Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([CH3:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[CH:5]2.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][OH:56].CN([CH:60]=[O:61])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:13]([F:16])([F:15])[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:55]([O:61][CH3:60])=[O:56])[CH:3]=2)[N:8]=1)([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(C(C)(C)C(F)(F)F)ccc2c1
Yield: 88 %

Procedure:
A mixture of 6-bromo-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline (950 mg, 3.0 mmol), triethylamine (1.25 ml, 9.0 mmol), 1,3-bis(diphenylphosphino)propane (123 mg, 0.3 mmol), palladium acetate (67 mg, 0.3 mmol) and methanol (4.8 ml) in DMF (10 ml) was stirred at reflux under carbon monoxide (1 atm) for 16 hours. Then the reaction was quenched with saturated sodium bicarbonate aqueous solution and the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation and purification through silica gel column chromatography, eluting with hexane/ethyl acetate (25:1), furnished the title compound (777 mg, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.74 (6H, s), 4.00 (3H, s), 7.71 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.25 (1H, d, J=8.8 Hz), 8.28-8.32 (1H, m), 8.58-8.59 (1H, m). MS (ESI): m/z 298 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(O)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (2.20 g, 23.42 mmol) was added to a stirred solution of 5-hydroxy-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 76; 5.2 g, 21.29 mmol), HOBT (3.59 g, 23.4 mmol) and EDC (4.49 g, 23.42 mmol) in dimethylformamide (100 ml) at room temperature. The reaction mixture was stirred at 25° C. overnight. Water was added, the solid was filtered and washed with ethyl acetate to yield the title compound as a white solid. 3.7 g.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH2:20]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)[CH3:21].[Cl-].[NH4+]>C1COCC1.CCCCCC>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:26]([C:25]1[CH:28]=[CH:29][C:22]([CH2:20][CH3:21])=[CH:23][CH:24]=1)[OH:27]
Reactant: Clc1ccncc1
Reactant: CCc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCc1ccc(C(O)c2cnccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 71.2 %

Procedure:
A 1.58 M n-hexane solution of n-butyllithium (30.1 mL, 0.0476 mol) and THF (125 mL) were mixed and a solution of diisopropylamine (6.67 mL, 0.0476 mol) in THF (25 mL) was added dropwise thereto at −20° C., followed by stirring for 25 minutes. After cooling the reaction mixture to −78° C., a solution of 4-chloropyridine (5.4 g, 0.0476 mol) in THF (25 mL) was added dropwise. After 15 minutes, a solution of 4-ethylbenzaldehyde (6.4 g, 0.0477 mol) in THF (25 mL) was added dropwise and stirred for 30 minutes. After warming the reaction mixture to room temperature, saturated aqueous ammonium chloride was added and the resulting mixture was then extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give (4-chloropyridin-3-yl)-(4-ethylphenyl)methanol (8.4 g, 71%) as a light-yellow crystal.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14][O-:15].[Na+].[CH2:17]([OH:19])[CH3:18]>>[CH2:1]([S:13][CH2:18][CH:17]([OH:19])[CH2:14][O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[O-]
Reactant: CCCCCCCCCCCCS
Reactant: CCO
Agent: [Na+]
Product: CCCCCCCCCCCCSCC(O)COCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving in 30 ml ethanol this oil was admixed with a mercaptide solution which had previously been prepared by reacting 1.94 ml 1-dodecylmercaptan in 20 ml ethanol with sodium methylate. After stirring overnight at room temperature, the solvent was removed by distillation, the residue was taken up in dichloromethane, washed twice with water and the organic phase was evaporated. The residue was purified by chromatography on silica gel 60 using ether/isohexane 1:5 as the eluant. Yield 3.9 g.
Reaction SMILES: O(CC([NH:11][CH:12]1[C:32](=[O:33])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.C(Cl)[Cl:35].N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(O)C(C)C>[ClH:35].[NH2:11][CH:12]1[C:32](=[O:33])[N:14]2[CH:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12
Reactant: C=C1CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Reactant: ClCCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(C)CO
Product: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc(OC)cc1
Product: Cl

