Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[Li].[CH:3]#C.C([SiH2]O[C:11]([CH3:31])(C)[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13]1)(C)(C)C>CS(C)=O.C1COCC1>[CH2:11]([CH:12]1[CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][CH2:17]1)[C:31]#[CH:3]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Reactant: C#C
Agent: N
Agent: [Li]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C#CCC1CCC(CO)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 3-neck 250 mL-flask equipped with a gas inlet tube and dry-ice condenser was cooled to −78° C. and charged with liquid ammonia (40 mL). To the reaction mixture was added lithium wire (600 mg, 86.4 mmol) generating a deep blue solution. The mixture was allowed to stir for 1 hour. Acetylene, passed through a charcoal drying tube, was added to the ammonia until all the lithium had reacted and the solution turned colorless, at which time the flow of acetylene was stopped, the acetylene-inlet tube and condenser removed and the flask outfitted with a thermometer. DMSO (20 mL) was added and the ammonia evaporated with a warm water bath until the mixture reached a temperature of 30° C. The solution was stirred at this temperature for 2 hours until the solution stopped bubbling. The mixture was cooled to 5° C. and compound 84 (11.25 g, 27.3 mmol), in DMSO (10 mL), was added. The temperature was maintained at 5° C. The mixture was allowed to stir at 5° C. for 0.5 hours. Then the solution was gradually warmed to room temperature and stirred for an additional 18 hours. The brown/black reaction mixture was poured slowly over ice (300 g) and extracted with ether (4×100 mL), dried with anhydrous sodium sulfate, and concentrated in vacuo to yield a yellow oil. The oil was subsequently dissolved in THF (200 mL) and changed to a brownish color upon addition of TBAF hydrate (11.20 g, 35.5 mmol). The solution was allowed to stir for 24 hours under N2 atmosphere. After stirring, the reaction was quenched with water (200 mL) and extracted with ether (3×100 mL). The ether extracts were combined and concentrated in vacuo. The crude product was purified by chromatography, on a silica gel column, eluting with 1:1 ether/petroleum ether to yield 86 (3.91 g, 93%) as a yellow oil. 1H NMR (CDCl3) δ 3.45 (d, J=6.2, 2H), 2.10 (d, J=6.2, 2H), 1.9 (s, 1H), 1.94–1.69 (m, 4H), 1.52–1.34 (m, 2H), 1.16 –0.83 (m, 4H); 13C NMR (CDCl3) δ 83.8, 69.5, 69.0, 40.8, 37.7, 32.3, 29.7, 26.5.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:17](OCC)=[O:18])([C:12](OCC)=[O:13])[CH2:11][CH:10]=[CH:9][CH2:8]1>O1CCCC1.O.[OH-].[Na+]>[C:7]1([CH2:17][OH:18])([CH2:12][OH:13])[CH2:11][CH:10]=[CH:9][CH2:8]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(CO)CC=CC1
Temperature: 26 °C
Reaction time: 2 h
Yield: 177.3 %

Procedure:
To an ice-cooled suspension of lithium aluminum hydride (25.54 g, 672.8 mmol) in tetrahydrofuran (2 L) was added a solution of diethyl cyclopent-3-ene-1,1-dicarboxylate (42.0 g, 198 mmol) in tetrahydrofuran (100 mL) over 30 min. The reaction mixture was warmed to 26° C. After 2 h, the reaction was diluted sequentially with water (26 mL), 3M aqueous sodium hydroxide solution (26 mL), and water (78 mL). The mixture was stirred at 0° C. for 15 min and filtered. The filtrate was concentrated to afford product as a colorless oil (45 g, 89% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]=2[CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:38][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:13])=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]=2[CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2oc(C(=O)O)c(OC(C)C)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)NCc3ccccc3)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-methoxy-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 1.00 mmol) [Connor, et al., J. Med. Chem. 35, 935(1992)] and 1,1'-carbonyldiimidazole (211 mg, 1.30 mmol) in 7 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.66 mL, 6.00 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:3 to 1:1) provides 5-methoxy-3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 79% yield; mp=68°-69° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=O)(=[O:3])[CH3:2].CC[O-].[Na+]>C(O)C.O>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:7]1[C:6]2[C:5](=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:4][C:1](=[O:3])[CH:2]=1
