Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:17](=[O:18])[C:16]3[C:8]4[C:9]([CH:13]=[CH:14][N:15]=3)=[CH:10][CH:11]=N[C:7]=4[C:5]=2[CH:6]=1.C[O:20]C1C=NC2C3C=CC=CC=3C(C3C=2C=1C=CN=3)=O.CC1C2=C3C(=NC=C2)C(=O)C2C(=CC=CC=2)C3=NC=1.BrC1C(=O)C2C(C(=O)C=1)=CC=CC=2.CN(C)N=C/C=C/COC.CN(C)N=C/C=C/CC>>[CH3:11][CH2:10][C:9]1[CH:13]=[CH:14][N:15]=[C:16]2[C:17]([C:4]3[C:5]([C:7](=[O:20])[C:8]=12)=[CH:6][CH:1]=[CH:2][CH:3]=3)=[O:18]
Reactant: O=C1c2ccccc2-c2nccc3ccnc1c23
Reactant: COc1cnc2c3c(nccc13)C(=O)c1ccccc1-2
Agent: CC/C=C/C=NN(C)C
Agent: COC/C=C/C=NN(C)C
Agent: Cc1cnc2c3c(nccc13)C(=O)c1ccccc1-2
Product: CCc1ccnc2c1C(=O)c1ccccc1C2=O

Procedure:
It was unexpectedly discovered that a modification of the foregoing method for preparing sampangine enabled the preparation of 3-methoxysampangine (19) and 3-methylsampangine (14) heretofore never achieved. The Hetero Diels-Alder reaction of 2-bromo-1,4-naphthoquinone (1) with (E)-4-methoxy-2-butenal N,N-dimethylhydrazone (17) or (E)-2-pentenal N,N-dimethylhydrazone (12) gave 4'-methoxycleistopholine (18) or homocleistopholine (13), respectively, in modest yield. Generation of the sampanglue nucleus (i.e., 3-methoxysampangine (19)and 3-methylsampangine (14)) was accomplished through condensation of the corresponding cleistopholine with dimethylformamide dimethylacetal. For the 3-methylsampangine reaction, at least two additional compounds, 4'-oxohomocleistopholine (15) and dimer 16, were produced in significant quantities. The exact yields for 15 and 16 remain undetermined due to difficulty in isolation. Chromatography of the reaction product gave fractions consisting of recovered homocleistopholine (11%), 3-methylsampangine (6%), and a fraction consisting of compounds 14-16. Recrystallization of the latter fraction from ethyl acetate followed by manual separation of the crystal types gave pure 15 and 16; 3-methylsampangine crystallized as long yellow needles, 4'-oxohomocleistophiline (6%, 15) as nearly perfect golden octahedra, and dimer 16 (6%) as rectangular yellow plates. ##STR3##
Reaction SMILES: C(OCC(F)(F)C(F)(F)C(F)([F:12])CO)CCC.[CH2:18]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@@H:40](O)[CH2:41][O:42][CH2:43][C:44]([F:58])([F:57])[C:45]([F:56])([F:55])[C:46]([F:54])([F:53])[CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:18]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@H:40]([F:12])[CH2:41][O:42][CH2:43][C:44]([F:58])([F:57])[C:45]([F:56])([F:55])[C:46]([F:54])([F:53])[CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:34][CH:33]=2)=[N:30][CH:31]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCc1cnc(-c2ccc(OC[C@@H](O)COCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)nc1
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)CO
Product: CCCCCCCCc1cnc(-c2ccc(OC[C@H](F)COCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Examples 3 and 4 by combining 5-butoxy-2,2,3,3,4,4-hexafluoropentanol (3.1 g, 11.7 mmol, prepared essentially by the method described in U.S. Pat. No. 5,399,291 (Janulis et al.)) with (S)-5-octyl-2-[4-(2,3-oxiranylpropoxy)phenyl]pyrimidine (2.0 g, 5.87 mmol) to produce 5-octyl-2-[4-((S)-2-hydroxy-3-(-5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)propoxy)phenyl]pyrimidine. This chiral (S)-hydroxy compound (2.0 g, 3.3 mmol) was treated with diethylaminosulfur trifluoride (1.06 g, 6.6 mmol) to produce the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccccc1F

