Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[S:10](=O)(=[O:13])([OH:12])[OH:11]>O>[CH3:9][O:8][C:1]1[CH:7]=[C:6]([S:10]([OH:13])(=[O:12])=[O:11])[CH:5]=[CH:4][C:2]=1[OH:3]
Reactant: COc1ccccc1O
Reactant: O=S(=O)(O)O
Solvent: O
Product: COc1cc(S(=O)(=O)O)ccc1O

Procedure:
A solution of guaiacolsulfonic acid in sulfuric acid was prepared. Water in the recirculating water bath was heated to 65 degrees Centigrade. The weight of available stock guaiacol, purified reagent, that contained 1.63 moles of guaiacol was calculated. The amount of available stock of sulfuric acid NF that contained 3.41 moles of sulfuric acid was calculated. A 1 liter Corning Pyrix bottle No. 1395 was placed on the Mettler PG-5002-S balance. A 600 mL beaker was filled with approximately 400 mL guaiacol, purified reagent from the available stock bottle. A quantity of 1.63 moles of guaiacol as guaiacol, purified reagent by weight from the beaker was added to the bottle.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:20]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:20]2)[CH:7]=1
Reactant: OO
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a solution of 4-[1-(5-bromo-2-fluorophenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (9.30 g, 29.00 mmol) in methanol (280 ml) at 35° C. is added 50% aqueous hydrogen peroxide (3.36 ml, 50.40 mmol), followed immediately by 2M aqueous lithium hydroxide (3.68 ml, 7.36 mmol). Stirring is continued at this temperature for 1 hour, then the reaction mixture is allowed to cool to room temperature, then quenched with saturated sodium metabisulfite (100 ml) and extracted with ether (×3). Organics are combined, dried over magnesium sulfate, then filtered and the filtrate concentrated in vacuo to afford 2-(5-bromo-2-fluorophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (6.60 g, 68%) as a yellow gum.
Reaction SMILES: C(O)=O.[C:4]1([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26]=O.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[CH3:26][N:12]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)[CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=O
Reactant: c1ccc(CCNC2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: CN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
136 ml of formic acid was added to 210 g of 4-(2-phenylethylamino)-1-benzylpiperidine. Since the temperature of the mixture increased to about 90° C., the mixture was ice-cooled. To the reaction mixture was added 64 ml of 37% formalin at 50°-60° C.; the ice bath was removed; and the mixture was stirred for 1 hour. To the resulting reaction mixture were added 1 liter of ethanol and 120 ml of concentrated hydrochloric acid, followed by concentration under reduced pressure. To the residue was added 1 liter of ethanol. The resulting insolubles were collected by filtration and then washed with ethanol to obtain 251.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-benzylpiperidine dihydrochloride as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C1COCC1.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[O:10])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of 6-methylpicolinic acid (5.0 g, 36 mmol) in THF (60.0 ml) was treated with two drops of DMF and 3.5 ml (5.09 g, 40 mmol, 1.1 equiv.) of oxalyl chloride were added dropwise. The solution was stirred for 30 min at room temperature. The reaction mixture was then evaporated to dryness in vaccuo. The residue was taken up in 40 ml of dry THF, and cooled to 0° C. Triethylamine (6.1 ml, 4.43 g, 44 mmol, 1.2 equiv.), and a solution of 4.23 ml (5.12 g, 40 mmol, 1.1 equiv.) of 3-chloro-aniline in 15 ml of dry THF were added dropwise at 0° C. The reaction mixture was stirred for 5 min. at 0° C. and then allowed to warm up to room temperature. After stirring for 1 h at r.t., the dark brown suspension was filtered. The filtrate was concentrated in vaccuo, and the residue was dissolved in 200 ml of ethyl acetate, which was washed once with brine. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. Concentration in vaccuo yielded 7.7 g of a dark brown residue which was purified by flash chromatography (heptane/ethyl acetate 4:1) to yield a the title compound as a white solid (total 5.05 g, 56%), MS (ISP): m/e=247.1, 249.1 (M+H+).
