Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.C(Cl)(Cl)[Cl:39]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:39])=[CH:7][C:3]=1[C:4]([NH:28][NH:27][C:25](=[O:26])[C:24]1[CH:29]=[CH:30][C:21]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:22][CH:23]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: ClC(Cl)Cl
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1

Procedure:
Under a blanket of nitrogen, 8.8 g (0.087 mol) 2,4-dichlorobenzoyl chloride was added to a solution of 23.0 g (0.087 mol) 4-octoxybenzoyl hydrazine and 12.13 ml (8.8 g, 0.087 mol) freshly distilled triethylamine in 348 ml dry chloroform. After about one hour of stirring a dense white precipitate of the required product was formed. Stirring was continued until the next day. The product was collected by filtration and recrystallized from ethanol/water to give 31 g (81.5% yield) of 2,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide as a white solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C(C)=CC=CC=1>[I-:20].[CH2:21]([P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCI
Solvent: Cc1ccccc1C
Product: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Yield: 93.9 %

Procedure:
A mixture of 28.82 g of triphenylphosphine, 21.2 g of 1-iodo-hexane and 200 ml of xylene was refluxed for 5 hours and then was cooled. The solvent was decanted and the gummy residue was triturated with ether and dried at 90° to 100° C. under reduced pressure to obtain 44.53 g of n-hexyltriphenylphosphonium iodide melting at 106° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]([S:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CC[O:38]C(C)=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]([S:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1)(=[O:38])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(Cc1ccccc1)S(=O)N1CCC(Cc2ccccc2)CC1)OCc1ccccc1
Reactant: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: O=C(CC(Cc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1)OCc1ccccc1
Temperature: 0 °C
Yield: 81 %

Procedure:
The product from Step D (430 mg, 0.91 mmol) was taken up in acetonitrile (1.5 mL) with stirring and cooled to 0° C. RuCl3.3H2O (0.5 mg) and NalO4 (290 mg, 1.37 mmol) were added followed by water (2 mL). The resulting mixture was stirred at room temperature for 2½h until tlc (hex/EtOAc 1:1) indicated the absence of starting material. The reaction was diluted with DCM, the layers separated and the aqueous layer was further extracted with DCM. The organic extracts were combined, dried, filtered and concentrated in vacuo to give the product as an oil (360 mg, 81%). 1H-NMR δ (CDCl3) 7.37-7.09 (15H, m), 4.96 (1H, d, J=12.2 Hz), 4.94 (1H, d, J=12.1 Hz), 3.91 (1H, m), 3.89-3.68 (2H, m), 3.31 (1H, dd, J=4.5, 14.0 Hz), 2.88-2.45 (7H, m 1.72-1.50 (3H, m) and 1.29-1.15 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[S:9]([O:14]C)([O:12][CH3:13])(=[O:11])=[O:10]>CCOCC>[CH3:13][O:12][S:9]([O-:14])(=[O:11])=[O:10].[CH3:13][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: COS(=O)(=O)OC
Reactant: Clc1nsc(Cl)c1Cl
Solvent: CCOCC
Product: COS(=O)(=O)[O-]
Product: C[n+]1sc(Cl)c(Cl)c1Cl