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.335 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.03 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 2-fluorophenylboronic acid (0.210 g) in ethanol (1 ml). The mixture was heated under reflux for 5.5 hours, cooled and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, washed with water (25 ml), brine (25 ml) and then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white crystalline solid, m.p. 197° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].NC1[NH:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1>C(#N)C>[N:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:12][C:11]=2[NH:10][C:9]=1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Yield: 73.3 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (8.91 g, 50 mmol) and 2-aminobenzimidazole (6.66g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 19 hours. The resulting precipitate was collected by filtration to provide 8.92 g (73%) of the titled product: IR (KBr, cm-1) 3058, 2621, 1623, 1580, 1509, 1469, 1445, 1355, 1290, 1252, 1212, 1153, 1099, 1081, 1048, 925, 898, 746, 659; 1H NMR (300 MHz, DMSO-d6) δ 13.24 (br s, 2H), 8.52 (s, 1H), 7.87 (s, 1H), 7.57 (m, 2H), 7.33 (m, 2H), 6.96 (s, 1H); MS (FAB) m/e 244 (M+1); UV (EtOH) 351 nm (ε=18204), 283 nm (ε=13099), 227 nm (ε=17339), 204 nm (ε=31915).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH:6]=[CH:5]1>CO.O>[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]=[CH:5]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)C=CC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Sodium borohydride (5.03 g, 133 mmol) was added portion-wise to a stirred solution of 4,4-dimethylcyclohex-2-enone (15.0 g, 121 mmol) in methanol (403 mL) in a water bath. Once addition was complete, the solution was allowed to stir under a nitrogen atmosphere at room temperature for 3 h. The reaction mixture was diluted with water (150 mL) and the majority of the methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (2×200 mL). The combine ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil under reduced pressure to afford 4,4-dimethylcyclohex-2-enol (13.4 g, 106 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.41-5.57 (m, 1H), 5.24-5.42 (m, 1H), 4.61 (d, J=5.47 Hz, 1H), 3.82-3.99 (m, 1H), 1.65-1.83 (m, 1H), 1.21-1.59 (m, 3H), 0.93 (d, J=15.23 Hz, 6H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10](F)=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1.Cl>CS(C)=O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCCCN
Agent: Cl
Solvent: CS(C)=O
Product: CCCCNc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of butylamine (1.25 g, 17.1 mmol) in DMSO (14 mL) was treated with 4-bromo-1-fluoro-2-nitrobenzene (1.50 g, 6.82 mmol), heated to 70° C. for 1 hour, added to 1M HCl (60 mL), and extracted with diethyl ether (3×75 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([CH2:31][NH2:32])=[CH:23]1>>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([CH2:31][NH:32][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)=[CH:23]1
Reactant: NCc1csc2ccccc12
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCc3csc4ccccc34)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1-benzothien-3-ylmethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 434.3. HPLC (Condition A), Rt: 4.30 min (HPLC purity: 89.9%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[S:3]([O:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][CH2:17][O:18][S:22]([CH3:21])(=[O:24])=[O:23])[O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(Oc1cccc2oc(CCO)cc12)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2o1

Procedure:
As shown in Scheme 15, 2-(2-Hydroxyethyl)-1-benzofuran-4-yl trifluoromethanesulfonate, prepared as described in Examples 85A-85C herein, is treated with methanesulfonyl chloride and triethylamine in CH2Cl2 at 0° C. to provide 2-{2-[(methylsulfonyl)oxy]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate. 2-{2-[(Methylsulfonyl)oxy]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is treated with (2R)-methylpyrrolidine mono-(L)-tartaric acid salt and Cs2CO3 in MeCN at approximately 35° C. for 1 to 4 days to provide 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate. 2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is processed as described in Murata, et al., Journal of Organic Chemistry (2000) 65, 164-168 to provide (2R)-2-methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-yl]ethyl}pyrrolidine. For example, one equivalent of 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-4-yl trifluoromethanesulfonate is treated with palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl2 dppf), 3 equivalents of triethylamine, and 1.5 equivalents of pinacolborane in 1,4-dioxane at 25° C. for several hours or until the reaction is complete as judged by TLC. (2R)-2-Methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-yl]ethyl}pyrrolidine is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst, such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent such as ethanol or tetrahydrofuran at 25° C. to 120° C. to provide compounds of formula (51). Compounds of formula (51) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (51) is partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][C:5]2[N:6]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:39][C:40]([F:51])([F:50])[C:41]1[CH:42]=[C:43]([CH2:47][CH2:48][NH2:49])[CH:44]=[CH:45][CH:46]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:39][C:40]([F:50])([F:51])[C:41]1[CH:42]=[C:43]([CH2:47][CH2:48][NH:49][C:2]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][C:5]3[N:6]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:7]([N:9]4[CH2:14][CH2:13][N:12]([C:15]5[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=5)[CH2:11][CH2:10]4)=[N:8][C:4]=3[CH:3]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2cc(Br)c(C(F)(F)F)cc21
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2cc(NCCc3cccc(C(F)(F)F)c3)c(C(F)(F)F)cc21
Temperature: 150 °C

