Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.C(N(CC)CC)C.[Cu]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:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (50 mg, 0.11 mmol) in DMF (1 mL) and triethylamine (1 mL), (trimethylsilyl)acetylene (0.045 mL, 0.33 mmol) was added at room temperature followed by copper(I) iodide (4.2 mg, 0.022 mmol) and bis(triphenylphosphine)dichloropalladium(II) (7.7 mg, 0.011 mmol). The resulting mixture was stirred under nitrogen at room temperature for 1 h, and then was quenched with water, extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamide (44 mg, 94%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.51 (d, J=7.0 Hz, 1H), 8.20 (dd, J=8.0, 1.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 2H), 7.72 (dd, J=8.0, 1.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.49 (t, J=8.0 Hz, 1H), 4.32-4.29 (m, 1H), 3.52 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.12-2.76 (m, 5H), 2.18-2.02 (m, 2H), 1.80-1.62 (m, 3H), 0.29 (s, 9H); MS (ESI+) m/z 444 (M+H); HPLC>99% (AUC), tR=14.91 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[N:15]=[C:16]([C:19]([OH:21])=O)[S:17][CH:18]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[N:15]=[C:16]([C:19]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:21])[S:17][CH:18]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1cnc2[nH]cc(-c3csc(C(=O)O)n3)c2c1
Reactant: C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1cnc2[nH]cc(-c3csc(C(=O)N4CCCCC4)n3)c2c1
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred solution of 82 (60 mg, 0.20 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (50 mg, 0.39 mmol), piperidine (40 mg, 0.47 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP; 180 mg, 0.35 mmol). After stirring for 1 h, the reaction mixture was filtered and purified by preparative LCMS (column LUNA 10 g C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 83 as a white solid (42 mg, 0.11 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 0.89 (d, J=6.6 Hz, 2H), 1.63-1.76 (m, 6H), 1.86 (nonet, J=6.6 Hz, 1H), 2.56 (d, J=7.2 Hz, 2H), 3.69-3.75 (m, 2H), 4.32-4.39 (m, 2H), 7.45 (s, 1H), 7.70 (d, J=2.6 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 9.26 (s, 1H). MS (CI) m/z 369 (MH+).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1.Br[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21]>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH:20]([C:13]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]2)[CH3:21])[CH:27]=[CH:26][CH:25]=1
Reactant: N#CC1CCC1
Reactant: CC(Br)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1cccc(Cl)c1)C1(C#N)CCC1
Reaction time: 0.08 h

Procedure:
n-BuLi (4.7 mL, 11.8 mmol, 2.5 M in hexane) was added to a solution of diisopropylamine (1.13 g, 11.2 mmol) in THF (20 mL) at −78° C. After stirring for 5 min, neat cyclobutanecarbonitrile (0.8 g, 9.87 mmol) was added and the mixture was stirred at −78° C. for 1 hour. Then a solution of Example 44A (2.6 g, 11.8 mmol) in THF (10 mL) was added and the mixture was stirred at −78° C. for 1 h. The mixture was quenched with water and extracted with EtOAc (40 mL). The solvent was evaporated and the residue was used directly in the next step without further purification. LC-MS: m/z 220 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O.C1(C)C=CC=CC=1.C(OCC)C.C1COCC1>[C:12]1([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([B:29]([OH:34])[OH:30])[CH:11]=[CH:10]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2cc(-c3ccccc3)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1ccc2cc(-c3ccccc3)ccc2c1
Temperature: -20 °C
Yield: 66.2 %

