Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=3)[CH:10]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:9]2=[O:37])=[CH:4][CH:3]=1>C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)[CH:10]([CH2:27][CH2:28][O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:9]2=[O:37])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C2C(CCOc3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Solvent: O=CO
Product: O=C(O)COc1ccc(C2C(CCOc3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Yield: 101.2 %

Procedure:
A solution of 1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-4-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one (Method 7; 1.045 g, 2.05.1 mmol) in formic acid (4 ml) was stirred at room temperature for 22 hours. The solvent was removed under reduced pressure and the residue was dissolved in DCM (10 ml). The organic layer was successively washed with a saturated solution of sodium hydrogen carbonate (aq; 5 ml), water (5 ml) and brine (5 ml), dried and concentrated to give the title compound as a white solid (0.941 g; ˜quantitative yield). NMR (400 MHz) 2.25-2.45 (m, 2H), 3.20-3.30 (m, 1H), 4.00-4.20 (m, 2H), 4.65 (s, 2H), 4.80 (d, 1H), 6.75-6.80 (m, 2H), 6.85-7.00 (m, 6H), 7.20-7.30 (m, 4H); m/z: 454.0.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:20]([O-])=O)[CH:3]=1.Cl>C(O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=1
Reactant: Nc1cc(Oc2ccc(C(F)(F)F)cc2)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2)cc1N
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (5 g, 24.15 mmol) in DMSO (15 ml) was added potassium carbonate (6.62 g, 47.90 mmol) and 4-(trifluoromethyl)phenol (6.6 g, 40.71 mmol) in several batches. The resulting solution was stirred for 8 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was then quenched by the addition of water (200 ml), extracted with ethyl acetate (5×100 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (3×100 m), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to produce 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline as a yellow solid (1.43 g, 18%). Next, to a solution of 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline (499 mg, 1.50 mmol) in ethanol (30 ml) was added hydrogen chloride (conc) (0.4 mL) and Zn powder (586 mg) in several bacthes. The resulting solution was stirred for 1.5 h at 85° C. in an oil bath and then concentrated under vacuum. The residue was dissolved in ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to afford 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a red solid (359 mg, 79%). Finally, a solution of 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (100 mg, 0.33 mmol) in trifluoroacetic acid (5 ml) and HCl ((conc), 1 ml) was stirred for 4.5 h at 80° C. in an oil bath. The solution was poured into water (100 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (sat) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 11% ethyl acetate in petroleum ether to produce 5-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-1H-1,3-benzodiazole as a white solid (78.2 mg, 62%).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:5]([O:7]C)=[O:6]>CO>[CH3:3][CH:4]([C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 100.5 %

Procedure:
Aqueous sodium hydroxide (4M, 3 mL, 12 mmol) was added to a solution of (RS)-methyl α-methyl-3,5-bis(trifluoromethyl)benzeneacetate (Description 3, 0.96 g, 3.2 mmol) in methanol (5 mL) and the mixture was heated under reflux for 1 hour. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was diluted with water, acidified with hydrochloric acid (2M) and extracted with ethyl acetate (2×25 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.92 g, 99%). 1H NMR (360 MHz, CDCl3) δ 1.60 (3H, d, J 7.2 Hz), 3.90 (1H, q, J 7.2 Hz), 7.78 (2H, s) and 7.81 (1H, s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C@@:16]1([CH3:41])[N:21]=[C:20]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([CH3:38])([CH3:37])[S:18](=[O:40])(=[O:39])[CH2:17]1)(=O)=O.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)[C:45]1[CH:50]=CC=C[C:46]=1P(C1C=CC=CC=1)C1C=CC=CC=1.C([Sn](CCCC)(CCCC)CCCC)C=C>CC#N.CC#N.Cl[Pd]Cl.CN(C=O)C>[C:26]([O:25][C:23](=[O:24])[N:22]([C:20]1[C:19]([CH3:37])([CH3:38])[S:18](=[O:40])(=[O:39])[CH2:17][C@:16]([C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:50][CH:45]=[CH2:46])([CH3:41])[N:21]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2OS(=O)(=O)C(F)(F)F)CS(=O)(=O)C1(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1ccc([N+](=O)[O-])cc1[C@]1(C)CS(=O)(=O)C(C)(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Reaction time: 0.03 h
Yield: 468.5 %

