Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH:13](OCC)(OCC)OCC.[N-:23]=[N+:24]=[N-:25].[Na+]>C(O)(=O)C.O.CCOC(C)=O>[N:1]1([C:2]2[N:7]=[N:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=2)[CH:13]=[N:25][N:24]=[N:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)Cc1ccc(N)nn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(-n2cnnn2)nn1
Temperature: 80 °C

Procedure:
To a solution of methyl 2-(6-aminopyridazin-3-yl)acetate (418 mg, 2.50 mmol) in acetic acid (10 mL) was added triethyl orthoformate (0.667 ml, 4.00 mmol), followed by sodium azide (244 mg, 3.75 mmol). The mixture was heated at 80° C. for 1 h. After cooling, the mixture was diluted with water and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (2×) and the combined organics washed with water, brine, dried (sodium sulfate) and concentrated to provide crude methyl 2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)acetate (LC-MS (IE, m/z): 193 [M+1-28]+). The crude ester was dissolved in THF (5.0 mL) and treated with 1 N LiOH (3.75 mL) and the resulting mixture was stirred for 1 h. The resulting mixture was concentrated in vacuo and the resulting powder dried under high vacuum to provide title compound which was used directly in the next step without further purification. LC-MS (IE, m/z): 173 [M+1-28]+.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH2+:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]1[CH:34]=[C:35]([C:39]2[N:40]=[C:41]([CH3:44])[S:42][CH:43]=2)[CH:36]=[CH:37][CH:38]=1)=[C:31]=[O:32]>C1COCC1>[CH3:44][C:41]1[S:42][CH:43]=[C:39]([C:35]2[CH:34]=[C:33]([NH:30][C:31]([N:16]3[CH2:15][C:14]4[CH:13]=[N:12][C:11]5[NH:10][N:9]=[CH:8][C:20]=5[C:19]=4[CH2:18][CH2:17]3)=[O:32])[CH:38]=[CH:37][CH:36]=2)[N:40]=1
Reactant: Cc1nc(-c2cccc(N=C=O)c2)cs1
Reactant: c1nc2[nH]ncc2c2c1C[NH2+]CC2
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(NC(=O)N3CCc4c(cnc5[nH]ncc45)C3)c2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate (0.100 g, 0.25 mmol) in THF (5 mL) and Hunig's Base (0.26 mL, 1.50 mmol) was added 4-(3-isocyanatophenyl)-2-methylthiazole (0.0567 g, 0.25 mmol). The reaction was shaken at room temperature for 2 hours. The solvent was then removed under reduced pressure followed by addition of 1 M Na2CO3 (5 mL) and EtOAc (10 mL). The organic layer was separated, washed with water (3×10 mL) followed by adding water (10 mL). The EtOAC was then removed under reduced pressure. A white solid crashed out which was filtered, washed with water, dried under reduced pressure to give the pure desired product, N-(3-(2-methylthiazol-4-yl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as a white solid (0.069 g, 71%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH:24]=O)=[C:11]([C:19](OC)=[O:20])[CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](N)[CH:27](C)[CH3:28].[BH3-][C:32]#[N:33].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:11]2[C:10]=1[CH2:23][CH2:24][N:33]([CH2:32][CH:27]([CH3:28])[CH3:26])[C:19]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(C)CN
Reactant: COC(=O)c1cc(OCc2ccccc2)c(CC=O)c(C(=O)OC)c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)c2c(c1)C(=O)N(CC(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 223.4 %

Procedure:
To a solution of dimethyl 5-(benzyloxy)-4-(2-oxoethyl)isophthalate (1.5 g, 4.38 mmol) in MeOH was added isobutylamine (385 mg, 0.522 mL, 5.26 mmol). The reaction was stirred at room temperature for 2 hrs, then NaCNBH3 (84.1 mg, 1.34 mmol) was added. The mixture was stirred at 75° C. overnight. The solvents were removed under reduced pressure, diluted with ethyl acetate and washed with brine (3×). The product was purified via gradient silica gel chromatography using MeOH/CHCl3 (5/95 to 10/90) to provide the product (1.1 g, 50% yield) as a film 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.96 (dd, 6 H) 1.96-2.16 (m, 1 H) 3.05 (t, J=6.69 Hz, 2 H) 3.36-3.46 (m, J=7.63, 7.63 Hz, 2 H) 3.49-3.62 (m, 2 H) 3.88-4.02 (m, 3 H) 5.16 (s, 2 H) 7.32-7.56 (m, 5 H) 7.74 (d, J=1.32 Hz, 1 H) 8.42 (d, J=1.32 Hz, 1 H); MS (ESI, pos): 368.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:20](=[O:21])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])=[C:8]([CH3:11])[CH2:9][S:10][C@H:5]12.Cl>O1CCCC1.O>[CH3:1][O:2][NH:3][C@@H:4]1[C:20](=[O:21])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:18])[Cl:19])=[O:13])=[C:8]([CH3:11])[CH2:9][S:10][C@H:5]12
