Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:33])[C@@H:17]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH2:19]SC)[C@H:11]([CH2:34][CH2:35][CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+]>IC>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]2=[O:33])[C@H:11]([CH2:34][CH2:35][CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 30 °C
Reaction time: 72 h
Yield: 24.7 %

Procedure:
Examples 2t and 2u, Step 4: A sample of benzyl (S)-1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-propylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (4.0 g, 7.45 mmol) was dissolved in iodomethane (8 mL) and stirred at 30° C. for 3 days. The solution was concentrated in vacuo. The residue was dissolved in methylene chloride and the resultant solution was concentrated in vacuo again; this procedure was repeated twice before the residue was placed under high vacuum for 4 h. The resultant pale yellow foam solid was dissolved in THF (40 mL) and the resultant solution was cooled to 0° C. before being treated with sodium hydride (0.9 g, 37 mmol) in one portion. The mixture was slowly warmed to 30° C. and stirred for 12 h before being quenched with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-propylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (0.9 g). MS found: (M+H)+=489.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH:15]1[CH:16]=[CH:17][N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[NH:21][CH2:20][C:19]=12.CN(C)C1C=CC=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH2:24][N:18]3[CH:17]=[CH:16][CH:15]=[C:19]3[CH2:20]2)=[O:7])=[CH:4][C:3]=1[S:11]([NH2:12])(=[O:14])=[O:13]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Cl
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution containing 1.02 g (0.004 mol) of 4-chloro-3-sulfamoylbenzoyl chloride, 0.74 g (0.004 mol) of 10,11-dihydro-5H-pyrolo[2,1-c][1,4]benzodiazepine and 0.48 g (0.004 mol) of N,N-dimethylaniline in 50 ml of 1,4-dioxane was allowed to stand at room temperature for 2 hours. The reaction mixture was then poured into 500 mL of water with stirring. The precipitate was collected, washed and dried to provide the title compound (0.7 g), m.p. 137° C. dec.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[SiH:11]([CH3:13])[CH3:12])[CH:2]=[CH2:3].[I-].[C:15]([C:20]1C=CC([Zn+])=[CH:22][CH:21]=1)([O:17][CH2:18][CH3:19])=[O:16].[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH2:31]([C:7]1[CH:8]=[CH:9][C:4]([C:1]2[CH:22]=[CH:21][C:20]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:2]=2)=[C:5]([SiH:11]([CH3:13])[CH3:12])[CH:6]=1)[CH:27]=[CH2:28]
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Reactant: C1CCOC1
Reactant: C=CCc1ccc(I)cc1[SiH](C)C
Agent: [I-]
Product: C=CCc1ccc(-c2ccc(C(=O)OCC)cc2)c([SiH](C)C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 5 mol % Pd(Ph3)4 (288 mg, 0.25 mmol) and 1-allyldimethylsilyl-4-iodobenzene (1 Scheme 24, 1.5 g, 5 mmol) in dry THF (10 mL) was added (4-carbethoxyphenyl)zinc iodide (0.5 M solution in THF, 10 mL, 5 mmol). After degassing by bubbling with N2, the reaction mixture was sealed and stirred for 16 h at 60° C. The mixture was treated with saturated NH4Cl (10 mL) and extracted. The organic layer was dried over Na2SO4 and concentrated. The resulting crude product was purified by column chromatography (1:30 ethyl acetate/hexanes) to afford a colorless oil (12 g, 72%); 1H NMR (300 NMz, CDCl3) δ 0.39 (s,6H), 1.46 (t, J=7.5 Hz, 3 H), 1.85 (d, J 8.0 Hz, 2 H), 4.45 (d, J=7.5 Hz, 2 H), 4.94 (s, 1 H), 4.97 (m, 1 H), 5.84 (m, 1 H), 7.65(4 H), 7.70 (d, J=8.0 Hz, 2 H), 8.18 (d, J=8.18 (d, J=8.0 Hz, 2 H); HRMS (EI) calcd for C20H24O2Si 324.1545, found 324.1545.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])([O-])=O>CC(O)=O.CCO.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(OCC(=O)O)c1