Procedure:
To a solution of 4.3 g. of p-methoxybenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate in 50 ml. of methylene chloride were added 880 mg. of dry pyridine and 2.3 g. of phosphorus pentachloride and the mixture was stirred at the reflux temperature for 3 hours. The reaction mixture was then cooled in an ice-water bath and 5 ml. of isobutanol were added. The mixture was stirred in the cold for several hours during which time 2.2 g. of the reaction product, p-methoxybenzyl 7-amino-3-methylenecepham-4-carboxylate hydrochloride, precipitated from the mixture. The product was filtered and washed with cold methylene chloride and was dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH:21](O)[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:21]([C:14]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])[CH3:22])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Reactant: COc1cccc(F)c1C(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(C)Oc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-3-nitrophenol (this compound was synthesized according to the procedure described in the International publication WO97/39064) (0.2 g), 1-(2-fluoro-6-methoxyphenyl)ethanol (0.22 g) and triphenylphosphine (0.4 g) in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 0.84 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=8/1) to give 2-fluoro-5-[1-(2-fluoro-6-methoxy -phenyl)ethoxy]-1-nitrobenzene (0.15 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL), nickel (II) bromide (5 mg) and sodium borohydride (55 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (0.11 g).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Br[CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>CS(C)=O.CCOCC.O>[C:3]1([N:9]([CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(Nc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a suspension of sodium hydride (0.78 g) in DMSO (20 ml) was added 2-(N-phenylamino)pyridine (5.0 g) in DMSO (15 ml). The mixture was stirred and slowly heated under nitrogen to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and N-(3-bromopropyl)phthalimide (7.88 g) in DMSO (15 ml) added dropwise. After standing overnight the mixture was poured into water and ether extracts made with the pH adjusted between 2 to 4. The extracts were dried (MgSO4), stripped and the residue crystallised from ethanol to give N-[3-(N-phenyl-N-pyrid-2-ylamino)propyl]phthalimide, 3.69 g (35%) mp 103°-5° C. (ii) N-[3-(N-phenyl-N-pyrid-2-ylamino)propyl]phthalimide (3.1 g) and conc. hydrochloric acid (30 ml) were heated under reflux for 21 hr. Phthalic acid was filtered off on cooling and the filtrate stripped. The residue was taken back up in water and the solution extracted at pH 1 with chloroform. The pH was raised to 13 (NaOH) and the solution extracted again with ether. The ether extracts were dried (K2CO3) and stripped to give 2-[N-(3-aminopropyl)-N-phenylamino]pyridine, 1.84 g as an oil. (iii) 2-[N-(3-aminopropyl)-N-phenylamino]pyridine (0.9 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.86 g) were heated together under reflux in pyridine (2.5 ml) for 24 hr. The mixture was stripped and the residue recrystallised from ethanol to give 2-[3-(N-phenyl-N-pyrid-2-ylamino) propylamino]-5-(6-methylpyrid-3-ylmethyl) pyrimid-4-one, 1.03 g (73%) mp 216°-18° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1([CH2:31][C@H:32]([C:34]2[CH:43]=[CH:42][C:37]3[C:38](=[O:41])[O:39][CH2:40][C:36]=3[C:35]=2[CH3:44])[OH:33])[CH2:16][CH2:15][N:14]([CH2:17][C@H:18]([C:20]2[CH:29]=[CH:28][C:23]3[C:24](=[O:27])[O:25][CH2:26][C:22]=3[C:21]=2[CH3:30])[OH:19])[CH2:13][CH2:12]1>C(Cl)Cl>[OH:19][C@@H:18]([C:20]1[CH:29]=[CH:28][C:23]2[C:24](=[O:27])[O:25][CH2:26][C:22]=2[C:21]=1[CH3:30])[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([CH2:31][C:32]([C:34]2[CH:43]=[CH:42][C:37]3[C:38](=[O:41])[O:39][CH2:40][C:36]=3[C:35]=2[CH3:44])=[O:33])[CH2:16][CH2:15]1
Reactant: Cc1c([C@H](O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(C(=O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (71 uL, 0.82 mmol) in DCM (30 mL) was dropped DMSO (120 uL, 1.6 mmol) at −78° C. After stirring the mixture for 10 minutes, a DCM solution of 5,5′-{piperazine-1,4-diylbis[(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one) (380 mg, 0.82 mmol) was added into the reaction. The reaction was stir for another 20 minutes before TEA (570 uL, 4.1 mmol) was added to the reaction mixture. The reaction was then allowed to warm up to RT slowly. TLC analysis showed two new spots right above the SM. LC analysis suggested formation of the mono-ketone as well as the di-ketone. The reaction was diluted with DCM, washed with water, dried over sodium sulfate, and purified by flash chromatography. The title product was collected after removal of solvent.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][N:4]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[OH-].[Na+].C1(C)C=CC=CC=1>[CH3:16][C:2]1([CH2:3][N:4]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[O:19][CH2:18][CH2:17][O:1]1
Reactant: OCCO
Reactant: CC(=O)CN(c1ccc(Cl)cc1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(CN(c2ccc(Cl)cc2)S(C)(=O)=O)OCCO1