Procedure:
Under an argon gas atmosphere, a mixture of 100.0 g (353.1 mmol) of 2-bromo-6-phenylnaphthalene, 1.2L of dehydrated THF and 1.2L of dehydrated diethylether was cooled down to −20 degrees C., and added with 280 ml (437 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for one hour at −20 degree C. The reaction mixture was further cooled down to −60 degrees C., and added with 199.3 g (1.06 mol) of triisopropyl borate in drops. The reaction mixture was subsequently warmed up to room temperature, and stirred for 16 hours at room temperature. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was cleansed with water and dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by hexane, 58.0 g of 6-phenylnaphthalene-2-boronic acid was obtained at an yield of 55%.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([S:11]([OH:14])(=[O:13])=[O:12])[C:8]2[C:3](=[CH:4][C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:6][C:7]=2[NH2:15])[CH:2]=1.[OH-].[Na+:21]>O.C(O)C>[Na+:21].[Na+:21].[NH2:15][C:7]1[CH:6]=[C:5]([S:16]([O-:19])(=[O:18])=[O:17])[CH:4]=[C:3]2[C:8]=1[C:9]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:10][CH:1]=[CH:2]2
Reactant: Nc1cc(S(=O)(=O)O)cc2cccc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(S(=O)(=O)[O-])cc2cccc(S(=O)(=O)[O-])c12
Yield: 87 %

Procedure:
To a solution of 25.0 g of 1-naphthylamine-3,8-disulfonic acid in 100 ml of water is added 20 ml of 5 N sodium hydroxide with stirring. The mixture is warmed on a steambath and diluted with absolute ethyl alcohol to yield a crystalline precipitate. The solid is collected at room temperature and is washed with 75% aqueous ethyl alcohol, ethyl alcohol and ether. The product is dried in vacuo at 110° C. overnight to yield 22.8 g of (87%) 8-amino-1,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1([F:37])[O:35][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24][CH2:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=4)[NH:21][C:20]=3[CH:34]=[C:16]2[O:15][CH:14]1[F:36].C(N(CC)CC)C>C(OCC)(=O)C.C(Cl)Cl>[F:37][C:13]1([F:12])[O:35][C:17]2=[CH:18][C:19]3[N:23]=[C:22]([S:24]([CH2:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=4)=[O:6])[NH:21][C:20]=3[CH:34]=[C:16]2[O:15][CH:14]1[F:36]
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)C(F)(F)O4)c1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A solution of 0.81 g of approximately 85% pure m-chloroperoxybenzoic acid in 20 ml of ethyl acetate is added dropwise to a solution of 1.5 g of 6,6,7-trifluoro-6,7-dihydro-2-[(4-methoxy-2-pyridyl)methylthio]-1H-[1,4]-dioxino[2,3-f]benzimidazole in 50 ml of methylene chloride at -20° C. to -15° C. in the course of 30 min., with stirring, and stirring is continued at this temperature for 30 min. 0.66 ml of triethylamine is added and the organic solution is washed with 1M potassium bicarbonate solution and then with water, dried with magnesium sulfate and concentrated in vacuo. The residue is allowed to crystallize from ether. 1.2 g (77%) of the title compound of m.p. 166°-167° C. (decomposition), from ethyl acetate, are obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=NN.[CH2:18]([N:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:18]([N:24]1[C:25](=[O:30])[CH:26]2[CH:27]([C:4]2([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:3][C:2]([F:17])([F:16])[F:1])[C:28]1=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NN=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN1C(=O)C=CC1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 223.4 %

