2CCOCC2)c2cc(C3OCCO3)ccc21

Procedure:
The title compound was prepared from 300 mg (0.672 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) in analogy to the procedure described in Example 21A. The procedure was modified by using 5 equivalents of 2-(morpholin-4-yl)ethanol as the alcohol reactant and by switching to toluene as solvent. After treating the mixture in a microwave oven at 140° C. for 2 h, the same amounts of catalyst and ligand were added again, and the mixture was refluxed for further 7 days using conventional heating. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient) to afford 93 mg (30% of th.) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C@H:42]3[CH2:47][CH2:46][C@H:45]([N:48]4[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]4)[CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CN1CCN([C@H]2CC[C@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-2-methyl-4-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-2,3-dihydro-1H-isoindol-1-one. 1H NMR (CDCl3, 400 MHz): δ=1.25-1.30 (m, 6 H), 1.40-1.55 (m, 2 H), 1.62 (q, J=12.80 Hz, 2 H), 1.97 (d, J=12.63 Hz, 2 H), 2.13 (d, J=11.87 Hz, 2 H), 2.37 (s, 3 H), 2.50 (d, J=12.13 Hz, 2 H), 2.61 (br. s., 2 H), 2.77 (br. s., 3 H), 3.14-3.20 (m, 2 H), 3.22 (s, 3 H), 3.93 (s, 3 H), 4.00-4.10 (m, 4 H), 4.38 (s, 2 H), 6.89 (dt, J=8.15, 2.24 Hz, 1 H), 6.94 (t, J=2.02 Hz, 1 H), 7.34 (d, J=8.59 Hz, 1 H), 7.63 (s, 1 H), 8.29 (d, J=8.59 Hz, 1 H), 8.39 (s, 1 H), 8.63 (d, J=8.59 Hz, 1 H), 10.50 (s, 1 H). MS (ES+): m/z 760.32 [MH+]; HPLC: tR=1.20 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: NC(=O)C1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: NC(=O)C1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidine-4-carboxamide. MS (ESI): mass calcd. for C22H22FN5O3S, 455.14; m/z found, 455.9 [M+H]+. 1H NMR (500 MHz, DMSO-δ6) δ 8.51 (d, J=1.4, 2H), 8.02 (dd, J=8.0, 1.3, 1H), 7.78-7.71 (m, 1H), 7.69-7.63 (m, 1H), 7.61-7.54 (m, 1H), 7.45 (dd, J=7.6, 1.4, 1H), 7.32 (dd, J=11.8, 1.7, 1H), 7.26 (dd, J=7.9, 1.8, 1H), 7.17 (s, 1H), 6.88 (s, 2H), 6.73 (s, 1H), 3.26-3.19 (m, 2H), 2.47-2.38 (m, 2H), 2.13-2.02 (m, 1H), 1.59 (dd, J=13.9, 3.8, 2H), 1.31-1.17 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]3[CH2:17][CH2:16]3)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Pd]>[C:19](=[N:32][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]3[CH2:17][CH2:16]3)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1COCC(c2cc(Br)ccc2F)(C2CC2)N1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Product: O=C1COCC(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)(C2CC2)N1