Procedure:
100 ml RBF was charged with (R)-2-(5-((bis-(tert-butoxycarbonyl))amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-nitrophenyl trifluoromethanesulfonate (794 mg, 1.204 mmol), bis(acetonitrile)palladium(II)dichloride (31.2 mg, 0.120 mmol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (130 mg, 0.241 mmol) and DMF (6 ml). The mixture was stirred for 2 min until all solids dissolved. Allyltri-n-butylstannane (0.746 ml, 2.407 mmol) was added, the vial was sealed and stirred at 75° C. (heating block) for 30 min. The mixture was concentrated in vacuo and purified by FC on 40 g RediSep Gold column using 5-70% EtOAc in heptane to afford (R)-tert-butyl-N-(5-(2-allyl-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (623 mg, 1.129 mmol, 94% yield). LC/MS (ESI+) m/z=574 (M+Na).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[C:5]([O:18][CH2:19][CH:20]2[CH2:22][S:21]2)[CH:4]=1>C(OCC)(=O)C>[Cl:1][CH2:22][CH:20]([SH:21])[CH2:19][O:18][C:5]1[CH:4]=[C:3]([OH:2])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([S:8][C:7]=2[CH:6]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: Cl
Reactant: O=c1c2ccccc2sc2cc(OCC3CS3)cc(O)c12
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2sc2cc(OCC(S)CCl)cc(O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-hydroxy-3-(thiiran-2-ylmethoxy)-9H-thioxanthen-9-one (10 mg, 0.03 mmol) prepared in Example 8, followed by stirring at room temperature for 3 hours, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to give the title compound (8 mg, 71.8%) as a yellow solid.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:9]([N:12]([CH:38]([CH3:40])[CH3:39])[CH2:13][CH2:14][C@@H:15]([C:22]1[CH:27]=[C:26]([N:28]=NC2C=CC(C)=CC=2)[CH:25]=[CH:24][C:23]=1[OH:37])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:11])[CH3:10].Cl>O.C(O)C.C(OCC)C>[CH:38]([N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14][C@@H:15]([C:22]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:23]=1[OH:37])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:40])[CH3:39]
Reactant: Cc1ccc(N=Nc2ccc(O)c([C@H](CCN(C(C)C)C(C)C)c3ccccc3)c2)cc1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(N)ccc1O)C(C)C

Procedure:
A solution of Na2S2O4 (1.23 g, 12.8 mmol) in water (10 mL) was added to a solution of (R)-N,N-diisopropyl-3-[2-hydroxy-5-(4-methylphenylazo)phenyl]-3-phenylpropanamine (0.55 g, 1.28 mmol) in ethanol (50 mL) at 75° C. during 15 min. More dry Na2S2O4 (1.23 g, 12.8 mmol) was added in 10 portions. Water was added to the solution which was then extracted with diethyl ether. The organic layer was dried (MgSO4) and evaporated to give an oil, which was chromatographed on silica (n-hexane-ethanol-triethylamine 7:3:1) to give an oil. The product was dissolved in ethanol and hydrogen chloride in diethyl ether was added. The solvent was evaporated, redissolved in water and vacuum-dried wich yielded 0.25 g (60%).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[N:22]=2)=[C:17]([CH3:30])[C:16]=1[CH:31]1[C:44]2[C:43](=[O:45])[CH2:42][C:41]([CH3:47])([CH3:46])[CH2:40][C:39]=2[O:38][C:37]2[CH2:36][C:35]([CH3:49])([CH3:48])[CH2:34][C:33](=[O:50])[C:32]1=2.O.N.O>C1COCC1.CN(C=O)C.C(OCC)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH2:3])=[O:29])[N:22]=2)=[C:17]([CH3:30])[C:16]=1[CH:31]1[C:32]2[C:33](=[O:50])[CH2:34][C:35]([CH3:48])([CH3:49])[CH2:36][C:37]=2[O:38][C:39]2[CH2:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43](=[O:45])[C:44]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2ccnc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(-c2ccnc(C(N)=O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.5 h
Yield: 86 %

