Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([OH:37])[C@H:14]([N:22](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([OH:37])[C@H:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](O)[C@@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Reaction time: 0.03 h
Yield: 101.4 %

Procedure:
Dissolve 2-(S)-[(2-(R)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (610 mg, 1.2 mmol) in methanol (13 mL). Add 20% palladium hydroxide on carbon (157 mg). Bubble hydrogen gas through the mixture and stir under 1 atmosphere of hydrogen gas overnight. Bubble nitrogen through the mixture for 2 min, filter through a filtering agent, wash with methanol and concentrate to give the title compound (390 mg, 99%)
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[C:7]1([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:17][CH2:16]2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:24].[ClH:5].[C:7]1([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][SH:3])[CH2:17][CH2:16]2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: CC(c1ccccc1)N1CCN(CCCCl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(c1ccccc1)N1CCN(CCCS)CC1
Yield: 50.4 %

Procedure:
The procedure described in Example 1(b) was followed, using 9.8 g of thiourea, 29.0 g of 1-(1-phenylethyl)-4-(3-chloropropyl)piperazine dihydrochloride, 8.3 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as above, gave 14.5 g (51% of theory) of 3-[4-(1-phenylethyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 252°-255° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=O)[CH:15]=[CH:16][N:17](C)C)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]([F:32])([F:31])[C:23]1[C:28]([NH:29]N)=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:29]([C:28]3[C:23]([C:22]([F:32])([F:21])[F:31])=[N:24][CH:25]=[CH:26][CH:27]=3)[N:17]=[CH:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)C=CN(C)C)cc([N+](=O)[O-])c1OC
Reactant: NNc1cccnc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: COc1cc(-c2ccnn2-c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-prop-2-en-1-one (0.5 g, 1.79 mmol) and (2-trifluoromethyl-pyridin-3-yl)-hydrazine (0.33 g, 1.87 mmol) in ethanol (10 mL) was added 10 drops of concentrated hydrochloric acid and the mixture was heated at reflux for two hours. The mixture was allowed to cool to room temperature and the resulting precipitate was filtered off, washed with ethanol and dried to give 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine, 0.58 g (82%).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.C([Li])CCC.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17](N(C)OC)=[O:18])=[CH:13][CH:12]=1>C1COCC1>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([CH:1]2[CH2:3][CH2:2]2)=[O:18])=[CH:13][CH:12]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: BrC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)C1CC1
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of cyclopropylbromide (1.24 g, 10.24 mmol) in THF (10 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (4.0 mL, 10.00 mmol) at −78° C. and the reaction mixture was stirred for 1 h at this temperature. Then a solution of 6-chloro-N-methyl-N-(methyloxy)pyridine-3-carboxamide (1.00 g, 4.98 mmol) in THF (5 mL) was added quickly at −78° C., and the cooling bath was removed. Stirring was continued for 1 h, then the solution was poured into saturated ammonium chloride (100 mL), extracted with ethyl acetate (3×50 mL) and the organic layers were washed with brine (50 mL), dried over sodium sulfate then filtered and concentrated. Column chromatography on silica (hexanes:ethyl acetate 9:1 to 8:2) afforded (6-chloropyridin-3-yl)(cyclopropyl)-methanone (0.62 g, 68% yield). 1H NMR (400 MHz, CDCl3): 9.04 (d, 1H), 8.22 (dd, 1H), 7.46 (d, 1H), 2.61 (m, 1H), 1.32 (m, 2H), 1.15 (m, 2H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4].[CH2:13]([O:15][C:16](=[O:30])[CH:17]([C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][C:19](=O)[CH3:20])[CH3:14].C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:13]([O:15][C:16]([C:17]1[CH:18]=[C:19]([CH3:20])[N:9]([C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=2)[C:22]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:30])[CH3:14]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(C)n(-c2cccc(S(C)(=O)=O)c2)c1-c1ccccc1

Procedure:
3-Methylsulfonylaniline hydrochloride (5.8 mmol, 1.2 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5.8 mmol, 1.44 g), triethylamine (5.8 mmol, 0.61 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and solvents removed under vacuum. The crude material was purified over silica to yield the named product (m.p. 131° C.-133° C.).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-chlorophenylboronic acid. The title compound was obtained in 71% yield as yellow foam. MS (m/e): 516.2 (MH+, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].[CH3:19]N(N=O)C(N)=O.[OH-].[K+].CC(O)=O>CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2cc(C(=O)O)ccc2c1
Reactant: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1ccc2cc(COC(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 139.8 %

