Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=1[CH2:16][CH2:17]Cl.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([N:24]2[C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]=3[CH2:16][CH2:17]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1nc2ccnn2c(Cl)c1CCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccnn2c2c1CCN2C1CCCC1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
In 48 ml of anhydrous DMF were dissolved 3.6 g of ethyl 7-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate. While stirring at room temperature under a nitrogen atmosphere, 7.3 ml of cyclopentylamine were added to the solution, and the mixture was stirred for 1 hour and 20 minutes. The reaction mixture was poured into 250 ml of ice water. Insoluble matter was collected by filtration and air-dried to obtain 3.20 g (yield: 85.3%) of ethyl 8-cyclopentyl-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]-pyrimidine-5-carboxylate. While stirring at -5 to 0° C., 1.16 g of this product were gradually added to mixed acid prepared by mixing 7.8 ml of concentrated sulfuric acid and 3.9 ml of 90% nitric acid. After being stirred for 5 minutes under the same conditions, the reaction mixture was poured into 200 ml of ice water, followed by extraction with chloroform. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was then distilled off, and the residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:1) to obtain 0.76 g (yield: 57.0%) of Compound 21.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(C)C.[Pt]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Yield: 7.4 %

Procedure:
To a solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b -hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 1,200 mg) in isopropanol (20 ml) was added platinum on carbon (10% w/w, 20 mg) and the resulting mixture was hydrogenated at room temperature with stirring under 1 atmosphere pressure of hydrogen for 18 hours. The mixture was filtered through celite and concentrated in vacuo to give a white solid. The solid was purified by preparative HPLC (1 inch diameter Ultrasphere C18 column, 2 injections; 70:30 acetonitrile:water) to give the product as a white solid (89 mg).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])C.[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29]>CCO>[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH:36][C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=1[F:24])[CH:10]=2)=[O:5])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3c(F)cccc3F)ccc2c1O
Yield: 103.1 %

Procedure:
A mixture of 1-cyano-7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (26 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (26 mg) in EtOH (0.5 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (36 mg). LC MS ESI+: 498 (M+1)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8]([CH2:11][CH2:12][CH2:13][CH3:14])([F:10])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:18]([O:17][C:15]([N:6]1[CH2:7][C:8]([CH2:11][CH2:12][CH2:13][CH3:14])([F:10])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCCC1(F)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1(F)CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
To a solution of 4-butyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (270 mg, 0.89 mmol) in THF (12 mL) and water (4 mL), was added lithium hydroxide monohydrate (45 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 16 hours. THF was removed under vacuum and the residue was taken up in ethyl acetate (150 mL), washed with 10% citric acid (100 mL) and brine (20 mL). Removal of solvent provided 4-butyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (260 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:43][N:44]([CH3:46])[CH3:45]>C(OCC)(=O)C.CCOCC>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:44]([CH3:46])([CH3:45])[CH3:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: CN(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[N+](C)(C)C)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.17 h
Yield: 9.2 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 490 mg, 0.68 mmole) in ethyl acetate (14 ml) was added a 0.1M trimethylamine solution in ether (13.6 ml) in one portion. The mixture was stirred for 10 minutes and evaporated to dryness, and the residue was triturated with ether (20 ml). The resulting solid (490 mg) was added to trifluoroacetic acid (0.2 ml) containing one drop of anisole. After 1.5 hours' stirring, the mixture was evaporated to dryness under reduced pressure and the residual oil was triturated with ether (20 ml). The resulting precipitate was collected by filtration and dissolved in H2O (20 ml). Some insolubles were removed, and the aqueous solution was eluted on a C18 reverse phase column (the packing of PrepPAK-500/C18 cartridge, Waters' 30 ml) using water as eluant. Fractions containing the desired compound were combined and concentrated to a small volume and lyophilized to afford 30 mg (9.2%) of the title compound (I-1D) (8/E=1/1) as a colorless amorphous powder, melting at >150° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13](=[C:21]2[C:22](=[O:23])[O:24][C:17]([CH3:25])([CH3:16])[O:18][C:19]2=[O:20])[OH:15])[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(O)=C2C(=O)OC(C)(C)OC2=O)CCC1
Reaction time: 8 h

