Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:36]([C:39]1[N:44]=[C:43]([CH2:45][N:46]2[C:54]3[CH:53]=[CH:52][CH:51]=[C:50]([NH2:55])[C:49]=3[CH:48]=[N:47]2)[CH:42]=[CH:41][CH:40]=1)([CH3:38])[CH3:37].[OH-].[Na+].[NH4+].[Cl-]>O.CN1C(=O)CCC1>[CH:36]([C:39]1[N:44]=[C:43]([CH2:45][N:46]2[C:54]3[C:49](=[C:50]([NH:55][C:20]([C:17]4[N:14]5[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[CH:12][C:13]5=[N:19][CH:18]=4)=[O:21])[CH:51]=[CH:52][CH:53]=3)[CH:48]=[N:47]2)[CH:42]=[CH:41][CH:40]=1)([CH3:38])[CH3:37]
Reactant: CC(C)c1cccc(Cn2ncc3c(N)cccc32)n1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(Cn2ncc3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (188 mg, 0.595 mmol) was added NMP (5 mL, distilled over oven dried MgSO4 directly into the 25 mL flask charged with the lithium salt). A heat gun was used to dissolve the starting material. The flask was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (94.2 μL, 0.590 mmol) was added drop-wise. The cold bath was removed after addition was complete, and the reaction mixture was stirred for another hour. The reaction mixture turned from a clear solution to slightly cloudy. 1-((6-Isopropylpyridin-2-yl)methyl)-1H-indazol-4-amine (120 mg, 0.451 mmol) was added in one portion to the reaction mixture and the reaction was heated to 88° C. for 5 hours. NMP was removed by a vacuum distillation (at the same bath temperature) until the reaction mixture became a thick oil. NaOH (1.8 mmol) in H2O (10 mL) was added to the thick oil and the solution was stirred at 80° C. for 30 minutes. The solution was cooled to ambient temperature and the pH of the dark solution was adjusted to pH 12 to 13 with saturated NH4Cl. The solution was cooled to 0° C. and H2O (20 mL) was added. Stirring was continued for 30 minutes, during which time solids precipitated out of solution. The mixture was filtered and the filtrate was washed with saturated NaHCO3 and H2O. The resulting solid was dissolved in DCM, dried (Na2SO4), filtered and concentrated. The residue was triturated with MTBE give final product (15%). MS (ES+APCI) m/z=553.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[I:11]I.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cn1
Temperature: 40 °C

Procedure:
A flask was charged with 6-chloro-1H-pyrazolo[4,3-c]pyridine (3.0 g, 19.54 mmol), iodine (13.11 g, 51.7 mmol), KOH (3.29 g, 58.6 mmol) and DMF (60 mL). The mixture was heated at 40° C. for 16 h and then additional iodine (7.8 g, 30.7 mmol) and KOH (1.6 g, 28.4 mmol) were added. The mixture was heated at 70° C. for 3 h then quenched with 1N Na2S2O3 and extracted with EtOAc. The organic phase was washed with water, brine, and dried over Na2SO4. After evaporation of volatiles DCM was added. A solid precipitated and filtered to yield 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. for C6H4ClIN3 [M+1]+ 280. found 280.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24](O)=[O:25])[CH:21]=[CH:20][S:19]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.CC(=O)OCC.CCCCCCC>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:24]([C:23]2[N:22]3[C:18]([S:19][CH:20]=[CH:21]3)=[N:17][C:16]=2[CH3:15])=[O:25])[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Cc1nc2sccn2c1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101 %

Procedure:
A mixture of (R)-3-amino-1-N-Boc-piperidine (800 mg), 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (801.5 mg), PyBOP (2.08 g), DIEA (1.57 mL) in dry DMF (10 mL) was stirred at RT under nitrogen for 20 h. The reaction mixture was diluted with EA, washed with water. The aqueous phase was extracted twice with EA, the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield a crude light brown oil. FC (EA/n-heptane: 1/1 to EA) gave 1.47 g (100%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.ClC1C(C2C=CC(Cl)=CC=2)=CC2N(C(=O)N(CC3C=NC(C(F)(F)F)=CC=3)N=2)N=1>>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:9]2[C:8](=[O:11])[N:6]3[N:7]=[C:2]([Cl:1])[C:3]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)=[CH:4][C:5]3=[N:10]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Agent: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Yield: 60 %

