Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Br[CH:3]([CH3:9])[C:4]([O:6]CC)=[O:5].O.[OH-].[Na+].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH3:14][CH:13]([O:16][CH:3]([CH3:9])[C:4]([OH:6])=[O:5])[CH3:15]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(C)OC(C)C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, addition funnel, condenser and nitrogen bubbler was charged with 250 milliliters of dry isopropyl alcohol. Sodium metal (7.1 grams, 0.31 mole) in small pieces was added and the solution was heated to reflux to complete the reaction. After cooling to 60° C., 54.3 grams (0.30 mole) of ethyl 2-bromopropionate in 50 milliliters of isopropanol was added dropwise over a 20 minute period, and then the solution was refluxed for 2 hours, and left standing overnight. One hundred fifty (150) milliliters of water and 13.0 grams of sodium hydroxide pellets were added and then the mixture was distilled at 90° C., then cooled in an ice bath and acidified to pH2 with concentrated hydrochloric acid. The oil phase which formed was extracted with 150 milliliters of dichloromethane, CH2Cl2, and the extract was dried over anhydrous magnesium sulfate, filtered and topped on a roto-vac at 70° C. to yield 27.8 grams of a pale yellow viscous liquid of 2-(1-methylethoxy)propanoic acid.
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH3:16])[C:7]=1[C:8](N)=[O:9]>O.S(=O)(=O)(O)O>[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH3:16])[C:7]=1[C:8]([OH:2])=[O:9]
Reactant: Cc1cc(Cl)nc(Cl)c1C(N)=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)nc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
A solution of sodium nitrite (2.73 g, 39.6 mmol) in water (15 mL) was added slowly to a solution of commercially available (Maybridge) 2,6-dichloro-4-methyl-nicotinamide (4.5 g, 22 mmol) in concentrated sulfuric acid resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 7 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting white precipitate was collected by filtration and washed with hexane. The aqueous filtrate was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was combined with the white precipitate to afford 2,6-dichloro-4-methyl-nicotinic acid (4.39 g, 97%) as a white solid: LCMS RT: 1.20 min, MH+: 206.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[O:9][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]
Reactant: Oc1ccc(I)cc1Cl
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1ccc(I)cc1Cl)(C(C)C)C(C)C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 2-chloro-4-iodophenol (351.2 g, 1.38 moles) in toluene (1750 ml) under nitrogen, was added triethylamine (168 g, 1.66 moles), dimethylaminopyridine (8.5 g, 0.069 moles) and chlorotriisopropylsilane (320 g, 1.66 moles), then stirred for 16 hours. After this time the reaction was quenched by the addition of aqueous hydrochloric acid (2M, 1000 ml) and the organic phase washed with water (1000 ml). The solution was dried by azeotropic distillation of toluene, to give the title compound as a clear oil (497 g, 87%).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]([NH:21][CH2:22][C:23](=O)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1>C(O)(=O)C.C1(C)C(C)=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]2[N:2]([CH3:1])[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][N:21]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: COc1cc(/C=C/C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Reactant: CN
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: COc1cc(/C=C/c2ncc(-c3ccccc3)n2C)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of methylamine (2 M solution in methanol, 2.7 mL) in acetic acid (5 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxo-2-phenylethyl)acrylic acid amide (100 mg) in xylene (10 mL), and the reaction solution was heated under reflux for 3.5 hours while evaporating methanol. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=5:1) to obtain 11 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.C(N(CC)CC)C.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](Cl)=[O:32]>ClCCl>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:32]
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Reactant: O=C(Cl)Cc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC[C@H](NC(=O)Cc2ccccc2Br)[C@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.8 %

Procedure:
To a solution of 250 mg (1.2 mmol) of (4S,5S)-amine 1 in dichloromethane (3 mL) was added 0.16 mL (1.2 mmol) of triethylamine followed by dropwise addition of 0.17 mL (1.2 mmol) of 2-bromophenylacetyl chloride. After stirring for ˜96 h at 25° C., the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (hexanes/ethyl acetate) to yield 290 mg (60%) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:24]([Cl:25])[C:18]=2[N:17]=1>>[Cl:25][C:24]1[C:18]2[NH:17][C:16]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:6][CH2:5]3)=[N:20][C:19]=2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=1
Reactant: OCc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Product: OCc1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CC1

Procedure:
The piperazine from step (a) above (97 mg, 0.5 mmol) reacted with 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (85 mg, 0.33 mmol, Example 5b) under the conditions of Example 3c to give the title compound as a white solid. M.p. 252° C. MS (ESI, pos. ion) m/z: 412 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26].[CH3:28][Li]>O1CCCC1>[CH3:26][C:3]1([CH3:27])[C:2]([CH3:28])([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(O)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 69 %

Procedure:
By reacting (S)-N-{3-[4-(4-oxo-3,3-dimethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.3 mmol) and methyl lithium (2.3 mmol) in tetrahydrofuran (20 ml) followed by silica gel chromatographic separation of diastereomer the compound was obtained in 69% yield. M.P. 114-116° C. and MS (M+1)=394 (MH+, 100%) for M.F.=C20H28FN3O4.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27][CH3:28])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:29].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27]([CH3:28])=[O:29])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1Cl
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 71 %