Reactant: CON=C1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12
Yield: 60.2 %

Procedure:
In tetrahydrofuran (25 ml) is dissolved 2,2,2-trichloroethyl 7-methoxyimino-3-methyl-3-cephem-4-carboxylate (5.80 g) and under ice-cooling stirring, a 1 M tetrahydrofuran solution of borane-tetrahydrofuran complex (198 ml) is added dropwise over a period of 80 minutes. The reaction mixture is diluted with water (20 ml), adjusted to pH 1 with dilute hydrochloric acid and stirred at room temperature for 1.5 hours. The organic solvent is distilled off, the residual aqueous solution is adjusted to pH 7 with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate is then distilled off, the residue is dissolved in a mixture of methanol (120 ml) and 12.5% aqueous ammonium chloride (60 ml) and the mixture is stirred at room temperature for an hour. The organic solvent is distilled off and the residual aqueous solution is extracted with ethyl acetate. The extract is washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated. The oily residue is subjected to silica gel (90 g) column chromatography and elution is carried out with ethyl acetate-methylene chloride. By the above procedure is obtained 2,2,2-trichloroethyl 7β-methoxyamino-3-methyl-3-cephem-4-carboxylate (3.51 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[O:16]C)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C(C)C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(C)C)c(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
step 3—A solution of 16 (3.38 g; 14.30 mmol) and CH2Cl2 (150 mL) were cooled to −78° C. and a solution of BBr3 (5.41 mL; 57.22 mmol) in 130 mL of CH2Cl2 were added dropwise over a 30 m period. The reaction mixture was stirred at −78° C. for 1 h, allowed to warm to rt for 4 h and re-cooled to −78° C. and carefully quenched with sat'd. NaHCO3 (80 mL). The aqueous layer was extracted with CH2Cl2 (1×100 mL), EtOAc (50 mL) and the combined aqueous layers washed with water and brine, dried (Na2SO4) and evaporated to yield a light brown oil. The phenol was purified by silica gel chromatography and eluted with CH2Cl2:hexane (3:1) to CH2Cl2 to CH2Cl2:EtOAc (100:4) to yield ethyl 4-iso-propyl-3-hydroxyphenylacetate (18a; 3.0 g; 94%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:42])[CH:28]=[CH:29][C:30]=1[O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:42][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][C:10]=2[CH3:16])=[O:15])[CH:28]=[CH:29][C:30]=1[O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:35])[CH3:34]
Reactant: COc1cc(N)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Suspend 5-(4-chloro-phenyl)-3-methyl-thiophene-2-carboxylic acid (2.13 g, 8.44 mmol) in CH2Cl2 (15 mL) and treat with oxalyl chloride (1.5 mL, 16.87 mmol), followed by the addition of DMF (2 drops). Stir the mixture at RT for 2 h and then evaporate down in vacuo. Dissolve the resulting solid material in CH2Cl2 (30 mL) and cool to 0° C. Add 3-methoxy-4-triisopropylsilanyloxy-phenylamine (2.62 g, 8.86 mmol) and Et3N (1.8 mL, 12.66 mol) in CH2Cl2 (10 mL) dropwise at 0° C. Stir the reaction at 0° C. for 10 min and at RT for 30 min. Dilute the reaction with CH2Cl2 (100 mL), wash with 0.1 M HCl (2×30 mL), 1.0 M NaOH (2×30 mL), dry over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 20% EtOAc/hexane to give 3.53 g (79%) of the title compound. LC-MS/ES m/z (37Cl) 531.2 [M+].
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[F:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[C:28]([F:35])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Fc1cc([Mg]Br)ccc1Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)c(F)c1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1.5 mL THF and 0.98 mL 0.5M 4-chloro-3-fluorophenylmagnesium bromide. Yield: 52 mg of a white solid. LC-MSD, m/z for C22H13BrClFN2O2 [M+H]+=471.0, 473.0; HPLC retention time: 2.6 min.