Procedure:
The title compound (469 mg, 60%) was prepared from 6-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (500 mg, 1.78 mmol) and 1-chloromethyl-4-trifluoromethyl benzene (425 mg, 1.78 mmol) according to the procedures described for 6-chloro-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 8E). LC/MS (Method C): retention time=3.91 min, (M+H)+=439.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7](C(O)=O)=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CC(=O)OCC>[OH-].[Na+]>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=c1ccn(C2CC2)c2nc(Cl)c(F)cc12
Reaction time: 1 h

Procedure:
7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (2.0 g) was added portionwise to a boiling solution of Dowtherm (50 ml heated at 250° C.) and further stirred at this temperature for 1 h. The reaction mixture was allowed to reach rt and diluted with 1N NaOH (100 ml) and extracted with EA. The org. phase was discarded. The aq. phase was acidified with 3N HCl and extracted with ether/EA. The aq. layer was filtered and the filtrate was extracted with ether/EA. The combined org. layers were washed with water and brine dried over MgSO4, filtered and evaporated under reduced pressure affording a solid which was stirred in Hept/EA and filtered. The filtrate was concentrated under reduced pressure and purified by CC (EA to EA/MeOH 9:1), affording a beige solid.
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH:2]2[C:8](=[O:9])[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[O:5][CH:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:3]2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccccc2OC(c2ccccc2)CC1Br
Solvent: c1ccccc1
Product: CN1CCN(C2CC(c3ccccc3)Oc3ccccc3C2=O)CC1
Yield: 55.1 %

Procedure:
970 mg (3.1 m moles) of 4-bromo-2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one (compound R14 of Reference Example 14) was dissolved in 100 ml of benzene, 3.1 g (10 equivalent amount) of N-methylpiperazine was added to the solution, and the whole was heated to reflux for 7 hours. After distilling off the solvent, water was added to the residue, and the mixture was extracted with methylene chloride. The organic phase was washed with water and dried with anhydrous magnesium sulfate. After filtrating off the magnesium sulfate, the filtrate was concentrated to obtain a residue, which was then applied to a silica gel column, and eluted with a mixture of methylene chloride/methanol (90:10) to obtain diastereomers R15a (700 mg; yield 55.1%) and R15b (220 mg; yield 17.3%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>[Pd]>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 100 °C
Yield: 90 %

Procedure:
The procedure was as in Example 5, but the 2,4-difluorocinnamic acid obtained was not isolated. The aqueous-acidic product suspension obtained was treated with 2 g of Pd/C (5% strength) at 50° C. with further stirring and heated to 100° C. It was then pressurized to 5 bar of hydrogen. After constant pressure had been achieved, it was cooled to room temperature, the pressure was released and the solid was filtered off. The filter cake was taken up in methylene chloride, the palladium catalyst was filtered off and the solvent was removed. After drying in vacuo, 100.5 g of 3-(2,4-difluorophenyl)propionic acid (90% of theory; melting point: 100° C.) were obtained.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:32](=S)=[S:33].[Cl-].[NH4+]>C(O)C>[F:24][C:2]([F:23])([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:32]([SH:33])=[N:22][N:21]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Reactant: S=C=S
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(S)o4)cc23)c1

Procedure:
A mixture of the obtained 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide, triethylamine (5.6 mL, 40.4 mmol), carbon disulfide (18.2 mL, 303 mmol) and ethanol (70 mL) was heated under reflux for 5 hr. After cooling, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/2) and recrystallized from hexane/ethyl acetate to give 5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:15])[CH2:9][CH2:8]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][CH2:6][C@@:7]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH3:15])[CH2:9][CH2:8]1
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCN=[N+]=[N-])(c2ccc(F)cc2)OC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCN)(c2ccc(F)cc2)OC1=O
Yield: 25.5 %