Procedure:
3-butyryl-4-(2-chlorophenylamino)-8-(2-methylthioethoxy)quinoline (0.34g, 0.82 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.37 ml) were added and the mixture was stirred for 2 h. Another portion of sodium hypochlorite (0.5 ml) was added and the stirring was continued for 2 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from a mixture of ethyl acetate and isopropyl ether and 0.25 g (71%) of the title compound was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=Cc1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a solution of 20 g (137 mmol) 1H-indazole-5-carbaldehyde in acetonitrile (580 ml), 28 g (157 mmol) 1-bromopyrrolidine-2,5-dione were added over 20 min at room temperature. The resulting suspension was stirred under reflux for 30 min, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1500 ml), and the solution was washed with water and with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with ethyl acetate. After filtration, the precipitate was dried under vacuum to yield the title compound as a white solid (30.9 g, 75% of th.).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[C:4](=[O:14])[O:3]1.C(O)(=O)C.N#N>CO.[Pd]>[C:2]([OH:7])(=[O:3])[CH3:1].[NH2:13][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:15])([CH3:1])[O:3][C:4](=[O:14])[C:5]=2[CH:11]=1
Reactant: CC1(C)OC(=O)c2cc(C#N)ccc2O1
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)OC(=O)c2cc(CN)ccc2O1
Reaction time: 22 h
Yield: 74.8 %

Procedure:
To a solution of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carbonitrile (12 g, 0.06 mol) in methanol (500 mL) was added glacial acetic acid (3.5 g, 0.059 mol) and passed N2 for 30 min. To this was added Pd/C (2.4 g, 20%) and hydrogenated under 2 Bars of pressure for 22 h. The reaction mixture was filtered through celite and filtrate concentrated under vacuum. To the solid was added EtOAc (200 mL), stirred for 20 h and filtered. The solid was dried under vacuum to give the title compound (6 g, 38%). TLC: CHCl3/MeOH, 9:1, Rf: 0.15
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].N1C=CC=CC=1>C(Cl)Cl>[OH:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Nc1ccccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. A solution of methanesulfonyl chloride (3.4 mL, 44 mmol) in anhydrous methylene chloride (40 mL) was added dropwise to a stirring solution of 2-aminobenzylalcohol (5 g, 40.6 mmol) and anhydrous pyridine (16 mL, 203 mmol) in anhydrous methylene chloride (80 mL). The resulting mixture was stirred at room temperature for 24 hours and concentrated to ⅓ volume and diluted with ethyl acetate. The organic solution was successively washed twice with 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude residue was passed through a pad of silica gel, washing with ethyl acetate/hexanes to give a yellow oil (6.1 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.84 (br s, 1H), 7.53 (d, 1H, J=8.1 Hz), 7.36-7.30 (dt, 1H, J=1.5, 7.8 Hz), 7.25-7.21 (dd, 1H, J=1.5, 7.8 Hz), 7.16-7.11 (dt, 1H, J=1.2, 7.5 Hz), 4.77-4.75 (d, 2H, J=5.1 Hz), 3.04 (s, 3H), 2.60 (t, 1H, J=5.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:36]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:26])[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2[C:14]([C:15]=1[Cl:36])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cl)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Yield: 95 %

Procedure:
A solution of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (13) (0.40 g, 1.13 mmol) and triethylamine (393 μL, 2.82 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 400 mg (95%) of 4-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (14) as white solids. 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.0 Hz, 3H), 3.62 (s, 3H), 4.30 (q, J=7.0 Hz, 2H), 5.47 (s, 2H), 6.81 (d, J=7.7 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H), 8.40 (dd, J=1.5, 7.5 Hz, 1H), 8.71 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 373 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH:15]3[NH:20][CH:21]=[O:22])[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:4].O.[CH3:24]I>C1(C)C(C)=CC=CC=1>[CH2:3]([N:5]1[C:17]2[CH:16]3[CH2:18][CH2:19][CH:13]([CH2:14][CH:15]3[N:20]([CH3:24])[CH:21]=[O:22])[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:4]
Reactant: CI
Reactant: CCn1c2c(c3ccccc31)C1CCC2C(NC=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCn1c2c(c3ccccc31)C1CCC2C(N(C)C=O)C1
Reaction time: 18 h

Procedure:
To a stirred suspension of sodium hydride (0.5 g of 57% oil dispersion, 0.011 mole) in dry xylene (15 ml), a solution of N-(9-ethyl-2,3,4,9-tetrahydro-1,4-ethano-1H-carbazol-2-yl)-formamide (0.9 g, 0.0034 mole, described in Example 6) in dry xylene (15 ml) was added dropwise under nitrogen. The suspension was refluxed with stirring for 18 hr. The reaction mixture was cooled. The water condenser was replaced by a dry ice/acetone condenser and methyl iodide (1.7 ml) was added. The reaction mixture was refluxed for 5 hr. Additional 1.7 ml of methyl iodide was added. The solution was refluxed for 4 hr and stirred at 20° C. for 18 hr. The reaction mixture was cooled in ice, and water was added dropwise to destroy the excess hydride. The compound was extracted with ethyl acetate and the organic layer was washed with water, dried and evaporated to afford the title compound as a yellow oil (ca. 1.2 g): IR (CHCl3) 1650 cm-1.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:15])=[C:9]([CH3:14])[C:10]=1[CH2:11][CH2:12][CH3:13])(OCC)=O.C=O>>[CH3:1][C:6]1[NH:7][C:8]([CH3:15])=[C:9]([CH3:14])[C:10]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1c(C(=O)OCC)[nH]c(C)c1C
Agent: C=O
Product: CCCc1c(C)[nH]c(C)c1C