Procedure:
A mixture of the product from step (a) above (88 mg, 0.14 mmol), 2-(3-trifluoromethylphenyl)ethylamine (45 mg, 0.24 mmol, Trans World Chemicals), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.01 mmol, Strem), 2-(di-t-butylphosphino)biphenyl (8 mg, 0.03 mmol, Strem) and sodium-tert-butoxide (31 mg, 0.33 mmol, Aldrich) in toluene (2 mL) was heated at 150° C. in a microwave synthesizer for 14 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (5 mL) and filtered through a Celite® pad. The filtrate was concentrated in vacuo and the residue dissolved in MeOH (4 mL), and purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as pale-yellow oil. MS (ESI, pos. ion) m/z: 733 (M+1).
Reaction SMILES: [NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Br:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C(OCC)C>C(Cl)Cl>[Br:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][O:22][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1
Reactant: C[C@@H](CO)CBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](CBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.7 %

Procedure:
Pyridinium-4-toluenesulfonate (PPTs) (0.18g, 0.072 mmol) was dissolved in dry CH2Cl2 (30 mL), (S)-(+)-3-bromo-2-methyl-1-propanol (1.1 g, 7.2 mmol) and 2,3-dihydro-4H-pyran (DHP) (0.60 g, 7.2 mmol) were added. The mixture was stirred under a N2 atmosphere at room temperature for 5 h. Diethylether (20 mL) was added and the resulting mixture was washed with brine (820 mL), dried (MgSO4) and the solvents were removed In vacuo. This afforded a crude product which on ball-tube-distillation (90° C./0.1 mmHg) gave the title compound 1.07 g (63%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[N:8]=[C:7]([S:21][CH3:22])[N:6]=1.[BrH:24]>C(O)(=O)C>[Br:24][C:11]1[C:10]2[C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)=[N:8][C:7]([S:21][CH3:22])=[N:6][C:5]=2[CH:4]=[CH:3][N:12]=1.[BrH:24]
Reactant: CSc1nc(/C=C/N(C)C)c(C#N)c(Nc2cccc(C)c2)n1
Agent: Br
Solvent: CC(=O)O
Product: CSc1nc(Nc2cccc(C)c2)c2c(Br)nccc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The crude 4-[(E)-2-(dimethylamino)ethenyl]-6-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile (1.47 g) was dissolved into acetic acid (5 mL) and a solution of 33% HBr in glacial acetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 20 min. The mixture was then concentrated under reduced pressure to give the bromopyridine as a HBr salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26](O)[CH2:27][CH3:28])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:13]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:25]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To THF solution of 0.409 g (2.4 mmol) methyl 3-hydroxyphenylacetate, 0.50 g (20.5 mmol) N-Boc-piperidin-4-yl-propanol and 0.645 g (24.6 mmol) triphenylphosphine was added diisopropyl azodicarboxylate at 0° C. slowly, then the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation, the residue was dissolved in 2 mL methylene chloride and was loaded on a silica gel column and, the product eluted with 80% hexane and 20% ethyl acetate. Methyl 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetate (0.5 g, 62%) was obtained. 1H NMR (500 MHz, CDCl3) δ 1.1 (m, 2H), 1.4 (m, 2H), 1.46 (s, 9H), 1.66 (d, 2H), 1.78(m, 2H), 2.67 (t, 2H), 3.58 (s, 2H), 3.68 (s, 3H), 4.05 (m, 2H), 6.75 (m, 3H), 7.18 (dd, 1H).
Reaction SMILES: [C:1]([O:4][CH:5]([C:14]1[CH:18]([OH:19])[O:17][C:16](=[O:20])[CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:19][CH:18]1[O:17][C:16](=[O:20])[CH:15]=[C:14]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:23])[CH3:22]
Reactant: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1OC(C)=O
Reaction time: 20 h