Reactant: CC(=O)Nc1ccccc1C(=O)c1cccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1cc(-c2cccs2)c2ccccc2[nH]1

Procedure:
To a solution of 2-(2-acetylaminobenzoyl)thiophene (4.8 g) in ethanol (60 cc) is added sodium ethylate (3.2 g). The reaction mixture is refluxed for 9 hours, treated again with sodium ethylate (0.5 g) and then allowed to reflux for 10 hours. The mixture is poured in iced water (200 cc). The precipitate formed is filtered, washed with distilled water until neutrality and then with acetone (3×50 cc) and dried at 40° C. under reduced pressure. The residue thus obtained is recrystallized in ethanol to obtain the product as a yellow solid. (m.p.=262°-264° C.)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cccc(C(F)(F)F)c1

Procedure:
In a manner analogous to the preparation of Example 83(a), 3-(3-trifluoromethyl-phenyl)-propan-1-ol (0.94 g, 4.61 mmol), Et3N (1.28 mL, 9.22 mmol) and MsCl (0.44 mL, 5.53 mmol) gave the desired compound as a light brown oil. 1H NMR (300 MHz, CDCl3) δ 2.10-2.16 (m, 2H), 2.82-2.86 (t, 2H) 3.02 (s, 3H), 4.24-4.28 (t, 2H), 7.38-7.52 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:17]([O:16][CH3:15])=[O:23])=[O:6]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 18.51 g (0.10 mol; 1.0 eq) of 2-fluoro-3-nitrobenzoic acid and 100 ml of thionyl chloride was refluxed for 3 hours. The excess thionyl chloride was then concentrated and the residue was co-evaporated twice with toluene. The resulting acid chloride was taken up in 250 ml of dichloromethane. To this mixture, cooled to 0° C., were added 16.56 g (0.10 mol; 1.0 eq) of L-proline methyl ester hydrochloride and then 30.50 ml (0.22 mol; 2.2 eq) of triethylamine. After 30 minutes at 0° C. and one hour at ambient temperature, the reaction medium was diluted and washed with 250 ml of a 1 M aqueous hydrochloric acid solution and then with 250 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. 25.64 g of methyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate were obtained. Yield=87%.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N+](C1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3)C(=O)C=2C=CC=1)([O-])=O.[N+](C1C2C(=O)C3C(=CC=CC=3[N+]([O-])=O)C(=O)C=2C=CC=1)([O-])=O.[OH-].[Na+].[H][H].C1(C=CC(O)=CC=1)O>[C].[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A 500 ml. electromagnetically stirred flask was charged with 5.0 g of crude 1-nitroanthraquinone having a purity of 97% and containing 2% of 1,5-dinitroanthraquinone and 1% of 1,8-dinitroanthraquinone as impurities (0.0l92 mole of 1-nitroanthraquinone, and 0.005 mole of all the dinitroanthraquinones), 100 g (0.1 mole) of a 4% aqueous solution of sodium hydroxide and 0.1 g of 5% palladium-carbon. The inside of the flask was purged with hydrogen, and at a reaction temperature of 30° C., they were stirred. In 3 hours, the reaction was stopped with the absorption of 0.08 mole of hydrogen. The amount of hydrogen absorbed was slightly in excess of the sum of the amount of hydrogen required to convert the nitro group to an amino group (0.0606 mole) and the amount of hydrogen required to convert 1-aminoanthraquinone to its hydroquinone derivative (0.0192 mole). The inside of the flask was purged with nitrogen, and the reaction mixture was filtered in an atmosphere of nitrogen to separate the catalyst. The filtrate was oxidized with air at 20° to 30° C. for 2 hours with stirring to afford 4.2 g of 1-aminoanthraquinone in a yield of 97.4% of theory. The product had a purity of 99% as determined by infrared absorption spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.O.CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCN(C(=O)OC(C)(C)C)C4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 72.9 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (233 mg, 0.681 mmol), 3-amino-1-N-Boc-piperidine (136 mg, 0.680 mmol) and TEA (0.200 mL, 1.44 mmol) in dioxane (5 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (251 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[N:28][C:29]3[N:30]([N:32]=[C:33]([CH3:35])[N:34]=3)[CH:31]=2)[CH:23]=[CH:24][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:36]3[CH:37]=[CH:38][C:39]([CH2:40][N:16]4[CH2:17][CH2:18][CH:13]([C:11]5[N:12]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=6)[NH:9][N:10]=5)[CH2:14][CH2:15]4)=[CH:42][CH:43]=3)=[N:28][C:29]3[N:30]([N:32]=[C:33]([CH3:35])[N:34]=3)[CH:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3cccc(F)c3)cn2n1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nc(C)nn6cc5-c5cccc(F)c5)cc4)CC3)n[nH]2)n1