Procedure:
(3-Nitro-phenoxy)-acetic acid (1.978 g; 10.0 mmol) was reduced by catalytic hydrogenation (10% Pd—C; 45 psi H2) in AcOH-EtOH-MeOH then filtered through diatomaceous earth and concd yielding the title aniline. LC-MS 168 ([M+H]+).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19]([NH:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:36])=[O:5])[S:12][CH:13]=3)=[O:20])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(Sc1nc(CCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.9 %

Procedure:
To a solution of 2-{[4-(2-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (33 g) synthesized in Example 483-1 in dichloromethane (30 mL) was added trifluoroacetic acid (50 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and purified by silica gel chromatography (elution solvent; ethyl acetate) to give the title compound (38 g) as a pale-brown oil.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.Cl>CN(C=O)C>[C:8]1([NH:14][NH:15][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(NNc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.54 mL (31.0 mmol) cyclobutanecarboxylic acid chloride were added dropwise at RT to 3.00 mL (30.2 mmol) phenylhydrazine and 4.75 mL (60.0 mmol) pyridine in 30 mL DMF. The mixture was stirred for 1 h at RT and poured onto 200 mL of a 1M hydrochloric acid solution. The precipitated solid was suction filtered, washed with 50 mL water and dried i. vac. The product was extracted with 50 mL ether and suction filtered. The solid was washed with 20 mL ether and dried in the air.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:25]([N:32]1C=CN=C1)(N1C=CN=C1)=[O:26].Cl.N[O:39][CH2:40][CH:41]([CH3:43])[CH3:42].C(N(CC)CC)C>CN(C)C=O>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:25]([NH:32][O:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:26]
Reactant: CC(C)CON
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CONC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 62.9 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), 1,1′-carbonyldiimidazole (297 mg, 1.833 mmol), 1-(aminooxy)-2-methylpropane hydrochloride (230 mg, 1.833 mmol), triethylamine (0.25 mL, 1.833 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 200, the title compound (170 mg, 63%) was obtained as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1.ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[F:12]
Reactant: O=C(CBr)c1ccc(Br)c(F)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CN1CCOCC1)c1ccc(Br)c(F)c1

Procedure:
To a 0° C. solution containing 0.55 g of 2-bromo-1-(4-bromo-3-fluorophenyl)ethanone (1.86 mmols) in 9 mL of THF was added 0.32 mL of morpholine (3.72 mmols). After 18 h the reaction mixture was diluted with 100 mL of dichloromethane and washed with water (1×10 mL) and saturated brine solution (1×10 mL). The organic layer was dried over MgSO4, filtered through a frit, and concentrated to a yellow-orange oil which was used without further purification. MS (ES) m/e 302, 303 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH:12](=O)[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>C(OC(=O)C)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1/[CH:12]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: COc1ccccc1C=O
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1/C=C1\CCCc2cc(C)cnc21