Procedure:
2-Carbethoxy-3-n-propyl-4,5-dimethyl-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4,5-trimethyl-3-n-propyl-pyrrole. ##STR94##
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][C:32](O)([C:35]#[C:36][C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:35]#[C:36][C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
Pyridine (1.12 ml) and trifluoromethanesulfonic anhydride (875 μl) were added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-hydroxy-4-(methoxycarbonyl-ethynyl)piperidine (490 mg) in dichloromethane (15 ml) at −78° C. After heating the mixture to room temperature in 1 hour, a saturated aqueous solution (50 ml) of sodium hydrogencarbonate and dichloromethane (10 ml) were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1→2:1) to obtain the title compound (249 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>C(O)C>[NH2:20][C:19]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: NNc1ccc(Cl)c(Cl)c1Cl
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Yield: 43.9 %

Procedure:
2,3,4-Trichlorophenylhydrazine (21.15 g) was added in portions to a refluxing solution of ethoxymethylenemalononitrile (12.2 g) in ethanol (100 ml). The solution obtained was then heated at reflux for one hour, cooled and evaporated to dryness. The residue thus obtained was triturated with diethyl ether (100 ml) to give 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (12.6 g), m.p. 158°-160° C., in the form of light brown crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[CH2:13]([O:15][C:16](=[O:24])[CH2:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1)[CH3:14].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[NH2:8][CH2:9][C:10]([NH:23][C:20]1[S:21][CH:22]=[C:18]([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:24])[N:19]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)CN)n1

Procedure:
A mixture of N-(tert-butoxycarbonyl)glycine (3.1 g), 2-amino-4-thiazoleacetic acid ethyl ester (3 g) and bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (7.54 g) in dimethylformamide (20 ml) was treated with N,N-diisopropylethylamine (6 ml). After 25 minutes N,N-dimethyl-4-aminopyridine (1.96 g) was added. After 24 hours the mixture was partitioned between ethyl acetate and brine. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, IN HCl and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 50% ethyl acetate in isohexane. The product (0.77 g) was dissolved in dichloromethane (25 ml) and trifluoroacetic acid (10 ml). After 2 hours the mixture was evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase was repeatedly extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. Yield 0.41 g.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][Cl:27]>O1CCCC1>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:12][CH2:11]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: ClCCCBr
Reactant: CCCCCCC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCC(=O)NC1CCN(CCCCl)CC1

Procedure:
A mixture of 4-heptanoylaminopiperidine (7.49 g; preparation 16), triethylamine (9.79 ml) and 1-bromo-3-chloropropane (5.38 ml) in 200 ml of dry tetrahydrofuran was refluxed for 4 hours, then a further 9.79 ml of triethylamine and 5.38 ml of 1-bromo-3-chloropropane were added. The reaction mixture was refluxed overnight, then concentrated to dryness, treated with 100 ml of saturated aqueous potassium carbonate solution and extracted with ethyl acetate (2×100 ml). The organic extracts were pooled, dried over sodium sulfate and concentrated to dryness to give 15 g of an oil which was purified by silica gel chromatography (eluent chloroformlmethanol 9:1) to give, after crystallization from 30 ml of hexane, 6.12 g of the product, m.p. 68-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: Oc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)c1cc(-c2ccc(Oc3ncccn3)cc2)n(-c2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a suspension of 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (ref hydrogenation below) (60 mg, 180 μmol) and Cs2CO3 (140 mg, 400 μmol) in acetonitrile (2 mL) was added 2-chloropyrimidine (66 mg, 580 μmol). The suspension was then heated to 80° C. in an oil bath. After stirring for 16 hours at 80° C. the suspension was filtered through a plug of silica gel (1 g), which was eluted with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with a gradient from 10% to 30% EtOAc/hexane to afford 2-(4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)pyrimidine (55 mg, 75% yield) as a white powder. MS(ES): 417 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCCCCN1CCN(CCCCCNC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCN1CCN(CCCCCN)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of {5-[4-(5-tert-butoxycarbonylamino-pentyl)-piperazin-1-yl]-pentyl}-carbamic acid tert-butyl ester (329 mg, 0.72 mmol) in DCM (10 mL) is treated with trifluoracetic acid (1 mL). The reaction was left to stir at RT for 4 days and then the solvent is removed in vacuo. The material was used crude and conversion was assumed quantitative to produce 5-[4-(5-amino pentyl)-piperazin-1-yl]-pentylamine.