Reaction time: 2 h

Procedure:
323 mg (1.02 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 8.8 mL NMP. After addition of 0.34 mL triethylamine the reaction mixture is stirred for two hours. 340 mg (1.02 mmol) 4-[6-(3-Fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-benzaldehyde and 0.1 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 251 mg (1.12 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 6 hours. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water and dried. After purification by preparative HPLC 13.2 mg (2.3%) of the desired product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(Cl)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (5 g, 0.018 mol), 4-chlorophenyl isothiocyanate (3.76 g, 0.022 mol) and toluene (20 ml) was heated under reflux for 3 hours, then cooled and diluted with ether to induce crystallisation of the product, which was recrystallised from ethanol/ether. Yield 6.69 g (82%), m.p. 179°-180 ° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][C:11]([Cl:41])=[C:12]([C:14](=[N:31][O:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:15]([NH:17][CH:18]2[C:29](=[O:30])[N:20]3[C:21]([C:26]([OH:28])=[O:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:10][C:11]([Cl:41])=[C:12]([C:14](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[C:15]([NH:17][CH:18]2[C:29](=[O:30])[N:20]3[C:21]([C:26]([OH:28])=[O:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nc(N)sc3Cl)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nc(N)sc3Cl)[C@H]2SC1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
Trifluoroacetic acid (9.2 ml) was added to a suspension of 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g) in dichloromethane (5 ml) and anisole (2.3 ml) at ambient temperature and the mixture was stirred for 1.5 hours at same temperature. To the resulting solution was added the isopropyl ether and stirred. The precipitates were collected by filtration, washed with isopropyl ether. The precipitates were added to a mixture of ethyl acetate and water, and adjusted to pH 7.5 with saturated aqueous sodium bicarbonate. The separated aqueous layer was adjusted to pH 2.2 with 10% hydrochloric acid under ice cooling. The precipitates were filtered off, washed with ice water and dried over phosphorus pentoxide in vacuo to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (1.4 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][C:21]1([CH3:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:23]2[CH2:24][CH2:25][CH2:26][C:21]([CH3:27])([CH3:20])[CH2:22]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1(C)CCCNC1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC#CCOc1cc(N2CCCC(C)(C)C2)ncn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Into 2 ml of acetonitrile were added 0.20 g of 4-(2-butynyloxy)-6-chloropyrimidine, 0.45 g of potassium carbonate and 0.20 g of 3,3-dimethylpiperidine hydrochloride, and the mixture was stirred for 2 hours at 80° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.27 g of 4-(2-butynyloxy)-6-(3,3-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (31)).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][CH:24]1[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][C:25]1([CH:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:26]3)[CH2:30]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2ncc[nH]2)C23CC4CC(CC(C4)C2O)C3)cc1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
5.0 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour at -60°, combined with 4.3 g of 2-adamantanone, further stirred for 1 hour, and heated to 25°. Then water is added, the mixture is extracted three times with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 6.66 g of crude 4-[2-hydroxy-adamant-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH2:13])C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:13]2[C:7]3[C:6](=[CH:11][C:10]([Cl:12])=[CH:9][CH:8]=3)[CH2:5][C:4]2=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)Cc1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3cc(Cl)ccc32)CC1