Procedure:
5,6,7,8-Tetrahydro-3-methylquinoline (6.6 g) was added to o-anisaldehyde (8.16 g) in acetic anhydride (10 ml) and was heated to reflux for 14 hours after which the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 ml) and was added to 2N HCl (150 ml), the aqueous layer was basified (Na2CO3) and extracted with ethyl acetate (4×100 ml) dried (MgSO4) and evaporated under reduced pressure. The residue was washed with several aliquots of hot hexane and was then dissolved in a small volume of boiling propan-2-ol and etherial hydrogen chloride was added in excess. On cooling a precipitate formed and was removed by filtration, washed with ether and dried under vacuum to give the title compound as the hydrochloride salt (2.6 g) m.p. 221°-222.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)[CH3:12].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([F:1])[CH:3]=2)=[O:22])=[CH:24][CH:25]=1)[CH3:12]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCOCCOc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(C(=O)Oc2ccc(C#N)c(F)c2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of 3-fluoro-4-cyanophenol (1.5 g, 11 mmols) dissolved in dry pyridine (5 cc) was added a solution of 4-(β-ethoxyethoxy)benzoic acid chloride (2.5 g, 11 mmols) dissolved in dry toluene (10 cc), followed by heating the mixture with stirring at 60° C. for 3 hours, thereafter adding it to water (100 cc), washing the resulting separated toluene layer with 6N-hydrochloric acid, 2N-NaOH aqueous solution and water, in this order, drying over anhydrous sodium sulfate, distilling off toluene from the toluene layer and recrystallizing the resulting oily residue from ethyl alcohol (10 cc) to obtain the objective 3-fluoro-4-cyanophenyl 4-(β-ethoxyethoxy)benzoate (2.1 g) (yield: 64%).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Cl)=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([OH:25])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[C:11]([CH2:12][O:25][C:23]2[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=2[CH3:26])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1O
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CCl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of 7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 7, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol (330 μL, 3.02 mmol), and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N,N-dimethylformamide (10 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (80 mL) and water (50 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (945 mg) as a colorless solid. (Yield 92%)
Reaction SMILES: [CH3:1]/[C:2](/[CH:27]=[CH:28]/[CH:29]=[C:30](/[CH:32]=[CH:33]/[C@:34]12[C:40]([CH3:42])([CH3:41])[CH2:39][C@H:38](O)[CH2:37][C@@:35]1([CH3:44])O2)\[CH3:31])=[CH:3]\[CH:4]=[CH:5]\[CH:6]=[C:7](\[CH:9]=[CH:10]\[CH:11]=[C:12](\[CH:14]=[C:15]=[C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][C@H:19](O)[CH2:18][C@:17]1(O)[CH3:25])/[CH3:13])/[CH3:8].C/C(/C=C/C=C(\C)/C=C/[C@]12C(C)(C)C[C@H](O)C[C@@]1(C)O2)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@]12C(C)(C)C[C@H](O)C[C@@]1(C)O2>>[CH3:44][C:35]1[CH2:37][CH2:38][CH2:39][C:40]([CH3:41])([CH3:42])[C:34]=1/[CH:33]=[CH:32]/[C:30](/[CH3:31])=[CH:29]/[CH:28]=[CH:27]/[C:2](/[CH3:1])=[CH:3]/[CH:4]=[CH:5]/[CH:6]=[C:7](\[CH3:8])/[CH:9]=[CH:10]/[CH:11]=[C:12](\[CH3:13])/[CH:14]=[CH:15]/[C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:25]
Reactant: C/C(C=C=C1C(C)(C)C[C@H](O)C[C@@]1(C)O)=C\C=C\C(C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\[C@@]12O[C@]1(C)C[C@@H](O)CC2(C)C
Agent: CC(/C=C/C=C(C)/C=C/[C@@]12O[C@]1(C)C[C@@H](O)CC2(C)C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\[C@@]12O[C@]1(C)C[C@@H](O)CC2(C)C
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1

Procedure:
The Tagetes erecta-flower petals according to claim 8 that further exhibit at least one of a neoxanthin plus violaxanthin ratio of about 1:5 to about 1:1, a β-carotene ratio of about 0.05 to about 0.9 for flower petals and about one for leaves, an α-cryptoxanthin ratio of about 0.25 to about 0.9, a phytoene ratio of about 0.3 to about 1 or a phytofluene ratio of about 0.2 to about 1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16]>>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][N:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH3:11]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CNCC(O)CO
Product: CN(Cc1cccc(C#N)c1)CC(O)CO