Procedure:
1-tert-Butoxycarbonylamino-cyclobutanecarboxylic acid (1.0 g, 4.6 mmol) and Meldrum's acid (2,2-dimethyl-[1,3]dioxane-4,6-dione, 0.74 g, 5.1 mmol) are dissolved in 20 ml dichloromethane. 4-Dimethylaminopyridin (0.88 g, 7.2 mmol) and EDCl (1.07 g, 5.6 mmol) are added and the mixture is left in a refrigerator (4° C.) overnight. The reaction mixture is diluted with additional 200 ml dichloromethane and washed twice with 0.1 N HCl and with brine. Drying of the organic phase and evaporation of the solvent delivered the crude title compound which is used in the subsequent step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:25][CH2:24]1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: Fc1cc(OC2CCNCC2)ccc1OC(F)(F)F
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)c(F)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 54.4 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3-fluoro-4-(trifluoromethoxy)phenoxy)piperidine (279 mg, 1.0 mmol) as crude materials, 137 mg title compound was generated and yield was 55%.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Cl:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH3:18])[C:16]([Cl:15])=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(=O)C(Cl)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(C)c1Cl
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a suspension of 153 g (0.74 mol) 3-amino-5-benzylthio-1,2,4-triazole in 250 ml of glacial acetic acid was added 100 g (0.74 mol) of 3-chloro-2,4-pentanedione in a dropwise manner. The reaction mixture was heated at reflux for 18 hours and cooled to room temperature. The reaction mixture was poured over ice and the oil which separated solidified upon stirring. The solid was collected by filtration and recrystallized from methanol to yield 116 g (79%) of the desired product as an off white solid, m.p. 164°-166° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]=12>>[Cl:17][C:15]1[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]2=[C:11]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:16]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: NCCc1cccnc1
Product: Cn1ncc2c(NCCc3cccnc3)nc(Cl)nc21

Procedure:
Reaction of 3-(2-aminoethyl)pyridine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-pyridin-3-yl-ethyl)-amine.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[C:12]([Cl:21])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH3:26])[CH:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[Cl:21][C:12]1[CH:11]=[C:10]([C:9]2[O:22][C:2]3[CH:3]=[C:4]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[CH3:35])[CH3:26])[N:5]=[CH:6][C:7]=3[N:8]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH:18]1[CH2:19][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCC3CC3)c(Cl)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2cn1
Temperature: 160 °C
Reaction time: 5 h
Yield: 11.1 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((3-chloro-4-(cyclopropylmethoxy)benzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (1.02 g), potassium carbonate (0.552 g) and copper(I) iodide (38.0 mg) in DMF (10 mL) was stirred at 160° C. for 5 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and to the obtained residue was added 2 M hydrogen chloride/methanol (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (92.4 mg). 1H NMR (300 MHz, CDCl3) δ 0.38-0.48 (2H, m), 0.64-0.77 (2H, m), 1.30 (3H, d, J=6.4 Hz), 1.33-1.44 (1H, m), 1.97 (3H, s), 3.99 (2H, d, J=6.8 Hz), 4.25-4.51 (3H, m), 6.01 (1H, d, J=6.0 Hz), 6.91 (1H, s), 7.02 (1H, d, J=8.7 Hz), 8.06 (1H, dd, J=8.7, 1.9 Hz), 8.24 (1H, d, J=2.3 Hz), 8.53 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[O:11])=[C:4]([I:12])[CH:3]=1.C([SiH](CC)CC)C.[CH2:20](O)[CH:21]=[CH:22][CH3:23].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][O:11][CH2:20][CH:21]=[CH:22][CH3:23])=[C:4]([I:12])[CH:3]=1
Reactant: COc1nc(Cl)cc(I)c1C=O
Reactant: CC=CCO
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC=CCOCc1c(I)cc(Cl)nc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 3-necked 500-mL round-bottom flask is equipped with a mechanical stirrer. Under nitrogen, the flask is charged with 6-chloro-4-iodo-2-methoxypyridine-3-carbaldehyde (53.0 g, 178 mmol) obtained as described in U.S. Pat. No. 5,254,690 to Comins et al. issued Oct. 19, 1993 and incorporated herein by reference, triethylsilane (42.7 mL, 267 mmol) and crotyl alcohol (60.8 mL, 713 mmol). The slurry is cooled to 0° C. and trifluoroacetic acid (90.0 mL, 1.17 mmol) is added over 1 h. The reaction is allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture is slowly poured into a rapidly stirred solution of saturated sodium bicarbonate in water (1.5 L). The mixture is extracted with methyl t-butyl ether (4×300 mL). The combined organic layers are washed with brine (700 mL) and dried over anhydrous sodium sulfate (150 g). The drying agent is removed by filtration and the solvents are removed in vacuo to afford 6-chloro-4-iodo-2-methoxy-3-(2-butenyloxymethyl)pyridine as crude product. The product can be purified by vacuum distillation to provide 6-chloro-4-iodo-2-methoxy-3-(2-butenyloxymethyl)pyridine as a light yellow oil. 1H NMR (200 MHz, CDCL3) δ1.75 (d, J=6.1 Hz, 3H), 3.92 (s, 3H), 4.00 (m, 2H), 4.59 (s, 2H), 5.74 (m, 1H), 5.75 (m, 1H), 7.39 (s, 1H).
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([C:26]=2[OH:27])=[N:24][C:23]([O:28][CH3:29])=[CH:22][CH:21]=3)[CH2:10][CH2:9]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[OH:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[N:24]=2)[N:19]=[CH:18][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([C:39]2[CH:40]=[CH:41][C:35]3[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=3[CH:38]=2)=[O:30])[CH2:9][CH2:10]1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)c(O)c2n1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)c(O)c2n1