Yield: 138.8 %

Procedure:
(2-Amino-5-chloro-phenyl)-acetic acid ethyl ester (3.3 g, 15.4 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.6 g, 23 mmol) were set stirring in CH2Cl2 (50 mL) and sodium triacetoxyborohydride (4.9 g, 23.1 mmol) was added followed by acetic acid (3 mL). After 5 days saturated NaHCO3 was added and the organics separated. The organics were dried (MgSO4) and evaporated to give 7.5 g of a clear golden oil. The oil was purified (silica, 50% EtOAc/hexanes) to give 3.4 g (63%) of a white solid. TLC (silica, 25% EtOAc/hexanes): Rf=0.18. MS (electrospray): exact mass calculated for C18H23ClN2O3, 350.14. m/z found, 373.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.40-7.30 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.40 (m, 2H), 3.63 (s, 2H), 2.94 (m, 2H), 2.45-2.30 (m, 2H), 1.82 (m, 2H), 1.62 (s, 9H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]([CH2:27][CH:28]=O)[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:30]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH:44][CH3:45])=[N+:31]=[N-:32].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[N:30]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N:44]([CH3:45])[CH2:28][CH2:27][N:16]([CH3:15])[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[N+:31]=[N-:32]
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Reactant: CNCCOCCOCCOCCN=[N+]=[N-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(CCOCCOCCOCCN=[N+]=[N-])CCN(C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
Sodium triacetoxyborohydride (3.55 g, 16.8 mmol) was added portionwise at room temperature to benzyl methyl(2-oxoethyl)carbamate (2.68 g, 12.9 mmol), 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-N-methylethanamine 222c (3.00 g, 12.9 mmol), and acetic acid (2 equiv.) in THF (20 mL). The mixture was stirred for 2 hours, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (Mg2SO4) and evaporated. The residue was purified by Combiflash purification system (ethyl acetate/dichloromethane) to give product as an oil (3.19 g, 58%); MS (ES, m/z): 424 [M+H]+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)=O.[OH:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOCCOCCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
34.04 g (0.105 moles) of 2-(2-butoxyethoxy)-ethyl tosylate (95%) were reacted with 14.5 g (0.105 moles) of 5-hydroxy-benzo[1.3]dioxole and 14.5 g (0.105 moles) of anhydrous potassium carbonate in 125 ml of acetone. The mixture was heated to reflux for 2 hrs, cooled to room temperature and kept, under stirring, at that temperature for 6 hrs. The mixture was then filtered and the organic solution was evaporated u.v. (20° C./21 mbar) . The residue was diluted with 100 ml of dichloromethane and washed with 12 ml of an aqueous solution of sodium hydroxide 1N and water. The organic phase was separated, washed with water and evaporated u.v (20° C./21 mbar). An oil residue was obtained that was purified on silica gel column (eluant n-hexane:ethyl acetate 4:1 v/v). After evaporation 14.84 g (97.43%) of 5-[2-(2-Butoxy-ethoxy)-ethoxy]-benzo[1,3]dioxole were obtained whose NMR and MS analyses corresponded to those of the aforementioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28](O)=[O:29])[CH:21]=[CH:22][CH:23]=1.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:28](=[O:29])[CH2:27][NH:26][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=2)=[O:31])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(Cl)cc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cl)cc2)c1
Yield: 15.5 %

Procedure:
The procedure used is similar to that described in Example 17, but starting with tert-butyl 2-[(4-chlorophenyl)amino]acetate (1.8 g), 2-[3-(3-methylphenyl)-ureido]acetic acid (1.56 g) and thionyl chloride (0.89 g). The product obtained is purified by chromatography on silica (0.04-0.063 mm) (60 g) contained in a column 2.5 cm in diameter [eluent: cyclohexane/ethyl acetate (80:20 by volume)], using an excess pressure of nitrogen of 40 kPa and collecting 20-cc fractions. Fractions 21 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After crystallisation in acetonitrile, tert-butyl 2-{N-(4-chlorophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (0.5 g), m.p. 125° C., is obtained.