Procedure:
Trichloroisothiazole (37.7 g, 0.20 mol) and dimethyl sulfate (9.5 ml, 0.1 mol) were mixed under a nitrogen atmosphere. The mixture was heated at 135°-140° for 1 hr. The reaction mixture was cooled and poured into 100 ml of ether. The resulting solid was collected and washed with warm glyme to yield 14.5 g, (46%), mp 130°. The NMR and IR were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]#[N:19])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1c2n(c3c(-c4cccc(C#N)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (69 mg, 86%), MS (ISP) m/z=320.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3-cyano-phenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Cl:11][C:12]1[C:13]([OH:21])=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:12]1[C:13](=[O:21])[N:14]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc([N+](=O)[O-])cc(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxybenzyl bromide (5.0 mL, 34.4 mmol) was added to a cold (0° C.) mixture 3-chloro-2-hydroxy-5-nitropyridine (5 g, 28.6 mmol) and K2CO3 (7.9 g, 57.3 mmol) in DMF (25 mL). The reaction mixture was allowed to warm to rt, stirred for 2 h, quenched by addition of a saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by trituration in EtOAc. ESI-MS: tR=0.98 min (LC-MS 1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]2[NH:25][C:24]1[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of ethyl 4-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (1.68 g), 4-methoxyaniline (0.78 g), dry THF (50 ml) and anhydrous potassium carbonate (1.74 g) was stirred at ambient temperature for 7 hours. Further amounts of 4-methoxyaniline (0.4 g) and anhydrous potassium carbonate (0.9 g) were added and the mixture stirred at ambient temperature for 32 hours. The mixture was evaporated to dryness and the residue diluted with water (100 ml). The mixture was extracted into dichloromethane to give an oil which solidified. The solid was purified by column chromatography on silica using ethyl acetate as the mobile phase to give ethyl 6-methoxy-4-(4-methoxyanilino)-1,5-naphthyridine-3-carboxylate, m.p. 115°-117° C.
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([N:33]=[C:34]=[O:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CS(C)=O.O>[C:25]([NH:33][C:34]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)[C:9]1=[O:17])=[O:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccccc21)c1ccccc1
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a stirred solution of 486 mg (2.0 mmole) of 3-(2-thenoyl)-2-oxindole and 445 mg (4.4 mmole) of triethylamine in 5 ml of dimethyl sulfoxide was added 324 mg (2.2 mmole) of benzoyl isocyanate. Stirring was continued for 1 hour, and then the mixture was poured into a mixture of 50 ml of water and 1.7 ml of 3 N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystallized from ca. 30 ml of 2:1 ethanol:water to give 190 mg of the title compound as fluffy, yellow crystals, mp 165°-166° C. (dec).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2].CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH3:16])[C:8]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2oc(=O)n(C)c2c1
Yield: 74.2 %

Procedure:
5-Acetylbenzo[d]oxazol-2(3H)-one (0.5 g, 2.82 mmol), methyl iodide (0.6 g, 4.23 mmol), and cesium carbonate (1.37 g, 4.23 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 5-acetyl-3-methylbenzo[d]oxazol-2(3H)-one (0.4 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.80 (s, 1H), 7.00 (d, 1H), 3.48 (s, 3H), 2.60 (s, 3H); MS (ESI) m/z: Calculated for C10H9NO3: 191.1. found: 192.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.O>CN(C)C(=O)C.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>[ClH:1].[OH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:3]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:26])[S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:37][CH:36]=1
Reactant: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1ccccc1
Reactant: OCc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(CCN1CCN(c2nccnc2-c2ccc(CO)cc2)CC1)S(=O)(=O)c1ccccc1
Product: Cl
Temperature: 70 °C
Reaction time: 72 h
Yield: 72.8 %

Procedure:
Combine N-[2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-N-methyl-benzenesulfonamide (0.300 g, 0.758 mmol), potassium carbonate (0.251 g, 1.82 mmol), (4-(hydroxymethyl)phenyl boronic acid (0.138 g, 0.909 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) in N,N-dimethylacetamide (1.5 mL). Add water (760 μL), and reflux reaction for 6 hr. Continue to heat at 70° C. for 18 hr. Add (4-(hydroxymethyl)phenyl boronic acid (0.069 g, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) and heat to 115° C. for 6 hr. Continue to stir at ambient temperature over 72 hr. Add dichloromethane and wash with water. Extract the aqueous layer three times with dichloromethane. Dry the combined organic layers and purify (silica gel chromatography, eluting with 0:100 to 100:0 ethyl acetate:hexanes), to give the free base of the title compound (278 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1.[CH:16]1([C:19](=O)[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C1C=CC=CC=1>CC(O)=O>[CH:16]1([C:19]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]3[CH:12]=[N:11][N:10]([CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:14]=3[N:15]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: COc1ccc(Cn2nccc2N)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2Cc1ccc(OC)cc1
Temperature: 63 °C
Yield: 71 %