Procedure:
The title compound was prepared following the general procedure 10, starting from 3-(bromomethyl)benzonitrile and 3-(methylamino)-1,2-propanediol. It was isolated as a colorless oil (920 mg, 82%). LC/MS (Method B): 221.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22]4[O:25][CH:26]=[CH:27][C:21]=4[CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH2:33]=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22]4[O:25][C:26]([CH2:33][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:27][C:21]=4[CH2:20]3)(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(/C=C\c2cccc(Cl)c2)cc1)N1CCc2occc2C1
Reactant: C1CCNC1
Reactant: C=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(/C=C\c2cccc(Cl)c2)cc1)N1CCc2oc(CN3CCCC3)cc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.666 g (1.665 mmol) of (Z)-5-(3-chlorostilbene-4'-sulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridin in 10 ml of acetic acid, 0.21 ml (2.5 mmol) of pyrrolidine and 0.20 g (2.5 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:38][C:39](O)=[O:40])[N:24]=[C:25]([O:26][C@@H:27]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]4[OH:29])[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:43][NH:44][CH3:45].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:38][C:39](=[O:40])[N:44]([CH3:45])[CH3:43])[N:24]=[C:25]([O:26][C@@H:27]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]4[OH:29])[C:18]=23)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(OCc4ccccc4)cc3)ccnc21
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Cn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(OCc4ccccc4)cc3)ccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of 4-[2-(4-benzyloxyphenyl)ethyl]-1-carboxymethyl-3-(β-D-glucopyranosyloxy)-1H-pyrazolo-[3,4-b]pyridine (50 mg) in N,N-dimethylformamide (2 mL) were added dimethylamine hydrochloride (9 mg), 1-hydroxy-benzotriazole (14 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (34 mg) and triethylamine (0.049 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1−8/1) to give 4-[2-(4-benzyloxyphenyl)ethyl]-3-(β-D-glucopyranosyloxy)-1-(N,N-dimethylcarbamoylmethyl)-1H-pyrazolo[3,4-b]pyridine (27 mg). This material was dissolved in methanol (4 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (20 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1.CCCCCC.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[S:35][CH:36]=[N:37][N:38]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1nncs1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)c1
Yield: 47 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (76 mg, 0.17 mmol) with 2-amino-1,3,4-thiadiazole (20 mg, 0.20 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 47% yield (40 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[N:21][OH:22])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1C2CCC1CN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
The mixture of 19 g (88 mmole) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (J. Med. Chem. 1994, 37, 2831), 200 ml of ethanol, 8.78 g (126.4 mmole) of hydroxylamine hydrochloride and 13 ml of pyridine are heated and stirred on a 100° C. oil-bath, then the mixture is evaporated. To the residue 65 ml of 2.5 N sodium hydroxide solution is added, the resulting solution is extracted with 3×120 ml of ethyl acetate. The extractum is dried over sodium sulphate and evaporated. The resulting oil is purified by column chromatography (n-hexane-ethyl acetate from 9:1 to 1:1) to obtain 11.05 g (54%) of white, crystalline material. M.p.: 92-95° C. (MH+)=231.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>O>[CH:1](=[N:12][CH:9]([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)N
Solvent: O
Product: CC(C)N=Cc1ccccc1
Reaction time: 0.67 h
Yield: 105.8 %

Procedure:
To a three neck round bottom flask, equipped with a cold water condenser, 30 g of water and 26.5 g of benzaldehyde were added. The mixture was mixed using a magnetic stirrer for 3 minutes at room temperature. i-Propylamine (17.7 g) was added to the reaction flask in one portion, followed by vigorous stirring for 40 minutes. The agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was separated from the reaction mixture. The upper layer was collected and dried over magnesium sulfate to give 38.9 g of product. This crude product could be further purified by distillation, collecting the fraction between 94°-95° C./18 mmHg. 1H NMR (300 Hz, CDCl3, ppm): 8.29 (1H, s), 7.70 (2H, m), 7.38 (3H, m), 3.53 (hep. J=6.3 Hz), 1.27 (9H, d, J=6.3 Hz); IR (NaCl film, cm-1): 3061, 3026, 2930, 2835, 1647, 1581, 1450, 1382, 1306, 1141,967, 755, 693.