Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOCC>[N:18]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CCC(OS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC(N=[N+]=[N-])C2

Procedure:
8.0 g (31 mmol) of 2-methanesulfonyloxy-6-methoxytetralin and 2.6 g (40 mmol) of sodium azide were heated for 3 hours at 90° C. in 100 ml of DMF. After the mixture had been cooled, it was diluted with ether, washed with water and saturated NaCl solution, dried and concentrated in vacuo. This gave 6 g (95% of theory) of a colorless oil which was further reacted directly.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[O:21]=[C:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[CH3:38][O:37][C:35]([CH2:34][CH2:33][CH2:32]/[CH:31]=[CH:30]\[CH2:29][CH:23]1[C:22](=[O:21])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:36]
Reactant: COC(=O)CCC/C=C\CBr
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CCC/C=C\CC1COCCC1=O
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
To a solution of lithium diisopropylamide (2.40 mmol) in tetrahydrofuran (5 ml), prepared from diisopropylamine (0.35 ml) with n-butyllithium (1.7 ml, 1.5 M solution in hexane) using an usual manner, was added 4-oxotetrahydropyran (220 mg) in tetrahydrofuran (2 ml) at -78° C. and the mixture was stirred for 30 minutes at the same temperature. To the resulting solution was added methyl(Z)-7-bromo-5-heptenate (500 mg) in tetrahydrofuran (2 ml) at -78° C. After being stirred at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride and the solution was extracted with ethyl acetate. The organic layer was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (10 g) with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-oxo-tetrahydropyran (100 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[O:54]1C2C=CC(C(O)=O)=CC=2[O:56][CH2:55]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][C:31]4[O:54][CH2:55][O:56][C:2]=4[CH:3]=3)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4c(c3)OCO4)nn2)cc(OC)c1OC
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 1,3-benzodioxole-5-carboxylic acid (60 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1,3-benzodioxole-5-carboxamide (127 mg, 100%) as a yellow oil. MS m/z 453 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:19][C:18]=2[C:37]2[N:45]=[C:44]([CH3:46])[N:43]=[C:42]3[C:38]=2[N:39]=[CH:40][N:41]3C2CCCCO2)=[CH:12][CH:11]=1.C(Cl)Cl>>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]([C:37]3[N:45]=[C:44]([CH3:46])[N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:21][N:22]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(CN3CCNCC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (3.00 mL, 38.9 mmol) was added to a stirred mixture of tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (155 mg, 0.252 mmol) in DCM (3 mL, 46.6 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and then diluted with DCM, NaHCO3 (aq) and water (10 mL each). The separated aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(piperazin-1-ylmethyl)pyridin-2-amine.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17]O)[CH:12]=[CH:13][CH:14]=2)[CH:2]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1cccc(C#Cc2cccc(-c3ccccc3)c2)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(C#Cc2cccc(-c3ccccc3)c2)c1

Procedure:
Coupling of 3-(3-(biphenyl-3-ylethynyl)phenyl)propan-1-ol with phthalimide was conducted following the method described in Example 21. Purification by flash chromatography (6% EtOAc-hexanes) gave 2-(3-(3-(biphenyl-3-ylethynyl)phenyl)propyl)isoindoline-1,3-dione. Yield (0.320 g, 42%): 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J=5.6, 3.2 Hz, 2H), 7.77 (m, 1H), 7.71 (dd, J=5.6, 3.2 Hz, 2H), 7.61-7.63 (m, 2H), 7.32-7.57 (m, 8H), 7.18-7.25 (m, 2H), 3.77 (t, J=7.2 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 2.02-2.09 (m, 2H).
Reaction SMILES: CON(C)[C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([C:4](=[O:13])[CH2:5][C:6]2[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)Cc1cccc(C)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccccc2)c1
Reaction time: 3 h
Yield: 84.1 %

Procedure:
Under N2, to a mixture of N-methoxy-N-methyl-2-m-tolylacetamide (500 mg, 2.6 mmol) in anhydrous THF was added phenylmagnesium bromide (6.5 mL, 6.5 mmol) at −78° C., and the mixture was stirred for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, washed with water and brine, concentrated, and purified by column chromatography (PE:EtOAc=30:1) to give Intermediate 4 (460 mg, yield 84.6%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].O>C(O)CC(C)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([OH:16])[CH2:11][CH2:12][N:13]([C:18]2[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(O)CCN(c2cc[n+]([O-])cc2)CC1
Yield: 36.8 %

Procedure:
To a suspension in isoamyl alcohol (35 ml) of conventionally known compounds: 4-[(t-butoxycarbonylamino)methyl]-4-hydroxypiperidine (2.00 g) and 4-chloropyridine 1-oxide (1.12 g), was added sodium hydrogencarbonate (1.75 g) and the mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool and water was added thereto. The reaction mixture was extracted with methylene chloride and the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent:methylene chloride:methanol=9:1-4:1) to obtain the title compound (1.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH2:19])[CH3:18])=[CH:7]2.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH:19][C:21]1[N:29]=[CH:28][N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][NH:25]3)[CH3:18])=[CH:7]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cscn1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cscn1