Reaction SMILES: C([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)(O)=O.[OH-:20].[Na+:21].[CH3:22][OH:23]>>[O:17]=[C:8]1[C:7]2[CH:18]=[CH:19][CH:4]=[C:5]([C:22]([O-:23])=[O:20])[C:6]=2[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=2.[Na+:21]
Reactant: CO
Reactant: [OH-]
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Na+]
Product: O=C([O-])c1cccc2c(=O)c3ccccc3ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25.0 G. of 2-carboxy-5-oxo-5H-dibenzo[a,d]cycloheptene is added to a mixture of 4.0 g. of sodium hydroxide in 500 ml. of aqueous methanol. The mixture is stirred for 3 hours at room temperature, then the mixture is evaporated to afford sodium (5-oxo-5H-dibenzo[a,d]cylohepten--yl)carboxylate -yl)-carboxylate (m.p. 300° C). By employing 5.6 g. of potassium hydroxide in place of the sodium hydroxide above, there is obtained potassium (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)carboxylate.
Reaction SMILES: C1(=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)CCCCC1.[CH3:26][C:27]1([CH3:36])[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=O)[CH2:28]1.[C:37]([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([C:7](=[C:29]2[CH2:28][C:27]([CH3:36])([CH3:26])[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30]2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:37])=[O:17])=[CH:10][CH:9]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: O=C([O-])[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred suspension of zinc powder (0.76 g, 11.54 mmol) in THF (30 mL) was slowly added TiCl4 (0.64 mL, 5.77 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of methyl 3-{4-[(4-hydroxyphenyl)carbonyl]phenyl}propanoate (8) (0.41 g, 1.44 mmol) and 3,3,5,5-tetramethyl cyclohexanone (0.68 g, 4.33 mmol) in THF (10 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (30 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc:hexanes to give light brown oil, which upon adding hexanes solidified. The solid was triturated with hot hexanes to afford 0.40 g (68%) of compound 169 as white solid. mp 129-130° C. 1H NMR (400 MHz, CDCl3): δ 0.92 (s, 12H), 1.27 (s, 2H), 1.94 (s, 2H), 1.95 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 3.66 (s, 3H), 4.57 (s, 1H), 6.73 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.04-7.10 (m, 4H). LCMS (ESI): m/z 429 (M+Na)+, m/z 405 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].[C:15]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:17])=[O:16].[CH:38]1C=CC=C[CH:39]=1>>[CH2:38]([O:17][C:15](=[O:16])[CH:18]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[CH:5][C:6]=1[OH:12])[CH3:39]
Reactant: c1ccccc1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=Cc1ccc(N(CC)CC)cc1O
Yield: 70 %

Procedure:
4-Diethylaminosalicylaldehyde (25.0 g, 129 mmol; Tokyo Kasei Ind. Co. Ltd.) and carboxymethylidene-triphenylphosphorane (49.0 g, 140 mmol; Aldrich Inc.) were stirred in 300 ml of anhydrous benzene at room temperature overnight under a nitrogen atmosphere and the reaction was allowed to complete, during which period the reaction was conducted in a dark room. Then, the solvent was removed in vacuo, and the resulting crude product was crudely purified by silica gel column chromatography (hexane/ethyl acetate 1:1 as a developing solvent) to give a mixture of cis- and trans-isomers. Further, this mixture was purified by column chromatography using aminopropyl-modified silica gel (300 g of NHDM-1020 silica gel available from Fuji Silicia Chemicals Co. Ltd; n-hexane/ethyl acetate 2:1 which elutes only the cis-isomer and chloroform/methanol 4:1 which elutes only the trans-isomer) to give 23.7 g of the desired product in 70% yield.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4](=[CH2:13])/[CH:5]=[CH:6]/[CH2:7][C:8]([O:10]CC)=[O:9]>CO.O1CCCC1.O>[CH3:13][C:4](=[CH2:3])/[CH:5]=[CH:6]/[CH2:7][C:8]([OH:10])=[O:9]
Reactant: C=C(C)/C=C/CC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)/C=C/CC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
2.5 g (0.1 mol) of lithium hydroxide are added at 0° C. to 10 g (0.07 mol) of ethyl trans-4-methyl-2,4-pentadienecarboxylate, dissolved in a solvent mixture of 75 ml of methanol, 17 ml of tetrahydrofuran and 2.5 ml of water, and the mixture is stirred for 20 hours at room temperature. After the mixture has been diluted with 200 ml of water, it is extracted once using diethyl ether, and a pH of 1 is established in the aqueous phase at 0° C. using concentrated hydrochloric acid. The mixture is extracted using diethyl ether, the combined organic phases are washed several times with water and saturated sodium chloride solution, and, after drying and concentrating, 6.1 g (76% of theory) of trans-4-methyl-2,4-pentadienecarboxylic acid are obtained. ##STR208##
