Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[C:30](=[O:31])[N:22]2[C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH2:25][S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O>[O:1]1[C:6]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([NH:19][CH:20]2[C:30](=[O:31])[N:22]3[C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH2:25][S:26][C@H:21]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CCCCCCON=C(C(=O)O)C1=CSCCO1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1=CSCCO1
Yield: 72.2 %

Procedure:
N,N-Dimethylformamide (0.579 g.), phosphoryl chloride (1.214 g.) and ethyl acetate (3 ml.) were treated in a conventional manner to give a Vilsmeier reagent and the reagent was added to ethyl acetate (7 ml.). To the solution was added 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 2.00 g.) under stirring to give an activated acid solution. On the other hand, 7-amino-3-cephem-4-carboxylic acid (1.46 g.), trimethylsilylacetamide (3.84 g.), bis(trimethylsilyl)acetamide (4.40 ml.) and ethyl acetate (24 ml.) were stirred to prepare a solution. To the solution was added all at once the activated acid solution at -10° C., and stirred at the same temperature for 1.5 hours. After adding water (30 ml.) and ethyl acetate (15 ml.) to the resultant solution, the solution was shaken sufficiently and the organic layer was separated. An aqueous solution of sodium bicarbonate (30 ml.) was added to the organic solution, shaken sufficiently and the aqueous layer was separated. The solution was adjusted to pH 2.0 with conc. hydrochloric acid and extracted with ethyl acetate (60 ml.). The extract was washed with water (20 ml.) twice, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether (50 ml.) and the precipitates were collected by filtration to give 7-[2-(2,3-dihydro-1,4-oxathiin-6yl)-2-n-hexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.40 g.).
Reaction SMILES: [OH:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1.CCCCCC>CCO>[Br:21][C:22]1[CH:23]=[N:24][C:25]([N:5]2[CH2:4][CH2:3][C:2]([OH:1])([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6]2)=[N:26][CH:27]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)C1(O)CCNCC1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of methyl 4-hydroxypiperidine-4-carboxylate (0.4 g, 2.52 mmol) in EtOH (10 mL) was added DIPEA (2.2 mL, 12.57 mmol) and the solution stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.49 g, 2.52 mmol). The mixture was then heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the desired product as a yellow solid (0.35 g, 44% yield). 1H NMR (DMSO-d6): δ 1.64 (m, 2H), 1.82 (m, 2H), 3.20 (m, 2H), 3.64 (s, 3H), 4.27 (m, 2H), 5.60 (s, 1H) and 8.44 (s, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH-].[Na+].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl>C1COCC1.O>[CH3:1][S:2]([NH:8][C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([OH:16])=[O:15])(=[O:4])=[O:3]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
A solution of methanesulfonyl chloride (0.593 mL, 7.62 mmol) in 1M NaOH (7.60 mL, 15.2 mmol) and THF (10 mL) was added drop wise to a stirred mixture of (L)-tert-leucine (1.0 g, 7.6 mmol), dissolved in THF (7.6 mL) and H2O (12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was acidified with 4M HCl and extracted with EtOAc. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give (2S)-2-methanesulphonylamino-3,3-dimethyl-butyric acid (0.486 g, 30%), which was analyzed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-methanesulfonylamino-3,3-dimethyl-butyric acid (0.476 g, 2.27 mmol), EDAC (0.481 g, 2.51 mmol), HOBT (0.338 g, 2.50 mmol), NMM (0.275 mL, 2.50 mmol), benzylhydrazine×2HCl (0.489 g, 2.51 mmol) and Et3N (0.700 mL, 4.98 mmol) which gave the title compound (0.416 g, 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([SH:38])[CH:33]=1.CCCCP(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:10]=[N:11][C:12]=3[CH:26]([CH3:27])[CH3:28])=[CH:17][C:18]=2[CH3:25])[CH3:23])[CH:33]=1
Reactant: COC(=O)c1cccc(S)c1
Reactant: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)O