Procedure:
A mixture of 1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazol-5-amine (3 g, 14.76 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (2.72 g, 14.76 mmol) and benzene (50 mL) were heated at 63° C. for 16 h. The solvent was removed under reduced pressure. The crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford 2.56 g of the desired cyclized product and 1.71 g of the uncyclized adduct. The uncyclized adduct was dissolved in 25 mL of AcOH and heated to reflux for 16 hours. The solvent was removed under reduced pressure and the residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford an additional 1.15 g of the desired cyclized product (combined yield=71%). LCMS E-S (M+H)=352.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.13 (m, 4H) 1.38 (t, J=7.07 Hz, 3H) 2.39 (s, 1H) 3.67 (s, 3H) 4.41 (q, J=7.07 Hz, 2H) 5.51 (s, 2H) 6.84 (d, J=8.84 Hz, 2H) 7.21 (d, J=8.59 Hz, 2H) 7.64 (s, 1H) 8.23 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:31]1[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]1[O:33][C:34](=[O:36])[CH3:35])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.ClC(Cl)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][N:13]([C@@H:31]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]3[O:33][C:34](=[O:36])[CH3:35])[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2cn[nH]c2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CC#N
Product: CCc1ccc(Cc2cnn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1
Temperature: 60 °C
Yield: 44.4 %

Procedure:
To a solution of 4-(4-ethylphenylmethyl)pyrazole 36 (495 mg) in acetonitrile (2.0 ml) was added N,O-bis(trimethylsilyl)acetamide (1.05 ml), and the mixture was stirred under heating at 60° C. for 2.5 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give crude 4-(4-ethylphenylmethyl)-1-trimethylsilylpyrazole 37, which was used in the subsequent reaction without further purification. (2) The above N-silyl compound 37 was dissolved in dichloroethane (7.0 ml), and added thereto were molecular sieve 4A powder (500 mg), 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 38 (1.04 g) and trimethylsilyl trifluoromethanesulfonate (0.51 ml). The mixture was stirred under heating at heating at 80° C. for 3 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and insoluble materials were filtered off. Subsequently, the filtrate was poured into a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with dichloromethane, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to give 4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) pyrazole 39 (610 mg) as a colorless semisolid. APCI-Mass m/Z 517 (M+H). (3) From the above tetraacetate compound 39, the desired 4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 40 was prepared in a manner similar to Example 106-(3) as colorless oil. APCI-Mass m/Z 349 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[S:11]([NH:14][C@H:15]([CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:13])=[O:12].[CH2:35](O)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:40]1[O:41][C:42]2[CH:43]=[CH:44][C:36]([CH2:35][N:14]([S:11]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=3[CH3:10])(=[O:12])=[O:13])[C@H:15]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:37][C:38]=2[O:39]1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Reactant: OCc1ccc2c(c1)OCO2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To a cooled (ice bath) solution of tert-butyl 2(R)-(2,6-dimethyl-4-methoxybenzene sulfonylamino)-3-phthalimido-propionate (6.9 g, 14.12 mmol) in dry benzene (150 ml) with piperonyl alcohol (3.22 g, 21.2 mmol) and tributyl phosphine (5.3 ml, 21.2 mmol) was added 1,1′-(azodicarbonyl)-dipiperidine (5.35 g, 21.2 mmol). The mixture was allowed to warm to ambient temperature overnight. The material was loaded onto a flash silica gel column using ethyl acetate-hexanes (30%) as eluant, providing tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-phthalimido-propionate as a white solid (8.59 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[NH2:10].[C:11](=S)=[S:12]>C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:11]([SH:12])[NH:10][C:3]=2[C:4]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1N
Reactant: S=C=S
Solvent: CCO
Product: Fc1ccc2nc(S)[nH]c2c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.2 %