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.[CH2:19]([N:21]([CH2:31][CH3:32])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH3:20].[CH3:33][Ge:34]([CH3:37])([CH3:36])Cl>C1COCC1.CCOCC>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Ge:34]([CH3:37])([CH3:36])[CH3:33])[C:23]=1[C:22]([N:21]([CH2:19][CH3:20])[CH2:31][CH3:32])=[O:30]
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Reactant: C[Ge](C)(C)Cl
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Ge](C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 44.9 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (21.8 mL, 28.3 mmol) was added dropwise to a dry ice/acetone cooled solution of the compound of example e (4.6 g, 21.7 mmol) in THF (60 mL), maintaining the internal reaction temperature ≤-65° C. This mixture was stirred at -78° C. for 45 min, then was quenched by the dropwise addition of a solution of trimethylchlorogermane (5.0 g, 32.6 mmol) in THF (30 mL), again maintaining the internal reaction temperature ≤-65° C. The reaction was warmed to 0° C., diluted with ether, and extracted with 10% HCl (2×) followed with sat aq NaHCO3. The ether was dried (MgSO4), concentrated, and purified by HPLC with 6% EtOAc in hexanes to afford 3.2 g of the title compound as a white solid, a 45% yield. m.p. 47°-48° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)(=O)C([Cl:30])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:30])=[O:8])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1cc(C(=O)O)ccc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1cc(C(=O)Cl)ccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a mixture of 50 g of product from Example 42 in 500 ml of methylene chloride and 15 drops of dimethylformamide is added, dropwise, 26.12 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is recrystallized from diethyl ether to give 52.3 g of the desired product as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.S(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2CCCC2)C1=O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
3-Cyclopentanecarbonyl-2-oxopyrrolidine-1-carboxylic acid t-butyl ester (1.2 g, 4.4 mmol) was dissolved in THF (3.5 mL, 43.7 mmol) under nitrogen. 2M BH3.Me2S in THF (6.6 mL, 13.1 mmol) was added via syringe over 15 minutes. The mixture was stirred at room temperature for 1 hour, then heated at 65° C. for 24 hours. After an additional 48 hours, the mixture was placed on an ice bath and the reaction slowly quenched with cold MeOH (100 mL). The mixture was stirred for 15 minutes, then diluted with EtOAc (30 mL), and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated by rotary evaporation to yield a yellow oil (300 mg). The oil was purified by preparative HPLC (2″ column; 5-50% MeCN/H2O; 0.1% TFA buffer; at 40 mL/min over 80 minutes). The desired fractions were collected, frozen and lyophilized to yield the title compound (939 mg). MS m/z: [M+H]+ calcd for C15H27NO3, 269.3; found 270.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][N:19]([CH3:26])[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:26])[CH:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH2:22][CH2:21]1
Reactant: CN(C)C1CCNCC1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCC(N(C)C)CC2)cc2c1cnn2C(C)C
Temperature: 115 °C
Reaction time: 15 h
Yield: 25 %

Procedure:
To a 10-mL microwave tube were added methyl 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (200 mg, 0.673 mmol), N,N-dimethyl-4-piperidinamine (95 mg, 0.740 mmol), toluene (3 mL), and cesium carbonate (329 mg, 1.010 mmol), and the mixture was degassed for 5 min by bubbling N2. BINAP (62.9 mg, 0.101 mmol) and Pd2(dba)3 (30.8 mg, 0.034 mmol) were added. The tube was sealed and the mixture was heated at 115° C. with stirring for 15 h. The mixture was diluted with methanol (5 mL) and filtered. The filtrate was concentrated and the residue was purified using reverse-phase HPLC to give 58 mg of product as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (d, J=8.0 Hz, 6H), 1.54-1.61 (m, 2H), 1.87-1.96 (m, 2H), 2.31 (m, 6H), 2.80-2.83 (m, 2H), 3.83-3.86 (m, 2H), 3.93 (s, 3H), 4.98-5.04 (m, 1H), 7.29 (s, 1H), 7.57 (s, 1H), 8.17 (s, 1H). LCMS: (M+H)+=345.2