Procedure:
1,1′-Carbonyldiimidazole (50.1 mg, 0.309 mol) was added to a solution of the 4-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyrimidine-2-carboxylic acid obtained in Example 75-4 (133 mg, 0.257 mmol) in THF (2.0 mL) and DMF (0.5 mL) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 30 minutes. Thereafter, 27% ammonia water was added to the resulting solution, and the mixture thus obtained was further stirred at the same temperature as above for 30 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate twice. The organic layer thus obtained was washed with 1 M-hydrochloric acid and brine, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The residue thus obtained was solidified with diethyl ether to obtain the title compound (114 mg, yield: 86%).
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@H:14]([O:16][C@@H]([C@H](O)[C@@H](O)C=O)[C@H](O)CO)[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33]>O>[CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][CH:14]([OH:16])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO
Solvent: O
Product: OC[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 24 h

Procedure:
To an aqueous solution having a final solid concentration of 0.2% (w/v) of panose, α-isomaltosylmaltose, α-isomaltosyltriose, α-isomaltosyltetraose, or cyclotetrasaccharide, were added 100 units/g solid of an isomaltodextranase specimen, obtained by the method in Experiment 15, except for using 100 or 3,000 units of the specimen for the aqueous solution of cyclotetrasaccharide, allowed to react at 40° C. and pH 5.5 for 24 hours, and kept at 100° C. for 20 min to suspend the enzymatic reactions. The saccharide composition for each reaction mixture was determined on HPLC. The conditions used in HPLC were: Column, “MCIGEL CK04SS” comercialized by Mitsubishi Chemical Industries, Ltd., Tokyo, Japan; 80° C., inner column temperature; 0.5 ml/min, a flow rate of water as an eluent; and detection, “RI-8012”, a diffraction refractometer commercialized by Tosoh Corporation, Tokyo, Japan. The results are in Table 18.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH2:16][C:17](OC)=[O:18])=[N:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[OH-].[Na+]>O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH2:16][CH2:17][OH:18])=[N:8]1
Reactant: COC(=O)Cc1nn(C2CCCCO2)c2ncccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1nn(C2CCCCO2)c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution methyl [1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetate (128 mg, 0.465 mmol) at 0° C. was added 2M LAH in THF (232 ul, 0.465 mmol) and stirred at 0° C. for 30 minutes. After this time, the reaction mixture was sequentially treated with water (18 ul) and 1.0N NaOH (54 ul) and stirred at 25° C. for 30 minutes. After this time, the mixture was filtered through celite and rinsing with THF. The filtrates were combined and the solvent evaporated in vacuo. The residue was purified by chromatography using RediSep column (12 g) and eluting with a gradient of 0-10% MeOH/CH2Cl2 to give the title compound. LRMS (M+1): 164.0.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)[CH2:2][CH:3]=[CH2:4].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:1]([C:5]1[CH:10]=[C:9]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[N:8]=[C:7]([S:12][CH3:13])[N:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: OB(O)c1ccco1
Reactant: C=CCCc1cc(Cl)nc(SC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCCc1cc(-c2ccco2)nc(SC)n1
Temperature: 110 °C