Procedure:
In an analogous manner to that described for the preparation of Building block A [f)], the palladium-catalyzed amination of (RS)-5-(5-bromo-2-fluoro-phenyl)-5-cyclopropyl-morpholin-3-one with benzophenonimine yielded the (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholin-3-one as a yellow foam. Mass (calculated) C26H23FN2O2 [414.478]; (found) [M+H]+=415.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22](C)([CH3:26])C(O)=O)=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C([O:45][C:46](=[O:56])CCSC1SC(N)=NC=1)C>>[CH3:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:13]([CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][CH2:22][CH2:26][C:46]([OH:56])=[O:45])=[CH:19][N:20]=2)[CH2:34][CH2:33]1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Agent: Sc1ccccc1
Product: C[C@H]1CC[C@H](N(CCCSc2ccccc2)C(=O)Nc2ncc(SCCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[C:6]=2[CH:16]=1.[CH3:18][C:19]1[C:20]([O:22][C:23](=O)[C:24]=1[CH3:25])=[O:21]>C(O)(=O)C>[CH3:25][C:24]1[C:23](=[O:22])[N:1]([C:2]2[C:3]([F:17])=[CH:4][C:5]3[O:9][N:8]=[C:7]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[C:6]=3[CH:16]=2)[C:20](=[O:21])[C:19]=1[CH3:18]
Reactant: COC(=O)C(C)c1noc2cc(F)c(N)cc12
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CC(=O)O
Product: COC(=O)C(C)c1noc2cc(F)c(N3C(=O)C(C)=C(C)C3=O)cc12

Procedure:
A solution of methyl 5-amino-6-fluoro-α-methyl-1,2-benzisoxazole-3-acetate (2.6 g, 11.0 mmol) in acetic acid is added to 2,3-dimethylmaleic anhydride (1.39 g, 11.0 mmol). The reaction mixture is refluxed for several hours and concentrated in vacuo to obtain a brown oil. A solution of the oil in ether is washed sequentially with sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a brown oil. Column chromatography of the oil using silica gel and ether/hexanes solutions gives the title product as a white solid, mp 106°-107° C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=1[CH2:20][CH:21]=[CH2:22])([CH3:3])[CH3:2].Cl>C(O)C.[Pd].CCOCC>[CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([CH3:3])[CH3:2]
Reactant: C=CCc1cc(OCCCC)ccc1OCCCNC(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCCOc1ccc(OCCCNC(C)C)c(CCC)c1
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A solution of N-isopropyl-3-(2-allyl-4-butoxy-phenoxy)propylamine (404 mg) in ethanol (15 ml) was hydrogenated at ambient temperature and pressure for 8 hours using a catalyst of palladium on carbon (10% w/w, 80 mg). The catalyst was removed by filtration and the filtrate evaporated to give a yellow oil. The oil was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 70:30:1 mixture of ethyl acetate, hexane and triethylamine to give an oil. The oil was dissolved in ether and excess ethereal hydrogen chloride was added until crystallisation began. The solid was collected by filtration and recrystallised from ethyl acetate to give N-isopropyl-3-(4-butoxy-2-propylphenoxy)propylamine (271 mg) as a white solid, m.p. 102 103° C.; microanalysis, found: C, 65.7; H, 10.2; N, 4.0%; C19H34NO2Cl. 0.25H2O requires: C, 65.5; H, 9.98; N, 4.02%; NMR ([CD3 ]2SO): 0.90(6H,m), 1.28(6H,d), 1.52(6H,m), 2.12(2H,m), 2.5(2H,m), 3.04(2H,m), 3.3(1H,m), 3.88(2H,t), 4.0(2H,t), 6.7(2H,t) and 6.85(1H,d); m/z 308 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][CH2:14][C@@:15]3([CH:19]=[CH:18][CH2:17][O:16]3)[C@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][C@H:11]2[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][C:44]=1I)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[Li+].C(N(CC)CC)C.C([O-])=O.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C)C=O>[CH2:1]([N:8]1[C@H:12]2[CH2:13][CH2:14][C@@:15]3([CH2:19][C@@H:18]([C:44]4[CH:45]=[C:46]([O:49][C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:48][C:43]=4[O:42][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:17][O:16]3)[C@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][C@H:11]2[S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]21C=CCO1
Reactant: FC(F)(F)Oc1ccc(OCc2ccccc2)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2OCc2ccccc2)CO1
Temperature: 60 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
Palladium acetate (140 mg, 0.6 mmol) was added to a degassed suspension of (1R*,2R*,5S*,6R*)-8-benzyl-2′,5′-dihydro-1-phenyl-6-phenylsulfonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Description 15; 2.9 g, 6.15 mmol), 2-benzyloxy-5-trifluoromethoxyiodobenzene (7.3 g, 18.5 mmol), tetrabutylammonium chloride, (1.7 g, 6.15 mmol), lithium chloride (2.6 g, 62 mmol), triethylamine (2.6 ml, 18 mmol), potassium formate (1.56 g, 18.5 mmol), N,N-dimethylformamide (40 ml) and water (3 ml). The mixture was stirred at 60° C. for 72 hours then partitioned between brine and ethyl acetate. The organic layer was washed (×3) with water then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5, 10, 15 and 30% ethyl acetate/iso-hexanes to yield the title compound (2.0 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH:16]1([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[CH2:18][CH2:17]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH:16]1([N:19]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=3)[CH2:22][CH2:21]2)[C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:17][CH2:18]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methyl-oxazol-5-yl)-benzoyl chloride (89 mg) is added portionwise to a mixture of cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine (100 mg) and ethyldiisopropylamine (100 μL) in dichloromethane (5 mL). The mixture is stirred for 1 h at room temperature, washed with water and 1 M HCl, dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 6): tR=1.83 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15].O[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[ClH:15].[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OC1CCNCC1
Agent: Cl
Solvent: CCO
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1