Procedure:
The title compound is prepared as a white lyophilizated powder following Scheme 1 and in analogy to Example 1 using {1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:17]([N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Combine 4-(piperidin-4-yloxy)-benzonitrile hydrochloride (64 mg, 0.268 mmol), benzaldehyde (55 μL, 0.536 mmol) and sodium triacetoxy borohydride (85 mg, 0.402 mmol) in CH2Cl2 (3 mL). Stir at room temperature overnight. Dilute the reaction mixture with CH2Cl2 (3 mL) and wash with NaOH (1M aq. 5 mL). Separate the organic layer and place it in an SCX column, eluting with ammonia (2.0M in methanol) to provide the title compound (74 mg, 95%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[N:20]\[OH:21])/[C:16]([NH:18][CH3:19])=[O:17])=[CH:3][CH:2]=1.[C:28](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[N:20]\[O:21][CH3:28])/[C:16]([NH:18][CH3:19])=[O:17])=[CH:5][CH:6]=1
Reactant: CNC(=O)/C(=N/O)c1ccccc1COc1ccc(-c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To (E)-2-[2-(biphenyl-4-yloxymethyl)phenyl]-2-hydroxyimino-N-methylacetamide(9.73 g, 0.027 mol), added were dry acetone (100 ml), potassium carbonate (11.20 g, 0.081 mol) and dimethylsulfate (6.81 g, 0.054 mol), and the reaction mixture was stirred overnight at room temperature. Then, undissolved materials were removed therefrom and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(biphenyl-4-yloxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (9.85 g; yield, 97.4%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:53](Cl)(=[O:55])[CH3:54]>ClCCl>[C:53]([N:40]1[CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][N:32]([C:21]3[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]4[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=4)([CH3:43])[CH3:42])=[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[CH3:31])[CH:22]=3)[CH2:33][CH:34]2[CH2:41]1)(=[O:55])[CH3:54]
Reactant: CC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN2CCN(c3cc(-c4ccc(F)cc4C)c(N(C)C(=O)C(C)(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cn3)CC2C1
Reaction time: 2 h

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (prepared with an analogous procedure to that described for D80, 89 mg, 0.14 mmol) in 5 mL of dichloromethane were added at 0° C. triethylamine (197 μL, 1.41 mmol) and acetyl chloride (75 μL, 1.0 mmol). The reaction was left at room temperature for 2 h. It was diluted with dichloromethane, extracted with sat NaHCO3 solution, the organics dried (Na2SO4), and the solvent was removed. The product was purified by flash chromatography (silica, cyclohexane: EtOAc 50:50 to EtOAc). Obtained 60 mg.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13]C(=O)C)[CH:8]=O)(=O)C.[NH:17]1[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18]1>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH2:8][N:17]1[CH2:18][CH:19]=[CH:20][CH2:21][CH2:22]1
Reactant: CC(=O)Oc1ccc(C=O)cc1OC(C)=O
Reactant: C1=CCNCC1
Solvent: CO
Product: Oc1ccc(CN2CC=CCC2)cc1O

Procedure:
Using a similar procedure to that described in Example 7, but starting from 3,4-diacetoxybenzaldehyde (18.6 g.) and 1,2,3,6-tetrahydropyridine (13.9 g.) in methanol (150 ml.), there was obtained 1-(3,4-dihydroxybenzyl)-1,2,3,6-tetrahydropyridine as the free base (0.45 g.), m.p. >300° C.; microanalysis,
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]3[S:43][CH:42]=[N:41][C:40]=3[CH:44]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:43]1[C:39]2[CH:38]=[CH:37][C:36]([C:6]3[C:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:27])=[N:14][C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=4)[N:7]=3)=[CH:44][C:40]=2[N:41]=[CH:42]1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4scnc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.37 mmol) in dioxane (5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (288 mg, 1.1 mmol), K3PO4 (234 mg, 1.1 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 2%-5% ethyl acetate in petroleum ether to afford methyl 2-(benzo[d]thiazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (120 mg, 83%).