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(SC(C)c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a room temperature solution of 1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanol (70 mg, 0.167 mmol) in toluene (2 mL) are added 3-mercapto-benzoic acid methyl ester (28 mg, 0.167 mmol) and tri-N-butylphosphine (62 μL, 0.251 mmol). The reaction mixture is cooled to 0° C. To the reaction mixture is added 1,1′-(azocarbonyl)-dipiperidine (63 mg, 0.251 mmol). The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is concentrated and the residue is chromatographed (40 g SiO2, 0% to 30% EtOAc/Hexanes) to yield 3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoic acid methyl ester (62 mg, 65%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCCC3)n2n1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol) and piperidine (52 mg, 0.603 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-45% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (31.2 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H), 1.70 (br. s., 6 H), 2.37 (s, 3 H), 3.73 (br. s., 4 H), 6.16 (s, 1 H), 7.28 (s, 1 H), 7.60 (d, J=8.59 Hz, 2 H), 7.99 (d, J=8.59 Hz, 2 H), 10.84 (s, 1 H); ESI-MS: m/z 394.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:22]([NH2:25])[C:23]#[CH:24].C(N)C#C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:25][CH2:22][C:23]#[CH:24])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: C#CCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 416.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (137.9 g, 0.624 mol) in anhydrous DMF (1.4 L) was cooled to 0° C., and anhydrous triethylamine (109 mL, 0.780 mol) was added. Propargyl amine hydrochloride (4.72 g, 51.6 mmol) and propargyl amine (38.4 g, 0.697 mol) were sequentially added dropwise, and the reaction was allowed to warm to room temperature and then heated at 40° C. for 22 hours. The volatiles were removed under reduced pressure, and water (1.5 L) and solid sodium carbonate (75 g) were added to the resulting oil. The mixture was then extracted with dichloromethane, and the combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 60:40 dichloromethane/hexane and dichloromethane) to provide 51.54 g of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine as a brown solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH:19]([CH3:21])[NH:18][CH:17]([CH3:22])[CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37].O>ClCCl>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH:19]([CH3:21])[N:18]([C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[C:33]([F:32])([F:43])[F:44])[CH:17]([CH3:22])[CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC1CN(c2ccc(C(=O)NCCC3CC3)nn2)CC(C)N1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC1CN(c2ccc(C(=O)NCCC3CC3)nn2)CC(C)N1C(=O)c1ccccc1C(F)(F)F
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a solution of 6-(3,5-dimethylpiperazin-1-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.40 g, 1.33 mmol) in dichloromethane (15 mL) was added diisopropyl ethylamine (0.34 g, 0.46 mL, 2.66 mmol) followed by 2-trifluoromethylbenzoyl chloride (0.31 g, 0.22 mL, 1.46 mmol) at ambient temperature. The reaction solution was stirred for 16 hours and poured into cold water (10 mL). The organic layer was extracted with dichloromethane (50 mL) and washed with saturated solution of NaHCO3 (2×10 mL) and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with ethyl acetate (100%) to obtain 0.18 g of colorless solid (28% yield). 1H NMR (300 MHz, CDCl3) δ 8.03-7.91, 7.70, 7.63-7.49, 7.32, 6.99-6.95, 5.00, 4.39-4.22, 3.64, 3.55-3.47, 3.39-3.17, 1.51-1.38, 1.24-1.14, 0.76-0.67, 0.42, 0.05. 13C NMR (75 MHz, CDCl3) δ 168.0, 163.0, 160.9, 144.9, 132.3, 131.9, 129.4, 129.3, 127.2, 127.0, 126.8, 111.5, 50.4, 49.1, 48.7, 48.5, 48.2, 45.5, 45.3, 39.6, 34.6, 20.2, 19.5, 8.6, 4.2.
Reaction SMILES: [NH2:1][C:2]([CH2:10][OH:11])=[CH:3][C:4](=[O:9])[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[C:14]([NH:19]N)=[N:15][CH:16]=[CH:17][CH:18]=1.Cl>C(#N)C>[Cl:12][C:13]1[C:14]([N:19]2[C:4]([OH:9])([C:5]([O:7][CH3:8])=[O:6])[CH2:3][C:2]([CH2:10][OH:11])=[N:1]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NNc1ncccc1Cl
Reactant: COC(=O)C(=O)C=C(N)CO
Agent: Cl
Solvent: CC#N
Product: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl

Procedure:
A mixture of methyl 4-amino-5-hydroxy-2-oxopent-3-enoate (1.59 g, 10 mmol), 3-chloropyridin-2-ylhydrazine (1.43 g, 10 mmol and HCl (1 g, 10 mmol, 37% solution in water) was stirred in 15 ml of acetonitrile at 25° C. for 20 hours. The solution was concentrated under reduced pressure and the residue was washed with water and isopropanol. This gave 2.13 g (75%) of the product, with a melting point of 111-113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH2:9]([CH2:13][C:14](=O)[CH3:15])[C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14]([CH3:15])=[CH:13][CH:9]=[C:10]2[CH3:12])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Cl)cn1
Yield: 100.5 %

Procedure:
2-Amino-5-chloropyridine (10.0 g, 77 mmol), acetonyl acetone (8.8 g, 77 mmol) and a catalytic amount of p-toluenesulphonic acid in anhydrous toluene (250 ml) was heated to reflux for 5 h under Dean and Stark conditions. The solvent was removed in vacuo, the residue slurried in hexane (250 ml), filtered through celite and the solvent removed in vacuo to give the title compound as a yellow oil (16.0 g): δH (CDCl3) 8.57 (1H, dd, J 2.7, 0.6 Hz), 7.78 (1H, dd, J 8.4, 2.7 Hz), 7.17 (1H, m, J 7.5, 0.5 Hz), 5.91 (2H, s), 2.14 (6H, s).