Procedure:
To a solution of (R)-6-(3-azidopropyl)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (210 mg, 0.54 mmol) in THF (5 mL) and H2O (0.25 mL) was added Ph3P (420 mg, 1.60 mmol). After refluxing for 3 h, the mixture was concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-aminopropyl)-3-((S)-1-cyclohexyle-thyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (50 mg, 25%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu+2].[I-].[I-].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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: C#CCCO
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: [I-]
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
In a dry reaction tube containing in suspension iodide copper (38 mg, 0.2 mmol), and triethylamine (11 mL, 80 mmol), were added 2-bromopyridine (632 mg, 4 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.2 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution of but-3-yn-1-ol (280 mg, 4 mmol) in triethylamine (2.2 mL). Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80° C. for 20 h. Triethylamine was concentrated under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography (prepacked 15 g silicagel column, from DCM 100% to DCM/MeOH: 98/2 as eluent) to afford 440 mg of 4-(pyridin-2-yl)but-3-yn-1-ol (Yield: 74%) as brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:14][N:13](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NCC1CNC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:12][NH:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)OC(=O)NCC1CNC1
Product: CC(C)(C)OC(=O)NCCC1CNC1

Procedure:
The title compound was prepared from 3-(N-tert-butyloxycarbonylaminoethyl)-1-benzhydryl azetidine according the procedure for 3-(N-tert-butyloxycarbonylaminomethyl) azetidine, in a yield of 1.2 g (70%).
Reaction SMILES: CC1(C)CC(=O)C=CC1.C(C1C=CC=CC=1C(Br)O[SiH](C)C)(C)(C)C.[CH2:26]=[C:27]1[CH2:32][CH2:31][CH2:30][C:29]([CH3:34])([CH3:33])[CH:28]1[CH2:35][C:36]1[CH:41]=[C:40](OC)[C:39](Br)=[CH:38][C:37]=1[OH:45]>>[CH2:26]=[C:27]1[CH:28]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[OH:45])[C:29]([CH3:34])([CH3:33])[CH2:30][CH:31]=[CH:32]1
Reactant: C=C1CCCC(C)(C)C1Cc1cc(OC)c(Br)cc1O
Agent: CC1(C)CC=CC(=O)C1
Agent: C[SiH](C)OC(Br)c1ccccc1C(C)(C)C
Product: C=C1C=CCC(C)(C)C1Cc1ccccc1O

Procedure:
This compound was prepared from 5,5-dimethylcyclohex-2-en-1-one (11) and 2-(tert-butyl)dimethylsilyloxybenzyl bromide (9) in three steps in the manner previously described for the synthesis of olefin 16, affording the desired phenol as a colorless oil. 1H NMR (400MHz, CDCl3) δ0.90 and 1.15 (2s, 2×3H, geminal-CH3 's), 1.85 and 2.24 (d of ABq, 2H, JAB =18.8 Hz, JA =5,5 Hz, JB =0 Hz, 4-H), 2.06 (dd, 1H, J=11.4, 3.2 Hz, 6-H), 3.30 and 2.88 (d of ABq, 2H, JAB =13.5 Hz, JA =11.4 Hz, JB =3.4 Hz, benzylic-CH2), 4.20 and 4.69 (2s, 2×1H, methylidene-CH2), 4.61 (s, 1H, OH), 5.77 (ddd, 1H, J=7.8, 5.4, 5.4 Hz, 3-H), 6.09 (dd, 1H, J=7.5, 2.2 Hz, 2-H), 6.75 (dd, 1H, J=7.1, 0.8 Hz, 3'-H), 6.82 (ddd, 1H, J=8.4, 7.3, 1.1 Hz, 5'-H), 6.97 (dd, 1H, J=5.9, 1.5 Hz, 6'-H), 7.05 ppm (ddd, 1H, J=9.3, 7.8, 1.7 Hz, 4'H). [Compound 34 is hereinafter also referred to as COMPOUND "C" or 120363]
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCc4ccc(OC)cc4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.7 %