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(thiazol-4-yl)-quinolin-3-yl)ethanamine (0.045 g, 0.155 mmol), 6-chloropurine (0.029 g, 0.19 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(8-chloro-2-(thiazol-4-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=16 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1 H), 8.63 (s, 1 H), 8.44-8.46 (m, 1 H), 8.42 (s, 1 H), 8.34 (s, 1 H), 7.88-7.93 (m, 2 H), 7.56 (t, 1 H), 1.77 (d, 3H), Mass Spectrum (ESI) m/e=408 (M+1).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:20][CH2:21][CH3:22]>>[CH3:2][C:3]1[CH:8]=[C:7]([O:9][CH2:20][CH2:21][CH3:22])[CH:6]=[C:5]([CH3:10])[C:4]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCBr
Reactant: Cc1cc(O)cc(C)c1N=Nc1ccccc1
Agent: [Na]
Product: CCCOc1cc(C)c(N=Nc2ccccc2)c(C)c1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of sodium (2.0 g) in absolute alcohol (120 ml) was added 2,6-dimethyl-4-hydroxyazobenzene (18.3 g) and 1-bromo propane (20 g). The mixture was refluxed for three hours and was left overnight at room temperature. A precipitate of sodium bromide was filtered off, was washed with some cold absolute ethanol, and was discarded. The alcohol was removed from the filtrate by distillation, the residue was dissolved in ether (200 ml), and was extracted with 2% sodium hydroxide solution (4×50 ml) and once with water. After drying (Na2SO4) and filtering, the ether solution was evaporated to dryness leaving a residual oily material (20.2 g), sufficiently pure for the following reaction step.
Reaction SMILES: [K].[CH3:2][N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]([CH3:13])[CH3:12].[O:14]=O.Cl>C(O)(C)(C)C.C(OP(OCC)OCC)C.O=P(N(C)C)(N(C)C)N(C)C>[OH:14][C:11]([C:4]1[N:3]([CH3:2])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1)([CH3:13])[CH3:12]
Reactant: O=O
Reactant: CC(C)c1ncc([N+](=O)[O-])n1C
Agent: CCOP(OCC)OCC
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cn1c([N+](=O)[O-])cnc1C(C)(C)O
Temperature: 0 °C
Yield: 74 %

Procedure:
A total of 21.5 g of potassium were dissolved in 450 ml of tert.-butanol with vigorous stirring and the solution heated to reflux. 300 ml of hexametapol were added to the cooled solution. The mixture was then cooled to -25°, a solution of 42.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 60 ml of triethylphosphite and 150 ml of hexametapol was added and dry oxygen was conducted through the mixture for 5 hours at -20° to -25° with vigorous stirring. The mixture was poured into a mixture of 1.5 liter of ice-water and 45 ml of 36% hydrochloric acid and extracted six times with 400 ml portions of ether. The combined ether extracts were washed twice with 250 ml portions of water and evaporated. The crude 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole (40.5 g; 87%) was purified by crystallization from 300 ml of water. There were obtained 30.2 g of pure 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole, melting point 106°-108° and a second crop of 4.2 g, melting point 102°-105° (total yield 74%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH3:28])=[C:23]([CH3:30])[CH:22]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24](/[C:27](=[N:3]/[NH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])/[CH3:28])=[C:23]([CH3:30])[CH:22]=1
Reactant: CC(=O)c1ccc(Cl)cc1C
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N/N=C(\C)c1ccc(Cl)cc1C

Procedure:
Ethyl carbazate (2.970 g, 28.53 mmol) and p-toluenesulfonic acid monohydrate (4.456 g, 28.53 mmol) were added to a stirred solution of 1-(4-chloro-2-methylphenyl)ethanone (4.81 g, 28.53 mmol) in toluene (50 mL). The mixture was heated to relux in a Dean-Stark apparatus. After 2 h the solution was evaporated and the viscous red-orange oil was purified by flash chromatography on silica (eluting with an EtOAc/hexanes gradient, 5–40% EtOAc). Ethyl (2E)-2-[1-(4-chloro-2-methylphenyl)ethylidene]hydrazine carboxylate was obtained as white crystals. MS m/z=255.6; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, J=6.8 Hz, 3H), 2.20 (s, 3H), 2.35 (s, 3H), 4.31 (q, J=6.8 Hz, 2H), 7.19 (m, 3H), 7.72 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C(O)CCC>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][NH:38][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)CC1
Temperature: 120 °C
Yield: 70.2 %