Procedure:
3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone hydrazone (Preparation 104, 150 mg, 0.6 mmol) was dissolved in dioxan (10 ml) and manganese dioxide (600mg, 7.1 mmol) was added in one portion at room temperature. After stirring for 30 min, the reaction mixture was filtered through a pad of ArbocelTm directly into a flask containing a stirred solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 44 mg, 0.2 mmol) in dioxan (10 ml). The filter pad was washed further with dioxan (40 ml), and was also added to the reaction mixture. The resulting amber-yellow solution was stirred for 16 h at room temperature. The colourless mixture was then heated under reflux for 1 h before cooling to room temperature and concentrating in vacuo. The residue was purified by chromatography on silica gel (10 g), eluting with hexane:ether (2:1) to give the product as a white solid (178 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4]([Cl:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[C:7]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8]2)=[C:4]([Cl:16])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]c(C3CCCC3)nc2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(C2CCCC2)nc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
A mixture 2,6-dichloro-8-cyclopentyl-7H-purine (0.2 g, 0.78 mmol) and potassium carbonate (0.32 g, 2.34 mmol) was taken in DMF (2.5 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (0.38 g, 2.34 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 4 hours, diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine solution and dried over Na2SO4 and concentrated. The residue was purified by column chromatography to obtain 2,6-dichloro-8-cyclopentyl-7-(2-trimethylsilanyl-ethoxymethyl)-7H-purine (0.12 g, 40%) as yellow oil.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)C.[F:34][C:35]([F:46])([F:45])[O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>CN(C=O)C>[CH3:32][C:7]([O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][C:35]([F:34])([F:45])[F:46])=[CH:38][CH:39]=3)[C:20](=[O:23])[N:19]2[CH3:24])=[CH:13][CH:14]=1)[C:6]([OH:5])=[O:33]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(OC(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32 %

Procedure:
NaH (8.8 mg, 0.22 mmol, 60% w/w in mineral oil) is added to a cooled (0° C.) solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (78.5 mg, 0.18 mmol) in DMF (1 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over one hour. After the solution is cooled again to 0° C., 4-(trifluoromethoxy)benzyl bromide (59 ul, 0.37 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for one hour. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is dissolved in methanol (5 ml), treated with 5N NaOH (0.5 ml), and stirred for 14 hours at ambient temperature. After concentration to remove methanol, the residue is partitioned between diethyl ether and water. The aqueous layer is adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified by MS/LC to yield an oil (33 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](OC(OCC)CBr)[CH3:12].Br>C(O)(C)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]2[N:6]([CH:11]=[CH:12][N:8]=2)[N:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1c(N)nnc(Cl)c1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(Cl)nn2ccnc2c1C
Yield: 89.7 %

Procedure:
To a solution of 6-chloro-4,5-dimethylpyridazin-3-amine (2.00 g, 12.7 mmol, 1.0 equiv) in isopropanol (40 mL) was added bromoacetaldehyde diethyl acetal (5.23 mL, 34.8 mmol, 2.7 equiv), and hydrobromic acid (2.00 mL) and heated to reflux for 2 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Purification by column chromatography using 20% ethyl acetate in hexanes elution gave 2.07 g of the white solid, 90%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].[CH3:26][Sn](C)(C)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH3:26])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCOCC3)cc2C1
Reactant: C[Sn](C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1N1CCOCC1)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Yield: 43 %