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.64 g, 8 mmol) and 4-(4-methoxyphenyl)-butyric acid (1.55 g, 8 mmol) are dissolved in CH2Cl2 (30 ml) at 25° C. Then N,N'-dicyclohexylcarbodiimide (1.65 g, 8 mmol) and 4-dimethylaminopyridine (0.97 g, 8 mmol) are added to the stirred solution. After the solution has been stirred for a further 14 hours at 25° C. the precipitate is filtered oft and washed with CH2Cl2 (20 ml). The combined organic phase is washed with water (2×10 ml), dried (Na2SO4), filtered and concentrated in the Rotavapor. The residue thus obtained is purified by flash chromatography (silica gel; mobile phase: CH2Cl2 :MeOH=9:1). The residue is freed from residual solvent under high vacuum in order to obtain 4,5α-epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinan-7-ene (3.71 g, 91.7%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15](C)([C:19](O)=O)[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C)(C(=O)O)C(=O)O)cc2s1
Solvent: O
Product: CCOC(=O)c1cc2ccc(C(C)C(=O)O)cc2s1
Temperature: 210 °C

Procedure:
[2-(ethoxycarbonyl)-1-benzothien-6-yl](methyl)malonic acid (0.19 g, 0.590 mmol) was suspended in H2O (5 mL) before heating at 210° C. in a microwave reactor for 40 seconds. The suspension was diluted with H2O (50 mL) and the products extracted into EtOAc (2×75 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give the product (white solid). 1H NMR (DMSO-d6) δ 12.41 (br s, 1H), 8.14 (s, 1H), 7.95 (br s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.37 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.81 (q, J=7.2 Hz, 1H), 1.40 (d, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>C(Cl)Cl>[C:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reaction time: 3 h

Procedure:
To a mixture of piperazine-2-one (1.037 g, 10.4 mmol) in 52 mL of CH2Cl2, was added BOC2O (2.5 g, 11.4 mmol). The reaction became homogeneous after 3 hours when the starting material was completely consumed. The reaction was diluted with CH2Cl2 and the organic layer was washed with water. The solvent was removed in vacuo to yield quantitative amount of product 33 as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.35-3.44 (m, 2H), 3.64 (t, 2H, J=5 Hz), 4.10 (s, 2H), 6.41 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][C:58]=2[F:67])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([C:63]([F:66])([F:64])[F:65])[CH:60]=[CH:59][C:58]=2[F:67])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:68][CH:69]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cc(C(F)(F)F)ccc2F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cc(C(F)(F)F)ccc2F)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 118 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After 3.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 90 mg light yellow viscous oil (53%). MS (EI) 530.2 (M)+.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1.C(O)C(N)(CO)CO.C(N(CC)CC)C.[F:43][C:44]([F:59])([F:58])[C:45]1[CH:46]=[C:47]([N:55]=[C:56]=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>O1CCCC1>[F:43][C:44]([F:58])([F:59])[C:45]1[CH:46]=[C:47]([NH:55][C:56]([N:25]2[CH2:26][CH2:27][N:22]([C:17]3[C:16]([O:15][CH2:14][C:11]4[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:23][CH2:24]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:52])[F:53])[CH:50]=1
Reactant: c1cnc(N2CCNCC2)c(OCc2ccncc2)c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NC(CO)(CO)CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ncccc2OCc2ccncc2)CC1
Reaction time: 1 h
Yield: 3.1 %

Procedure:
The crude 1-[3-(Pyridin-4-ylmethoxy)pyridin-2-yl]-piperazine trifluoroacetic acid salt (˜500 mg) was dissolved in 25 mL of tetrahydrofuran along with 2 g of trisamine resin. The suspension was stirred for 1 hr and the resin was removed by filtration. The filtrate was concentrated under vacuum. The free-based material was dissolved in 5 mL of dichloromethane. To this solution was added triethylamine (150 μL, 1.08 mmol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (150 μL, 0.864 mmol). The reaction was stirred at room temperature for 1 hr. The reaction mixture was concentrated under vacuum and re-dissolved in 25 mL ethyl acetate. The reaction mixture was washed 3 times each with 25 mL portions of water, 0.05 M HCl and saturated aqueous sodium chloride. The organic fraction was dried with magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography with a gradient of 0% to 10% methanol in ethyl acetate with 5% triethylamine, giving N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide (14 mg). 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 8.60 (d, 2H), 8.22 (s, 2H), 7.84 (d, 1H), 7.58 (s, 1H), 7.46 (d, 2H), 7.33 (d, 1H), 6.92 (dd, 1H), 5.23 (s, 2H), 3.62-3.68 (m, 4H) 3.37-3.41 (m, 4H) ppm.