Procedure:
A mixture of 4-(1-acetoxynonyl)-5-hydroxy-2(5H)-furanone (77.3 mg, 0.27 mmol), acetic anhydride (1/2 ml) and pyridine (1 ml) was stirred under argon at ca. 20° for 20h. After most of the solvent was removed under high vacuum (<40°), the residue was dissolved in ether (20 ml) and washed thoroughly with aqueous copper sulfate and water. Drying (magnesium sulfate) and evaporation gave a brown oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf 0.22 on evaporation afforded the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:13]=1[N+:24]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:13]=1[NH2:24]
Reactant: COCC(C)Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: COCC(C)Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1N
Yield: 74.9 %

Procedure:
[4-(2-Chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.45 g, 1.15 mmol) and Na2S2O4 (1.62 g, 9.32 mmol) were treated substantially as described in Part E of Example 9 to yield 0.31 g (74%) of 4-(2-chloro-4-trifluoromethyl-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 359.8 [(M+H)+, 97].
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]>CN(C=O)C>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([CH:43]3[CH2:48][CH2:47][N:46]([C:11]4[CH:12]=[CH:13][C:14]5[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=5)[N:16]=4)[CH2:45][CH2:44]3)=[CH:41][CH:42]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
DIPEA (5.21 mL, 29.93 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (6.06 g, 27.21 mmol) and 4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidine (9.40 g, 27.21 mmol) in DMF (200 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. Water (600 mL) was then added and the mixture extracted with DCM (2×600 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (13.80 g, 95%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:6]([CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[CH3:15][Li].[Cl-].[NH4+]>O1CCCC1>[CH3:15][C:4]1([OH:14])[CH2:5][CH:6]([CH3:13])[CH:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:2]([CH3:1])=[CH:3]1
Reactant: CC(C)=CCC1C(C)=CC(=O)CC1C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCC1C(C)=CC(C)(O)CC1C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 3,5-dimethyl-4-(3-methyl-2-butenyl)-2-cyclohexen-1-one (2.9 g, 0.015 mol), prepared according to Example 4, in anhydrous tetrahydrofuran (20 mL), was cooled to 0° C. under nitrogen and 1.6 M ethereal methyllithium (10 mL) added dropwise. The solution was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was poured into ammonium chloride solution and extracted with ether. The ether extracts were washed with water, brine and dried (Na2SO4). Solvent removal and kugelrohr distillation (bath temperature 95°-100° C./0.1 mm) gave 2.8 g of the alcohol.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O>S(=O)(=O)(O)O>[CH3:7][C:2]1([CH3:1])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:6])[CH2:3]1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)c2ccccc21
Temperature: 130 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
3-Methyl-3-phenyl-butanoic acid (247.2 g, 1.39 mol) was placed in a flask and warmed to 130° C. Sulphuric acid 95% (180 ml) was then added over 4 min and the mixture was stirred at 130° C. for 1 h, after which more sulphuric acid (10 ml) was added. After stirring for 45 min, the dark solution was poured onto ice (500 g) and extracted with hexane (200 ml). The organic phase was washed with NaHCO3 (50 ml), dried (MgSO4) and evaporated. The remaining oil was distilled in vacuo (78°0,065 Torr) to give 3,3-dimethyl-1-indanone (157.5 g).
Reaction SMILES: [OH:1][C:2]1([CH2:7][S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:33]I>>[CH3:33][O:1][C:2]1([CH2:7][S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:31][CH2:32]2)(=[O:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC1(O)CCCC1)CC2
Product: COC1(CS(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)CCCC1

Procedure:
The title compound was prepared in analogy to example 209 from 8-(1-hydroxy-cyclopentylmethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 210) and methyl iodide. Off-white solid. MS (ESI): 491.2 (MH+).