Procedure:
A mixture of N-(2-oxopropyl)-4'-chloromethanesulphonanilide (6.0 g), ethane-1,2-diol (10 ml), 4-toluenesulphonic acid (0.1 g) and toluene (75 ml) was stirred and boiled under reflux with water separation by means of a Dean and Stark receiver. After 3 hours the reaction mixture was cooled and poured into water (about 200 ml) containing a few drops of sodium hydroxide solution. The organic layer was separated, washed with water, dried (MgSO4) and evaporated to a brown oil, which gave fawn coloured crystals from a solution in toluene/80°-100° petrol. Yield 6.0 g (86%). Melting point 84°-85°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C@@H:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=3)[C@@H:21]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:20]2)[CH2:15][CH2:14]1>>[CH3:32][C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([CH3:33])[CH:29]=1)[C:25]([N:22]1[CH2:23][CH2:24][C@@H:19]([N:16]2[CH2:17][CH2:18][CH:13]([NH:12][C:5](=[O:6])[C:4]3[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=3)[CH2:14][CH2:15]2)[CH2:20][C@@H:21]1[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:34]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@@H](N3CCC(N)CC3)C[C@@H]2Cc2ccccc2)c1
Product: Cc1cc(C)cc(C(=O)NC2CCN([C@@H]3CCN(C(=O)c4cc(C)cc(C)c4)[C@@H](Cc4ccccc4)C3)CC2)c1

Procedure:
Using the same reaction procedure as described in example B6, 3,5-dimethylbenzoyl chloride was reacted with compound 22 to form (±)-trans-N-[1-[1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-3,5-dimethylbenzamide (compound 21, mp. 120.1° C.).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: O=C=Nc1ccccc1
Reactant: OCCNCCO
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(CCO)CCO
Reaction time: 1 h

Procedure:
0.163 mol of diethanolamine dissolved in 160 ml of dichloromethane is added, at 10° C., to a solution of 0.168 mol of phenyl isocyanate. After reacting for 1 hour at 10° C. and then for 12 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[O:12]([CH3:18])[C:13]([S:15]CC)=S.[CH3:19]O>O>[CH2:18]([O:12][C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[S:15])[CH3:19]
Reactant: CO
Reactant: CCSC(=S)OC
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=S)N[C@@H](CC(=O)O)C(=O)O
Temperature: 45 °C
Yield: 89 %

Procedure:
L-Aspartic acid (19.95 g, 0.150 mol) was suspended in 15 ml of water at 0° C., and 50% sodium hydroxide solution (24 g, 0.30 mol) was added dropwise with stirring. Methyl ethyl xanthate (22.44 g, 0.165 mol) in 15 ml of methanol was then added in one portion. The mixture was heated at 45° C. for 2 hours, cooled to room temperature, and washed with two portions of ethylene dichloride. The ethylene dichloride washes were discarded and the aqueous phase acidified with concentrated hydrochloric acid at 0° C. The solution was saturated with solid sodium chloride and extracted with two portions of ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate and evaporated in vacuo to afford 29.4 g (89%) of white crystalline N-ethoxythiocarbonyl-L-aspartic acid. mp 133° C.; nmr (DMSO-d6) δ1.23 (t, 3H, J=7 Hz), 2.67 (d, 2H, J=6 Hz), 4.37 (q, 2H, J=7 Hz), 4.93 (dt, 1H, J=6 Hz, 8 Hz), 9.26 (d, 1H, J=8 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:14]=1[Cl:20]>>[ClH:20].[Br:12][C:13]1[C:14]([Cl:20])=[C:15]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: CN1Cc2occc2C(O)C1
Product: CN1Cc2occc2C(Oc2cccc(Br)c2Cl)C1
Product: Cl