Procedure:
To a solution of 4-(3-buten-1-yl)-6-chloro-2-(methylthio)-pyrimidine (0.79 g, 3.69 mmol), 2-furanylboronic acid (0.45 g, 4.06 mmol), aq. Na2CO3 solution (2M, 4.1 mL) in dioxane (37 mL) at room temperature was added tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.185 mmol). The reaction mixture in sealed tube was stirred and refluxed at 110° C. for 18 hours. After the reaction was completed, the mixture was filtered through a pad of silica gel. The filtrate was evaporated in vacuo. The residue was dissolved in methylene chloride (30 mL). It was washed with water (30 mL×2). The organic layer was dried over MgSO4 and filtered, evaporated in vacuo. The residue was purified by column chromatography to provide the title compound. MH+247.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][C@H:21]([CH3:24])[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(Cl)Cl.O1CCOCC1>[CH3:24][C@@H:21]1[NH:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]=2[CH2:23][CH2:22]1.[ClH:25]
Reactant: C[C@H]1CCc2c(ncnc2N2CCN(C(=O)OC(C)(C)C)CC2)N1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1CCc2c(ncnc2N2CCNCC2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (7S)-4-(7-Methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (32 mg, 0.096 mmol) in DCM (2 mL) was added HCl in dioxane (4M, 2 mL). The mixture was stirred at room temperature for 3 hours. The solvent was removed to give (7S)-7-Methyl-4-piperazin-1-yl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine as HCl salt (22 mg, 99%). MS (APCI+) [M+H]+234.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1(C)C=CC=CC=1.O>[F:24][C:23]([F:26])([F:25])[CH2:22][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)COc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
In a nitrogen atmosphere, a suspension of 34 g of 1-naphthol, 40 g of 2,2,2-trifluoroethyl p-toluenesulfonate, 33 g of potassium carbonate, and 80 g of dimethyl sulfoxide was heated and stirred at 100° C. for 12 hours. After cooling, 100 g of water and 200 g of toluene were added to the suspension, after which an organic layer was taken out. It was washed 5 times with 100 g of 5 wt % sodium hydroxide aqueous solution, then 4 times with 100 g of water. The organic layer was concentrated, obtaining 36 g of oily matter. It was distilled in vacuum (75° C./13 Pa), obtaining 28 g (yield 76%) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.CC[Mg+].[Br-].[C:21](=[O:23])=[O:22].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:21]([OH:23])=[O:22])=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: O=C=O
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: CC[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: -30 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (700 g, 1.79 mol, 1.00 equiv) in tetrahydrofuran (13 L), followed by the addition of EtMgBr (1400 mL) dropwise with stirring at −30° C. over 60 min. To the above an excess of CO2 (gas) was introduced in over 3 h at −78° C. The resulting solution was warmed to room temperature naturally. The pH value of the solution was adjusted to 3 with hydrogen chloride (2 mol/L). The precipitates were collected by filtration, washed with 2×100 mL of EA and dried in a vacuum oven to afford 410 g (74%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25].O>C(O)C>[CH3:21][C:22]1[CH:23]=[C:24]([CH3:25])[N:18]([C:16]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH3:20])=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:17]=2)[N:19]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(F)cc3)nc(NN)nc21
Solvent: O
Solvent: CCO
Product: Cc1cc(C)n(-c2nc(Nc3ccc(F)cc3)c3ncn(C)c3n2)n1
Yield: 99.1 %

Procedure:
(4-Fluoro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine (900 mg, 3.29 mmol) and 2,4-pentanedione (0.47 mL, 4.16 mmol) in ethanol (25 mL) were heated to reflux for 20 min. Water was added and the white crystalline compound was collected by filtration, washed with water and dried to give [2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-(4-fluoro-phenyl)-amine (1.1 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(Cl)cc3)ccc2C(=O)O)CC1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
A solution of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(4-chloro-phenyl)benzoate (0.3 g 0.67 mmol) in dioxane (10 mL) and aqueous NaOH (2 g in 10 mL H2O) was heated at reflux for 4 h. The reaction was then cooled to room temperature, acidified to pH 3 with 1 N HCl, and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 0.293 g of product (100%).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:29])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)[CH3:19])[CH2:12][CH2:11]1.[NH2:36][C:37]1[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:39][CH:38]=1>>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:36][C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[CH:39][CH:38]=2)[CH2:12][CH2:11]1)=[O:29]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCO
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCNc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 51.5 %

Procedure:
The compound (94 mg, 0.195 mmol) obtained in Example 39b was used to give a crude aldehyde compound according to the method described in Example 4g. The resulting crude aldehyde compound and tert-butyl 4-aminobenzoate (62 mg, 0.293 mmol) were used to give the title compound (66 mg; yield, 52%) as a white solid according to the method described in Example 18b.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[CH3:12][NH2:13]>C1COCC1>[F:11][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][C:6]=1[CH2:7][NH:13][CH3:12])[C:1]#[N:2]
Reactant: CN
Reactant: N#Cc1ccc(CBr)c(F)c1
Solvent: C1CCOC1
Product: CNCc1ccc(C#N)cc1F
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A solution of 4-cyano-2-fluoro-benzylbromide (FluoroChem ltd, 16 g, 74 mmol) in dry THF (50 mL) was added to a 40% aqueous solution of methyl amine (700 mL) at 5-10° C. and allowed to stir for 5 min. The reaction mixture was extracted with DCM and the solvent was dried over Na2SO4 and concentrated under vacuum, affording (12.0 g, 95%) of the title compound as a brown liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.79-7.75 (m, 1H), 7.68-7.61 (m, 2H), 3.71 (s, 2H), 2.24 (s, 3H).