Reaction SMILES: CN(C)C1C=CC=CC=1.C[Si](C)(C)Cl.[NH2:15][C@@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([OH:35])=[O:34])=[C:20]([CH2:23][S:24][C:25]3[N:26]=[N+:27]([O-:32])[C:28]([CH3:31])=[CH:29][CH:30]=3)[CH2:21][S:22][C@H:17]12.[C:38]([O:42][C:43]([NH:45][CH2:46][C:47]1[S:51][C:50]([CH2:52][C:53](O)=[O:54])=[CH:49][CH:48]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O.C(N(CC)CC)C>[C:38]([O:42][C:43]([NH:45][CH2:46][C:47]1[S:51][C:50]([CH2:52][C:53]([NH:15][C@@H:16]2[C:36](=[O:37])[N:18]3[C:19]([C:33]([OH:35])=[O:34])=[C:20]([CH2:23][S:24][C:25]4[N:26]=[N+:27]([O-:32])[C:28]([CH3:31])=[CH:29][CH:30]=4)[CH2:21][S:22][C@H:17]23)=[O:54])=[CH:49][CH:48]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Reactant: Cc1ccc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n[n+]1[O-]
Agent: C[Si](C)(C)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cc4ccc(CNC(=O)OC(C)(C)C)s4)[C@H]3SC2)n[n+]1[O-]
Temperature: 40 °C

Procedure:
1.50 ml of triethylamine, 1.6 ml of N,N-dimethylaniline and 2,3 ml of trimethylchlorosilane are added to a stirred suspension of 2.13 g of 7β-amino-3-[(6-methyl-1-oxido-pyridazin-3-ylthio)-methyl]-ceph-3-em-4-carboxylic acid in 20 ml of methylene chloride at 20°-25° C. The mixture is warmed to 40° C over the course of 20 minutes, whilst stirring, and is then cooled to +5° C. At the same time, 1.95 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid are dissolved in 20 ml of methylene chloride, 0.05 ml of dimethylformamide and 5 ml of oxalyl chloride. The mixture is stirred for 30 minutes at the reflux temperature under a slight stream of nitrogen, the readily volatile constituents are distilled off in vacuo and the oily residue is dissolved in 10 ml of methylene chloride. This solution is added, at 5°-10° C, to the solution which contains the amine component which has now been silylated. This mixture is stirred for 2 hours at 10°-25° C and poured into water, the pH is adjusted to approx. 7 with sodium bicarbonate, the whole is extracted with methylene chloride and carefully acidified to approx. pH 2 with concentrated hydrochloric acid, and the precipitate formed is filtered off. It is repeatedly washed with water and after subsequent drying of the filter residue in a high vacuum over potassium hydroxide, 7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-[(6-methyl-1-oxido-pyridazin-3-yl-thio)-methyl]-ceph-3-em-4-carboxylic acid is obtained; thin layer chromatogram (silica gel; glacial acetic acid/water/butanol, 45:10:45): Rf = 0.58; infrared absorption spectrum (in mineral oil): bands at 5.63μ and 5.96μ.
Reaction SMILES: [CH3:1][C:2]([C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1)([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:2]([CH3:1])([N:4]5[CH2:8][CH2:7][CH2:6][CH2:5]5)[CH3:3])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(C(C)(C)N5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
To a solution of Intermediate 80c (180 mg, 0.46 mmol) in 1,4-dioxane (5.00 mL) was added DIPEA (160 μL, 0.92 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 185 mg, 0.46 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM. Further purification by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (58 mg, 20%). LCMS (Method 5): Rt 3.84 min, m/z 647.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.60 (6H, s), 1.70-1.76 (4H, m), 1.86-2.06 (2H, m), 2.11 (1H, m), 2.20 (1H, m), 2.38 (3H, s), 2.45-2.52 (2H, m), 2.55-2.62 (2H, m), 4.89 (1H, dd, J 5.6, 8.9), 5.29 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.62 (1H, d, J 9.9), 8.77 (1H, d, J 2.0).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:12][C:11]2[CH:10]=[CH:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=1.C[O:15][CH:16]([O:19]C)[CH2:17]Br.O>CN(C=O)C>[OH:15][CH:16]([OH:19])[CH2:17][N:8]1[CH:9]=[CH:10][C:11]2[O:12][C:4]([CH3:3])=[CH:5][C:6]=2[C:7]1=[O:13]
Reactant: COC(CBr)OC
Reactant: Cc1cc2c(=O)[nH]ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 0.32 g) was suspended in DMF(10 ml), and was cooled to 0° C. in an ice water bath. 2-Methyl-5H-furo[3,2-c]pyridin-4-one (0.57 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde dimethylacetal(2.3 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochloric acid(2 ml) was added to an acetone solution (10 ml) of the residue, and the liquid was stirred at 70° C. for 10 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound(0.56 g) as a white solid.