Procedure:
To a suspension of 1.08 g (4.43 mmol) of 6-acetoxymethyl-2-naphthoic acid in 150 mL of Et2O at 0° C. was added a cold solution of CH2N2 in Et2O which was prepared from 2.0 g (19 mmol) of N-methyl-N-nitrosourea and 30 mL of 40% aqueous KOH. The mixture was stirred at 0° C. for 10 min when all the solid went into solution. Excess CH2N2 was decomposed with HOAc. The reaction mixture was dried over Na2SO4 and concentrated to give 1.6 g of a white solid, which was purified on 100 g of silica gel (50% EtOAc/hexane) to give 1.04 g (91% yield) of the pure methyl ester. A portion was recrystallized from EtOAc/hexane to give white plates: mp 115°-116° C.; IR (mull) 1720, 1300, 1260, 1200, 1140, 1100, 1040, 980, 940, 900, 840, 820, 760 cm-1 ; 1 H NMR (CDCl3) δ2.15 (s, 3, CH3CO2), 3.98 (s, 3, CO2CH3), 5.28 (s, 2, CH2O), 7.3-8.7 (m, 6, ArH); MS calcd for C15H14O4 258.0892, found 258.0872.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[F-].[K+].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:6]#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: C1COCCN1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1N1CCOCC1
Temperature: 145 °C
Yield: 11.5 %

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (11 g, 56 mmol) and potassium fluoride (3.3 g, 56 mmol) in anhydrous N,N-dimethylformamide (150 mL) was added morpholine (15 g, 170 mmol) and the reaction was heated at 145° C. for 4 days. The solvent was evaporated in vacuo and the residue was partitioned between diethyl ether and water. The phases was separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. Purification on a silica gel column using toluene followed by chloroform as eluents gave 1.3 g (11% yield) of the title compound as white crystals: mp 85-86° C.; EIMS (70 eV) m/z (relative intensity) 202 (71, M+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][CH:12]1[N:16]([CH2:17][C:18]#[C:19][CH3:20])[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:14]([C:25](OC)=[O:26])[NH:13]1>O1CCCC1>[Br:11][C:12]1[N:16]([CH2:17][C:18]#[C:19][CH3:20])[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:14]([CH:25]=[O:26])[N:13]=1
Reactant: CC#CCN1C(C(=O)OC)=C(C(=O)OC)NC1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Temperature: -65 °C
Reaction time: 2 h

Procedure:
45 ml diisobutylaluminium hydride solution (1M in toluene) are added dropwise to 12.45 g dimethyl 2-bromo-3-(2-butyn-1-yl)-1H-imidazole-4,5-dicarboxylate in 150 ml of tetrahydrofuran under an argon atmosphere at −65° C. The reaction mixture is stirred for two hours at −65° C., then another 9 ml diisobutylaluminium hydride solution are added. After another hour the reaction mixture is quenched at −65° C. with a mixture of 1 M hydrochloric acid and tetrahydrofuran (1:1) and stirred for ten minutes. Then the cooling bath is removed, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (2:1 to 1:1).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]([C:14]3([CH3:17])[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:19].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH3:17][C:14](=[CH:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:15][CH2:16][Br:19]
Reactant: CC1(C(O)CCc2ccc3c(c2)OCO3)CC1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CC(=CCCc1ccc2c(c1)OCO2)CCBr

Procedure:
3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 17.6 g. of 2-(3,4-methylenedioxyphenyl)ethyl 1-methylcyclopropyl carbinol (Preparation B3), 20.3 g. of phosphorus tribromide, 18.5 g. of lithium bromide and 21 g. of zinc bromide according to the procedure given above in Preparation C1, affording 19 g. of product as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.C(B(CC)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Nc1cc(Br)ccc1S(N)(=O)=O
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cc(-c2cccnc2)ccc1S(N)(=O)=O
Yield: 96.3 %

Procedure:
A mixture of 4-bromo-2-aminobenzenesulfonamide (250 mg, 1.0 mmol), diethyl-3-pyridylborane (225 mg, 1.5 mmol), Pd(PPh3)2Cl2 (35 mg, 5 mol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (20 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 240 mg (96%) of 2-amino-4-(3-pyridyl)-benzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 240–243° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:9]([CH3:13])[CH2:10][CH2:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:14]([Sn:18]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19]I)[CH2:15][CH2:16][CH3:17].O>O1CCCC1.C(OCC)(=O)C>[CH3:13][N:9]([CH2:10][CH2:11][O:12][CH2:19][Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(CCO)C1CCCCC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)COCCN(C)C1CCCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a mixture of sodium hydride (50%, 241 mg, 5.0 mmol) and tetrahydrofuran (20 ml) was added 2-[cyclohexyl(methyl)amino]ethanol (791 mg, 5.0 mmol) at 0° C. (external temperature). Then, the reaction mixture was stirred at 60° C. for 30 minutes. After the reaction mixture was cooled at 0° C. (external temperature), to the reaction mixture was added dropwise a solution of tributyl-iodomethyl-tin (2.2 g, 5.0 mmol) in tetrahydrofuran (5 ml), and the reaction mixture was stirred at 60° C. for 1 hour. After the reaction mixture was cooled at room temperature (external temperature), water was added to stop the reaction. Ethyl acetate was added to the reaction mixture, and the organic layer was separated. After the organic layer was washed with water, an aqueous saturated sodium chloride solution, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=20:1, NH silica gel) to obtain the title compound (790.7 mg, 4.3 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:9][N:8]([CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:7][CH2:6]2.[H][H]>C(OCC)(=O)C.[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[NH2:13])[CH2:9][N:8]([CH:16]([CH3:19])[CH2:17][CH3:18])[CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: CCC(C)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)N1CCc2cc(OC)c(N)cc2C1
Yield: 96.1 %