Procedure:
A mixture of 69 (0.2 g, 0.57 mmol), 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 1.13 mmol) and DIEA (0.20 mL, 1.14 mmol) in 1-butanol (5 mL) was heated to 120° C. for 1.5 h. After concentration, the residue was purified by silica gel chromatography using 2-5% MeOH/DCM, to give 4-[2-(5,6-diphenyl-furo[2,3-d]pyrimidin-4-ylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester 71 (0.20 g). Compound 71 was subjected to 20 mL of 20% TFA/DCM at rt for 2 h, then the reaction was concentrated almost to dryness under reduced pressure, and purified by silica gel column chromatography using 0.1% MeOH/DCM containing 1 mL ammonium hydroxide, to give 72 (0.15 g). MS: 400.2(M+1). 1HNMR (DMSO-d6) ppm 8.36 (s, 1H), 7.61-7.33 (m, 10H), 5.49 (t, 1H, J=4.48 Hz), 3.45 (dd, 2H, J1=5.10 Hz, J2=5.84 Hz), 2.33 (t, 2H, J=5.80 Hz), 2.13 (br, 4H), 1.95 (br, 1H) (note: some peaks overlapped with water peak in DMSO-d6). 1HNMR (CCl3-d) ppm 8.43 (s, 1H), 7.60-7.50 (m, 6H), 7.50-7.26 (m, 4H), 5.39 (t, 1H), 3.54 (dd, 2H, J1=5.05 Hz, J2=6.20 Hz), 2.73 (t, 4H, J=4.71 Hz), 2.44 (t 2H, J=5.91 Hz), 2.28 (br, 4H), 1,87 (br, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18]N[CH2:16][CH2:15]1)(C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C=C.C(=O)([O-])[O-:25].[Na+].[Na+]>O1CCCC1>[CH2:15]([N:14]([CH2:19][CH3:18])[C:1](=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [Na+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9 mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) of allyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred at room temperature under nitrogen for 2 days. The reaction solution was poured into ice water/ethyl acetate and separated. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and placed on a column of silica gel. The diastereomers were separated by elution with a stepwise gradient of ethanol in dichloromethane. The first isomer was eluted with 1.3% ethanol in dichloromethane, and the second isomer was obtained with 1.6% ethanol in dichloromethane. Fractions containing the second isomer were combined and the solvent removed in vacuo to give 1.44 g of 4-(αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:17].[C:18](=[O:20])=[O:19].[Cl-].[Na+]>CN(C)C=O.O.CN(C)C=O.O>[C:11]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])[C:18]([O-:20])=[O:19])([CH3:14])([CH3:13])[CH3:12].[Na+:17]
Reactant: O=C=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)[O-])cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of dimethylformamide/water is distilled from a solution of 206 g (1 mol) of 2,6-di-tert.-butylphenol and 80 g of a 50% strength aqueous sodium hydroxide solution in 500 ml of dimethylformamide at boiling point 30°-50° C./approx. 20 mm Hg until the water content in the last sample of the distillate is approx. 1.5%. After releasing the vacuum with nitrogen, carbon dioxide gas is passed into the reaction solution, with vigorous stirring, in the course of which the temperature of the solution rises to approx 85° C. After 11/2 hours at this temperature, the reaction mixture is cooled to 60° C. and 450 ml of a 20% strength sodium chloride solution are added under carbon dioxide gas. The resulting clear reaction solution is thereafter cooled, whereupon crystallisation starts at room temperature and is completed by stirring for 0.5 hours at 0°-5° C. Filtration, successive washing with 200 ml of 20% strength sodium chloride solution and 200 ml of n-hexane and drying the crystals to constant weight in vacuo at 40° C. yields colourless sodium 3,5-di-tert.-butyl-4-hydroxy-benzoate, containing water of crystallisation; when this substance is dissolved in 500 ml of water and precipitated with concentrated hydrochloric acid, it yields 189 g (yield, 77% of theory) of 3,5-di-tert.-butyl-4-hydroxybenzoic acid of melting point 215° C.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C3C=C(F)C(C#N)=C(F)C=3)=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OCC1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1)CCCC.S(Cl)([Cl:57])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([Cl:57])=[O:22])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCOCc1ccc(-c2ccc(C(=O)Oc3cc(F)c(C#N)c(F)c3)cc2)cc1
Agent: CCCCCOCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCOCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
Preparation of 3,5-difluoro-4-cyanophenyl 4'-(pentyloxymethyl)biphenyl-4-carboxylate (in the formula (1), R=C5 H11, l=1, m and n=both, 1, o=0, A1 and A2 =both, 1,4-phenylene group, Z1 =covalent bond, Z2 =--COO--, X=CN, and Y1 and Y2 =both, F) (Compound No. 229) 4'-(Pentyloxymethyl)biphenyl-4-carboxyic acid (2.1 g, 7.0 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4'-(pentyloxymethyl)biphenyl-4-carbonyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH2:17][CH2:18][C:19]([OH:21])=[O:20].CCN(C(C)C)C(C)C>Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH:3]=2)=[CH:10][CH:11]=1
Reactant: NCC(=O)O
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2cc(NCC(=O)O)ncn2)cc1
Temperature: 200 °C
Yield: 60 %

Procedure:
45 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 14 mg of 2-aminoacetic acid and 56 mg of DIPEA were dissolved in 1 mL of n- and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: NEt3=50:1 solvent mixture. 2-(6-(4-Methoxyphenylamino)pyrimidin-4-ylamino)acetic acid in the form of a colorless solid was obtained.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1cccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)c1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-methoxy-phenyl)benzoic acid (1.03 g, 2.2787 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (3.12 g, 5.6934 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (817 mg, 1.9360 mmol, 85%).