Procedure:
The same method as in Example 1 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-2-chloro-3-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cu](C#N)[C:41]#[N:42]>CN1C(=O)CCC1>[O:33]([CH2:32][C:3]1[CH:4]=[C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:6]=[CH:7][C:2]=1[C:41]#[N:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Br)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask charged with a stir bar, 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene (14.7 g), copper cyanide (4.1 g), and NMP (100 mL) is heated at reflux temperature for 8 h. After dilution with water (600 mL), the precipitate is separated, washed a few times with water and subsequently dissolved in ethyl acetate (200 mL). The resultant solution is filtered through a plug of silica gel using ethyl acetate (300 mL) as the eluent. The filtrate is concentrated under reduced pressure and the residue is dissolved in dichloromethane (100 mL) to reacetylate the oxygen groups deprotected during the cyanation. Accordingly, pyridine (4 mL), 4-dimethylaminopyridine (0.3 g) and acetic anhydride (4.4 mL) are added in succession. The resulting solution is stirred at room temperature for 1 h. Then, the reaction mixture is diluted with dichloromethane (50 mL) and washed thrice with 1 M aqueous hydrochloric acid, once with aqueous sodium hydrogen carbonate solution and once with water. The organic phase is dried (sodium sulphate) and the solvent is removed. The residue is recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:2]#[CH:3].S(=O)(=O)(O)[OH:11]>CO.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[O:11]=[C:2]([CH3:3])[CH2:1][O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(=O)(O)O
Reactant: C#CCOCC(=O)OC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CO
Product: COC(=O)COCC(C)=O
Temperature: 25 °C

Procedure:
The product from Example 1A (56 g, 0.44 mol) in methanol (1.5 L) was treated with mercury(II) acetate (14 g, 44 mmol), treated with concentrated sulfuric acid (3 mL), refluxed for 1 hour, allowed to cool to ambient temperature, concentrated to a volume of 200 mL, treated with 1M HCl (500 mL) and extracted with dichloromethane (thrice, 300 mL). The combined dichloromethane layers were dried (MgSO4), filtered, concentrated and distilled (65-95° C. at 1 torr) to provide the title compound.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][C:23]=1[C:24](O)=[O:25].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:27][C:23]=1[C:24]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:8][CH:5]1[CH2:6][CH2:7][C:2]([F:1])([F:20])[CH2:3][CH2:4]1)=[O:25]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NC4CCC(F)(F)CC4)ncnc23)c1
Yield: 21.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-difluorocyclohexyl)quinazoline-4,8-diamine (Intermediate-9, 60 mg, 0.215 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 116 mg, 0.431 mmol), oxalyl chloride (81 mg, 0.65 mmol), DMF (1 drop) and DIPEA (84 mg, 0.65 mmol) in CH2Cl2 (3 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.13 (s, 1H), 8.71 (d, 1H), 8.49 (s, 1H), 8.19 (m, 2H), 8.05 (d, 1H), 7.57-7.54 (m, 3H), 7.41 (d, 1H), 4.41 (m, 1H), 4.31 (d, 2H), 2.00 (m, 6H), 1.75 (m, 2H), 1.12 (s, 9H); MS (m/z): 530.20 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:10]=2)[CH2:4][CH2:3]1.N[C@@H]1CC[C@H](NC2N=C3C(N=CN3CC)=C(NC3C=CC=C([Cl:54])C=3)N=2)CC1>>[Cl:54][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[CH2:18][CH3:19])=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[N:10]=1.[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N[C@H]3CC[C@@H](N)CC3)nc21
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N[C@H]3CC[C@H](N)CC3)nc21
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Product: NC1CCC(N)CC1

Procedure:
Analogously to Example 1, 2-(trans-4-amino-cyclohexyl-amino)-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine; FAB-MS: (M+H)+=386; HPLC: tret (grad20/2)=8.47 minutes, and 2-(cis-4-amino-cyclohexyl-amino)-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine; FAB-MS: (M+H)+=386; HPLC: tret (grad20/2)=9.37 minutes are obtained from 308 mg (1.00 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine [described in Stage 1.2] and 3.26 g (28.6 mmol) of 1,4-diamino-cyclohexane (cis/trans mixture) after 25 h at 100° C. and purification by means of column chromatography.