Procedure:
6-(methyloxy)-2-(1-methylpropyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.23 g, 0.87 mmol) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 6-(methyloxy)-2-(1-methylpropyl)-1,2,3,4-tetrahydro-7-isoquinolinamine (196 mg, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 0.90 (t, J=7.4 Hz, 3 H), 1.02 (d, J=6.6 Hz, 3 H), 1.28-1.40 (m, 1 H), 1.59-1.69 (m, 1 H), 2.56-2.75 (m, 5 H), 3.48-3.67 (m, 4 H), 3.77 (s, 3 H), 6.35 (s, 1 H), 6.47 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2([C:27]([F:30])([F:29])[F:28])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([Br:24])[C:21]([CH2:25]O)=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.C1(P([N:54]=[N+:55]=[N-:56])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O.C1COCC1>[N:54]([CH2:25][C:21]1[C:22]([Br:24])=[N:23][C:18]([N:15]2[CH2:16][CH2:17][C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:32])([F:31])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)([C:27]([F:30])([F:29])[F:28])[CH2:14]2)=[CH:19][CH:20]=1)=[N+:55]=[N-:56]
Reactant: OCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1Br
Yield: 83.2 %

Procedure:
To a mixture of (6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridin-3-yl)methanol (1.55 g), toluene (10 ml) and THF (5 ml), which had been stirred under ice cooling, diphenylphosphoryl azide (1.59 g) and subsequently 1,8-diazabicyclo[5.4.0]-7-undecene (0.88 g) were added, and then stirred overnight at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel chromatography to obtain 3-(azidomethyl)-6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridine (1.35 g).
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)(C)C>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][NH:21][CH:18]([CH3:20])[CH3:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CC(C)O
Product: CC(=O)NC=Cc1ccc(OCC(O)CNC(C)C)cc1

Procedure:
11.6 g (0.05 mol) of 1-[p-(2-acetylaminovinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 100 ml of isopropanol, 4.25 ml (0.05 mol) of isopropylamine are added and thereafter the mixture is heated to the boil for 3 hours under reflux. It is then evaporated in vacuo and the resulting crude base is crystallised from ethyl acetate. 1-[p-(2-Acetylaminovinyl)-phenoxy]-2-hydroxy-3-isopropylaminopropane of melting point 144°-146°C is obtained.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=O)[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: COC(=O)Cc1cn[nH]c1
Product: COc1ccc(N2CCN(C(=O)Cc3cn[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 7 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and (1H-pyrazol-4-yl)-acetic acid methyl ester with heating for 15 days to afford the title compound as an off-white solid (12 mg, 7%). LC/MS (Method B) 3.60 min, [M+1]+ 475.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([CH3:26])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1)([CH3:26])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1Oc1ccc(N)cc1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A mixture of 388B (1.20 g, 3.21 mmol), 10% Pd/C (360 mg) in MeOH (30 ml) was stirred vigorously under a balloon of H2 for 1.5 h, then filtered through celite and through 0.45μ syringe filter. The filtrate was concentrated to afford 388C (1.08 g, 98%) as a faintly reddish oil. LCMS Found: (M−tBu+2H)+=287.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:26]([N:33]1[CH:41]=[C:40]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:39]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(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>[NH2:1][C:2]1[C:7]2=[C:8]([C:37]3[CH:38]=[CH:39][C:40]4[C:35]([CH:36]=3)=[N:34][N:33]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]=4)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(Br)c3c(N)ncnn23)C1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 70.5 %

Procedure:
To a stirred, degassed mixture tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxypiperidine-1-carboxylate (292 mg, 0.71 mmol), Intermediate C (355 mg, 1.06 mmol), Na2CO3 (225 mg, 2.13 mmol) and H2O (1 mL) in DMF (6 mL) was added tetrakis(triphenylphosphine)palladium(0) (82 mg, 0.071 mmol). The reaction was heated (110° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was further extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 270 mg (71%) of the desired product, which contained trace impurities. ES-MS m/z 540.30 [M+H]+, HPLC RT (min) 2.91.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1.C(N(CC)CC)C.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CNCc2ccco2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1)Cc1ccco1
Yield: 93.4 %

Procedure:
A solution of 600 mg (1.75 mmol) of tert-butyl 3-(4-{[(2-furylmethyl)amino]-methyl}phenyl)-2,2-dimethylpropionate (Example I-5), 323 mg (0.87 mmol) of tetra-n-butylammonium iodide and 265 mg (2.62 mmol) of triethylamine in 10 ml of THF is treated with 438 mg (2.62 mmol) of ethyl bromoacetate and heated at reflux overnight. After cooling, the mixture is concentrated under reduced pressure, the residue is taken up in water and ethyl acetate, the aqueous phase is extracted 2× with ethyl acetate and the combined organic phases are washed with NaCl solution and dried over sodium sulphate. The solvent is removed under reduced pressure, and chromatographic purification on silica gel (cyclohexane→cyclohexane/ethyl acetate 10:1) then gives 702 mg (94%) of tert-butyl 3-(4-{[(2-ethoxy-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-di methylpropionate.