Reaction SMILES: C(S)CC.[H-].[Na+].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+].C(Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH:21]=[O:22])=[C:9]([O:8][CH2:7][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:18]=[CH:17]2
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(C=O)c(OC)ccc2c1
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Propanethiol (12.8 mL, 0.141 mol) was added over a 20 minute period to a suspension of sodium hydride (2.92 g, 0.122 mol) in N,N-dimethylformamide at 0° C. under a nitrogen atmosphere. To the resulting solution was added a solution of 2,6-dimethoxy-1-naphthalenecarboxaldehyde [21.6 g, 0.100 mol, described by N. P. Buu-Hoi et al, J. Chem. Soc., 2776 (1955)] in 100 mL of N,N-dimethylformamide, and the mixture was heated at 50°-60° C. for 3 hours. Anhydrous K2CO3 (28 g, 0.20 mol) and benzyl bromide (28.6 mL, 0.24 mol) were added and heating was continued for 2 hours. The mixture was cooled to room temperature overnight, then concentrated under vacuum. The residue was dissolved in water (800 mL) and ethyl acetate (1 L). The organic phase was collected and washed successively with 1M KOH, (400 mL), water (200 mL), and saturated NaCl and then dried over Na2SO4. After filtration and evaporation of the solvent, the residue was recrystallized from absolute ethanol to give 19.6 g, of the title compound as a yellow solid, m.p. 115°-117° C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23]C4CCCCO4)[C:15]([C:16]#[N:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.CCOCC>CO>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][OH:23])[C:15]([C:16]#[N:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: N#Cc1cnc(Oc2ccc3c(c2)COB3O)cc1OCCOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: N#Cc1cnc(Oc2ccc3c(c2)COB3O)cc1OCCO
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a suspension of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (1.8 g, 4.54 mmol) in methanol (15 mL) at 0° C. was added 1M HCl in ether (5.45 ml, 5.45 mmol) and left at the same temperature for 2 h. The solid that formed was collected by filtration and dissolved in minimum volume of 10% MeOH/CHCl3 and passed through a short column. The solvent was evaporated to yield the title compound (D119) (0.28 g, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.45 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.15-7.09 (m, 1H), 7.01 (s, 1H), 5.04 (t, J=5.3 Hz, 1H), 4.99 (s, 2H), 4.30 (t, J=4.5 Hz, 2H), 3.79-3.76 (m, 2H); MS (ES) m/z: 313 (M+1)−; HPLC purity 99.27% (Maxplot), 99.66% (220 nm). Elemental analysis for C15H13BN2O5: Calculated C, 57.73; H, 4.20; N, 8.98. found C, 57.53; H, 4.31; N, 8.95.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:18][O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[C:13]([N:15]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:27]3)=[N:14][C:5]=2[CH:4]=1
Reactant: NC1=Nc2cc(Cl)ccc2Nc2sccc21
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
Combine 7-Chloro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.20 g, 4.19 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (1.51 g, 10.48 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 24 hours, cool the mixture to ambient temperature and stir it for 16 hours. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 571.5 mg (36%) of an brown solid: mass spectrum (ion spray): m/z=377.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([Br:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:20][CH3:21])=[CH:9][CH:10]=2)[N:5]=[C:4]([Br:13])[CH:3]=1
Reactant: Oc1ccc2c(Cl)cc(Br)nc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc2c(Cl)cc(Br)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
4-Chloro(bromo)-7-hydroxyquinoline (200 mg) dissolved in N,N-dimethylformamide (DMF; 30 ml) was added with potassium carbonate (203 mg) and ethyl iodide (232 mg) and stirred at room temperature for 8 hours. The reaction mixture was added with water (50 ml) and methylene chloride (30 ml) and shaken to separate the organic layer. Further, the water layer was extracted three times with methylene chloride (30 ml). This extract solution was combined with the above-mentioned organic layer, washed with saturated saline solution and dried over magnesium sulfate. This extract solution was detected by thin-layer chromatography (TLC; MERCK, Art. 5554, methylene chloride : methanol=9 : 1) to find UV (254 nm) absorptive spots at Rf values of 0.7 and 0.4. After drying, the solvent was removed under reduced pressure from the extract solution. The residue was chromatographed by silica gel column chromatography (Wako Gel™ C-200, methylene chloride : methanol=9 : 1). Fractions corresponding to Rf value of 0.7 were collected and evaporated to obtain the aimed 4-chloro(bromo)-7-ethoxy-quinoline (185 mg). MS m/z: 207 (M+, 4-Cl derivative) and 251(M+, 4-Br derivative)