Procedure:
The starting material is prepared as follows: The mixture 268 of diphenylmethanol, 200 g of 4-hydroxypiperidine hydrochloride and 28.8 g of p-toulenesulfonic acid monohydrate is stirred and heated to 160° while reducing the pressure to 0.2 mm Hg with a vacuum pump for 3 hours. It is cooled to 80°, dissolved in 500 ml of ethanol and the solution cooled to 10°. The resulting suspension is filtered, the residue washed with isopropanol and dried at 60°, to yield the 4-diphenylmethoxy-piperidine hydrochloride. It is suspended in 1,800 ml of water, converted into the free base with 125 ml of aqueous ammonia and extracted with diethyl ether and the extract evaporated.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>[Pd].O>[F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])[CH2:11][CH2:12][C:13]2[N:17]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: [Pd]
Solvent: O
Product: N#Cc1ccc(C(O)CCc2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F

Procedure:
Product from Step F (8.93 g, 18.4 mmol), and 10% palladium on carbon (550 mg) were suspended in TBE (200 mL)/water (20 mL) and placed under a hydrogen atmosphere (1 atm) for 7 hours. The reaction solution was filtered through a Celite pad and concentrated in vacuo to provide the title compound as a white foam which was sufficiently pure for use in the next step.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:12][CH2:11][O:10][CH3:9])=[CH:6][N:7]=1
Reactant: Oc1ccc(F)nc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(F)nc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
To a 20 mL microwave vial, 6-fluoropyridin-3-ol (Alfa Aesar, 1.04 g, 9.24 mmol), 2-bromoethyl methyl ether (Aldrich, 1.04 mL, 11.1 mmol) and potassium carbonate (1.97 g, 14.2 mmol) were mixed into DMF (8 mL). The suspention was stirred at 45° C. for 1 h. The temperature was raised to 55° C. for 45 min. 2-Bromoethyl methyl ether (0.50 mL) was added and the mixture was stirred at 40° C. for overnight. The reaction mixture was poured into about 50 mL water and the aqueous phase was extracted with diethyl ether (2×40 mL). The aqueous phase was saturated with solid NaCl and extracted with diethyl ether (2×40 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The light brown oil was placed under an air stream for 30 min to remove residual ether to afford 2-fluoro-5-(2-methoxyethoxy)pyridine (1.64 g, 100% yield) as an amber oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.84-7.87 (m, 1H) 7.37 (ddd, J=9.05, 6.21, 3.13 Hz, 1H) 6.85 (dd, J=8.80, 3.52 Hz, 1H) 4.13-4.17 (m, 2H) 3.74-3.78 (m, 2H) 3.45 (s, 3H). m/z (ESI, positive ion): 172.1 (M+H)+.