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH:22]=[C:21]2[CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
Benzoyl chloride (217 ml, 1.9 mmol) was added to a stirred solution of [2-(5-benzyloxy-1H-indol-3-yl)ethyl]dimethylamine (500 mg, 1.7 mmol), triethylamine (473 ml, 3.4 mmol) and 4-(dimethylamino)pyridine (20 mg, 0.2 mmol) in dry dichloromethane (5 ml) at 0° C. The reaction was allowed to warm slowly to ambient temperature, and stirred at this temperature overnight. The reaction was quenched with saturated aqueous sodium hydrogen carbonate. The aqueous was then extracted with dichloromethane (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/aqueous ammonia (80:8:1) to give the title compound (327 mg, 48%) is a thick oil. δH (250 MHz, CDCl3) 2.30 (6H, s), 2.52-2.60 (2H, m), 2.78-2.84 (2H, m), 5.16 (2H, s), 7.06-7.10 (3H, m), 7.30-7.64 (10H, m), 8.28 (0.5H, s), 8.32 (0.5H, s).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=C=O.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([NH:21][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:13])[C@H:8]([C:18]([NH:45][C:41]2[CH:42]=[CH:43][C:44]3[N:32]([CH2:30][CH3:31])[C:33]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)Nc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 67% purity by LC/MS. MS(ESI+): m/z=496.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[N:21][CH:22]=1>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.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([CH:18]=2)[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OCc1cncc(Br)c1
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: Cc1ccccc1
Solvent: O
Product: OCc1cncc(-c2ccc(F)cc2)c1
Reaction time: 2 h

Procedure:
13.2 g of 4-fluorobenzeneboronic acid and 10.8 g of sodium hydrogen-carbonate are initially introduced, and a mixture of 16.1 g of 5-bromo-3-hydroxymethylpyridine, 30 ml of water and 60 ml of toluene is added with stirring and under a protective gas. A further 14 ml of water, 28 ml of toluene and 0.5 g of tetrakis(triphenylphosphine)palladium(0) are subsequently added. The reaction mixture is heated to reflux and held at this temperature for 2 hours. After cooling, the mixture is subjected to conventional work-up, giving 5-(4-fluorophenyl)nicotinyl alcohol. The alcohol is subsequently oxidized by conventional methods to give 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: COc1ncnc2sc(N=C(SC)SC)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc12
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A mixture of dimethyl 7-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (150 mg, 0.52 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (132 mg, 0.58 mmol) and cesium carbonate (427 mg, 1.31 mmol) in DMF (3 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (95 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (br. s., 1 H) 8.52 (s, 1 H) 4.16 (s, 3 H) 4.05 (d, J=9.54 Hz, 1 H) 3.70 (d, J=9.54 Hz, 1 H) 3.40 (dd, J=14.93, 1.88 Hz, 1 H) 2.70-3.07 (m, 5 H) 2.08-2.27 (m, 2 H) 1.68-1.85 (m, 1 H) 1.48-1.66 (m, 2 H). MS (LC/MS) R.T.=0.90; [M+H]+=347.34.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9](CO)O)[OH:8])O)=O.O=C[C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])O)O)[OH:18])O>>[C:2]1(=[O:1])[O:8][CH:7]([CH3:9])[CH2:5][CH2:3]1.[C:23]([OH:24])(=[O:1])[CH2:21][CH2:19][C:17]([CH3:15])=[O:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(=O)CCC(=O)O
Product: CC1CCC(=O)O1

Procedure:
While glucose is obtained from cellulose in quantitative yield (98-100%), glucose isomerization to fructose is economically limited to roughly 42% [17]. As a consequence, the market price of fructose is often twice as high as the market price of glucose. Thus, the production of HMF from glucose instead of fructose is a more cost-effect process. Herein is disclosed and claimed an integrated process using solid acid catalysts and biomass-derived solvents, γ-lactones, hydrofurans and hydropyrans for converting glucose to HMF. Optionally, the HMF so formed may be upgrading by hydrogenation or oxidation. As depicted in Reaction Scheme 2, below, γ-valerolactone (GVL) can be obtained from hydrogenation of levulinic acid, another platform molecule derived from monosaccharide dehydration. In addition, GVL is an important platform molecule used for the production of chemicals and fuels.[21, 22] Other γ-lactones with higher molecular weights can be obtained from GVL, as described elsewhere,[23, 24] or by ring closing of unsaturated acid.[25] Thus, in addition to using GVL, the Examples below also disclose reactions using γ-hexylactone (GHL), γ-octalactone (GOL) and γ-undecalactone (GUL). Similar to GVL, THF can be derived from biomass from the decarbonylation and hydrogenation of furfural, a product of xylose dehydration.[26, 27]