Procedure:
To a stirred solution 0.38 mmol 5-chloro-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A44(a)) in 3 ml dioxane were added 0.02 mmol bis(tri-tert-butylphosphine)palladium(0), 0.84 mmol cesium fluoride and 0.77 mmol tetramethylstannane and the mixture was heated at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light yellow solid (43% yield). MS (m/e): 219.4 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH2:22])=[O:21])[CH:4]=1.C1C=CC=CC=1.[H-].[Na+].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>C(OCC)(=O)C.CN(C=O)C>[CH2:31]([O:33][CH2:34][NH:22][C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[N:6]=1)=[O:21])[CH3:32]
Reactant: CCOCCl
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(N)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOCNC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
1.0 g (0.0032 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in a mixed solvent containing about 20 ml of benzene and about 10 ml of DMF, and the obtained solution was mixed with 0.14 g (ca. 60% in mineral oil; 0.0032×1.1 mol) of NaH, followed by treating the solution under reflux for several minutes. Thereafter, the resultant reaction solution was mixed with 0.61 g (0.0032×2.0 mol) of chloromethyl ethyl ether, followed by treating the solution under reflux for about 3 hours. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water and then washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: C([O:3][C:4](=[O:51])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C@H:16]([N:20]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[C:15]3[CH:42]=[C:43]([CH3:50])[C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:14]2=3)[CH2:8][CH2:7]1)C.[OH-].[Na+]>CO.O>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1)[CH2:27][N:20]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:51])=[O:3])[CH2:7][CH2:8]2)[C:14]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[C:43]([CH3:50])=[CH:42][C:15]1=2
Reactant: CCOC(=O)CN1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCN(CC(=O)O)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-piperidin-1-yl)-acetic acid ethyl ester (0.11 mmol) in methanol (5 mL), add 5.0 N sodium hydroxide (2 mL). After heating at 60° C. for 6 h cool to room temperature and dilute with water (20 mL). Extract the organics with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum, to afford the title compound as a colorless foam. MS (ES+): 708 (M+H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C.[I-].ClCC1C=CC=C[NH+]=1>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: ClCc1cccc[nH+]1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 1.13 g of benzoic acid (9.3 mmol), in 33 ml of methylene chloride at 0° C., was added N,O-dimethylhydroxylamine hydrochloride (906.7 mg; 10.23 mmol), 4.26 ml of triethylamine (3.09 g; 30.6 mmol) and 2-chloromethylpyridinium iodide (2.6 g; 10.23 mmol). After stirring at 25° C. for 12 hours, the reaction mixture was poured into 250 ml of methylene chloride, then this solution was extracted with 150 ml of 1N hydrochloric acid, 150 ml saturated, aqueous solution of sodium bicarbonate, and 150 ml of brine. The organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to give a oil, which was purified by flash chromatography (SiO2; 50% ethyl acetate/hexane) to give 0.872 of N-methoxy-N-methyl-benzenecarboxamide as an oil: Anal. Calc'd. for C9H11NO2+0.25 H2O: C, 63.70; H, 6.29; N 8.14. Found: C, 63.73; H, 6.83; N, 8.25
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[NH2:5][N:6]1[CH2:14][C:13]2[C:8](=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=2[CH3:15])[CH2:7]1>C(COC)OC>[CH3:1][NH:2][C:3]([NH:5][N:6]1[CH2:7][C:8]2[C:13](=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[CH3:16])[CH2:14]1)=[S:4]
Reactant: Cc1ccc(C)c2c1CN(N)C2
Reactant: CN=C=S
Solvent: COCCOC
Product: CNC(=S)NN1Cc2c(C)ccc(C)c2C1
Reaction time: 15 h
Yield: 61.2 %

Procedure:
3.7 g (0.05M) of methyl isothiocyanate in 10 ml of dimethoxyethane is dripped into 8.0 g (0.05M) of 2-amino-4,7-dimethylisoindoline in 50 ml of 1,2-dimethoxyethane. Conventional processing was conducted after 15 hours, yielding 7.1 g of 1-methyl-3-(4,7-dimethylisoindolin-2-yl)-thiourea.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1.[CH3:18][N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23]C(O)[CH2:21][C:20]1([CH3:29])[CH3:28].[NH2-].[Li+].CO>CCCCCCC>[CH3:18][N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23][CH:1]([O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]2[CH2:7][C:8]([CH3:16])([CH3:15])[N:9]([CH3:14])[C:10]([CH3:13])([CH3:12])[CH2:11]2)[CH2:21][C:20]1([CH3:29])[CH3:28]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)CNC1CC(C)(C)N(C)C(C)(C)C1
Agent: [Li+]
Agent: [NH2-]
Solvent: CO
Solvent: CCCCCCC
Product: CN1C(C)(C)CC(NCC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Yield: 78.6 %

Procedure:
To the same flask as used in Example 1 were added 24.2 g (0.1 mole) of N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine methyl ester, 18.7 g (0.11 mole) of 1,2,2,6,6-pentamethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 30 g of N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine(1,2,2,6,6-pentamethyl-4-piperidinyl)ester as a pale yellow liquid. Yield, 79% based on N-(1,2,2,6,6-pentamethyl-4-piperidinyl)glycine methyl ester. A pale yellow oily product was obtained by the subsequent column chromatographic separation.