Reaction SMILES: [CH2:1]([N:6]1[C:11](=[O:12])[CH:10]2[CH2:13][C:8]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)([CH2:9]2)[C:7]1=[O:23])[C:2]([CH3:5])([CH3:4])[CH3:3].C(OCC)C>C(OCC)(=O)C.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:8]23[CH2:9][CH:10]([CH2:13]2)[C:11](=[O:12])[N:6]([CH2:1][C:2]([CH3:4])([CH3:3])[CH3:5])[C:7]3=[O:23])=[CH:19][CH:18]=1
Reactant: CC(C)(C)CN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)CN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 4.1 g of 3-neopentyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 80 ml of ethyl acetate, hydrogenated in the presence of 0.4 g of 5% palladium-on-carbon and worked up. Melting point 141.5°-143° (from diethyl ether).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].CN(C=O)C.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[N:20][N:19]=1>O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([O:1][CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:19][N:20]=2)=[CH:34][CH:33]=1
Reactant: OCc1ccncc1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Nc2nnc(OCc3ccncc3)c3ccccc23)cc1
Reaction time: 0.33 h

Procedure:
A mixture of 1 g (9.16 mmol) 4-hydroxymethylpyridine, 0.44 g (11.0 mmol) sodium hydride (60% dispersion in oil) and 15 ml DMF is incubated for 20 min at 0° C. while stirring in a nitrogen atmosphere. At RT, 1 g (3.07 mmol) 1-chloro-4-(4-chloroanilino)phthalazine hydrochloride is added to the mixture, which is stirred for about 1 h at 500C and for 15 h at 80° C. Addition to the reaction mixture of a little water, evaporation under vacuum, recrystallization of the residue from methanol, and drying under HV yield the title compound with a water content of 3.36%; m.p. 139-141° C.; ESI-MS: (M+H)+=363.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH:13]([NH:19]C(=O)OC(C)(C)C)[CH2:14]2)[CH3:9].[ClH:27].C(OCC)C>C(Cl)Cl>[ClH:27].[ClH:27].[CH2:8]([N:10]1[CH:11]2[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:14][CH:13]([NH2:19])[CH2:12]2)[CH3:9]
Reactant: CCN1C2CCCC1CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C2CCCC1CC(N)C2
Reaction time: 2 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 9-ethyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamate from Step C (50 mg, 0.19 mmol) in methylene chloride (1 mL) at room temperature and the mixture was stirred under nitrogen for 2 h. The mixture was concentrated and the residue was dissolved in methanol (1 mL). HCl in diethyl ether (1.0 M, 2.0 mL, 2.0 mmol) was added dropwise at room temperature and the mixture was stirred for 5 min. The mixture was concentrated again and dried under vacuum overnight to give 9-ethyl-9-azabicyclo[3.3.1]nonan-3-amine dihydrochloride (45 mg, 99%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.75 (br s, 1H), 8.39 (br s, 3H), 4.14 (br s, 1H), 3.73-3.71 (m, 2H), 3.25 (q, J=7.0 Hz, 2H), 2.55-2.48 (m, 2H), 2.05-1.95 (m, 3H), 1.80-1.76 (m, 1H), 1.50-1.22 (m, 7H); MS (ESI+) m/z 169 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][CH:4]=[C:3]2[C:2]([F:1])([F:14])[F:15])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: Nc1cccc2c(C(F)(F)F)ccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 61 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-trifluoromethyl-quinolin-8-ylamine (Intermediate 469) (350 mg, 1.65 mmol), 2-nitrobenzenesulfonyl chloride (474 mg, 12.1 mmol), DMAP (cat), pyridine (2 ml) and DCM (5 ml) gave the title compound (400 mg, 60%) after purification by column chromatography with n-hexane/EtOAc (80:20) as the eluent.