Procedure:
To a solution of 1,2-diamino-3,4-difluoro-benzene (996 mg, 6.9 mmol) in 20 mL of ethanol in a 25 mL microwave tube, are added 2.0 mL (33.3 mmol) of carbon disulfide. The tube is capped and the reaction mixture is heated under microwaves at 120° C. twice for 20 minutes, upon which 1.0 mL (16.6 mmol) of carbon disulfide is added and heating under microwaves is pursued for 20 minutes. Carbon disulfide 2.0 mL (33.3 mmol) is added and heating is pursued for 30 minutes under microwaves at 150° C. The reaction mixture is then cooled to room temperature and concentrated to dryness under reduced pressure. The residue is dissolved into ethyl acetate and concentrated to dryness under reduced pressure. The residue is triturated into diisopropylether, filtered and washed once with diisopropylether. The solid is dried under reduced pressure. 0.35 g of 6,7-difluoro-1H-benzimidazole-2-thiol is obtained as mauve solid. LCMS-DAD-ELSD: 185(−): [M−H]−; 186(+): [M+H]+.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1/[CH:9]=[CH:10]/[C:11]([OH:13])=O.C([N:18](C(C)C)CC)(C)C.N[N:25]([CH:33]=[NH:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[NH:18]=[C:33]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH:34][C:11](=[O:13])/[CH:10]=[CH:9]/[C:2]1[C:1]([CH3:14])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8]
Reactant: CC(C)(C)OC(=O)N(N)C=N
Reactant: Cc1cc(C)c(/C=C/C(=O)O)c(C)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C/C(=O)NC(=N)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
(2E)-3-Mesitylacrylic acid (8.0 g; 42 mmol), diisopropylethylamine (27.2 g; 210 mmol), tert-butyl amino(imino)methylcarbamate (8.03 g; 50 mmol), and 1-hydroxybenzotriazole monohydrate (7.73 g; 50 mmol) were dissolved in N,N-dimethylformamide (170 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (19.2 g; 50 mmol) was added thereto, and the mixture was stirred for 20 hours at room temperature. To the reaction solution, ethyl acetate (500 mL) was added, and the mixture was washed with 10% aqueous citric acid solution, brine, saturated aqueous sodium bicarbonate solution, and then brine. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure, to give 13.9 g of the title compound (yield 100%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:21]3[N:30]([CH3:31])[C:29](=[O:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH3:20])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C=O.[CH3:35]N(C=O)C.C([BH3-])#N>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]([CH3:35])[CH:19]([C:21]3[N:30]([CH3:31])[C:29](=[O:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH3:20])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N2CCC(NC(C)c3nc4ccccc4c(=O)n3C)CC2)cc1
Reactant: CN(C)C=O
Agent: C=O
Agent: [BH3-]C#N
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCC(N(C)C(C)c3nc4ccccc4c(=O)n3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-{1-[1-(4-methoxy-benzenesulfonyl)-piperidin-4-ylamino]-ethyl}-3-methyl-3H-quinazolin-4-one (183 mg, 0.4 mmol), formaldehyde (39 μL, 0.48 mmol, 37% wt. solution in water) and DMF (1 mL) was added MP-Cyanoborohydride (300 mg, 2-3 mmol/g) and the reaction was stirred overnight at room temperature. The reaction mixture was then filtered and purified by HPLC to yield the product. HPLC ret. time 2.41 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.0 Hz, 1H), 7.93 (t, J=7.2 Hz, 1H), 7.68 (m, 4H), 7.03 (d, J=8.6 Hz, 2H), 4.93 (m, 1H), 3.98 (s, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 3.10 (s, 3H), 2.58 (m, 2H), 2.21 (m, 2H), 1.78 (d, J=6.6 Hz, 3H), 1.31 (m, 4H); ESI-MS m/z 471.3 (M+1)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:32][CH2:31][C:19]3([CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:30])[CH2:20]3)[CH2:18][CH2:17]2)=[CH:10][CH:9]=1>C(O)(=O)C.O=[Pt]=O>[C:3]([OH:5])(=[O:4])[CH3:2].[C:27]([OH:29])(=[O:28])[CH3:26].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][C:19]3([CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:30])[CH2:20]3)[CH2:31][CH2:32]2)[CH2:10][CH2:9]1
Reactant: O=C(O)CN1C(=O)CC2(CCN(CCc3ccncc3)CC2)CC1=O
Reactant: O=C(O)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CC2(CCN(CCC3CCNCC3)CC2)CC1=O

Procedure:
To a solution of 0.5 g (1.25 mmol) of the compound from Example 26. Step C in 40 ml 90% acetic acid were added 100 mg PtO2. The mixture was filled into an autoclave and hydrogenated at 20 atm and room temperature for 22 h. The solvent was removed under reduced pressure, and the residue was stirred with ether. The insoluble title compound was separated and dried in vacuo.