Reaction SMILES: C(OCC)(=O)C[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=O)([C:5]([O:7][CH2:8][CH3:9])=[O:6])O.[H][H].O1CCC[CH2:23]1>>[CH2:10]([CH2:3][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:11]1[O:13][CH2:14][CH2:15][CH2:23]1.[OH:7][CH2:5][CH2:3][CH:10]1[CH2:15][CH2:14][O:13][CH2:11]1
Reactant: [H][H]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Reactant: C1CCOC1
Product: CCOC(=O)CCC1CCCO1
Product: OCCC1CCOC1
Yield: 30 %
Yield: 39 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 175° C. and 50 bar together with 1100 ml of tetrahydrofuran and 60 g of catalyst F (4-mm tablets) until the take-up of hydrogen had ceased. The reaction product was freed from tetrahydrofuran and distilled under reduced pressure, giving 101 g (39%) of ethyl tetrahydrofurfurylacetate and 57 g (30%) of 3-(2'-hydroxyethyl)tetrahydrofuran.
Reaction SMILES: [C:1]([CH:3]=[C:4]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)OS(C1C=CC(C)=CC=1)(=O)=O)#[N:2].Cl.[NH2:27][CH:28](C(OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30].[O-][CH2:40]C.[Na+].Cl>C(O)C.O1CCCC1>[NH2:2][C:1]1[CH:3]=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:40])=[O:21])=[CH:24][CH:25]=2)[NH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: COC(=O)c1ccc(C(=CC#N)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc(N)c(C(=O)OCC)[nH]2)cc1
Temperature: 0 °C

Procedure:
To a suspension of methyl 4-(2-cyano-1-{[(4-methylphenyl)sulfonyl]oxy}vinyl)benzoate (17.5 g) and diethyl aminomalonate hydrochloride (10.36 g) in a mixed solvent of ethanol (165 mL)-tetrahydrofuran (80 mL) was added dropwise a solution (50 mL) of 20% sodium ethoxide in ethanol under ice-cooling. After stirring under ice-cooling for 1 hr, the mixture was stirred at room temperature for 21 hr. the reaction mixture was poured into ice water (400 mL) and adjusted to pH 7 with 1N hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (250 mL×3). The organic layers were combined, washed with saturated brine (150 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1→1:1) and the obtained solid was recrystallized from ethyl acetate to give the title compound (4.76 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[C:14](/[C:16](/[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[C:25]([O:31][CH3:32])[N:24]=2)=[CH:17]\[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=[CH:12][C:11]=1[OH:33].O>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[C:14](/[C:16](/[C:23]2[N:24]=[C:25]([O:31][CH3:32])[C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=2)=[CH:17]\[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:13]=[CH:12][C:11]=1[O:33][CH3:1]
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(O)c(Cl)c2)nc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(OC)c(Cl)c2)nc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
Potassium carbonate (188 mg) and methyl iodide (73 μL) were sequentially added to a solution of 2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenol (163 mg) in N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→2:1) to give 6-[(E)-1-(3-chloro-4-methoxyphenyl)-2-cyclopentylethenyl]-3-ethyl-2-methoxypyridine as a yellow oil (131 mg, 77%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:20][C@@H:21]([CH2:51]O)[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:63]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:28][C:25]1[CH:26]=[CH:27][N:23]([CH2:22][C:21]([OH:20])([CH3:51])[CH3:63])[N:24]=1)[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO[C@@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccn(CC(C)(C)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
(2S,4S)-2-t-butoxycarbonylamino-4-ethoxy-pentanoic acid (401 mg, 1.536 mmol) was mixed with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 334 mg, 2.16 mmol) in N,N-dimethylformamide (10 mL). benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.23 g, 2.77 mmol) and N,N-diisopropylethylamine (0.7 mL) was added at 0° C. The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and saturated sodium chloride solution. The solvents were evaporated and the crude material was purified by flash column chromatography (silica gel, 10-80% ethyl acetate/hexanes) to afford {(1S,3S)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butyl}-carbamic acid t-butyl ester (486 mg, 80%) as a white solid: LR-ES-MS m/z calculated for C19H34N4O5 [M]+ 398, observed [M+H]+ 399.