Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][OH:22])(=[O:12])=[O:11])=[C:5]([CH3:23])[CH:4]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:22][CH2:21][CH2:20][CH2:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[S:10]([C:6]1[C:5]([CH3:23])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH3:9])(=[O:11])=[O:12])(=[O:34])=[O:33]
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCOS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
3-(1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propan-1-ol (1.19 mmol, 1 eq) was dissolved in methylene chloride (5 ml), and triethylamine (2.99 mmol, 2.5 eq) and methanesulfonic acid chloride (1.43 mmol, 1.2 eq) were added at 0° C. The mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with methylene chloride (20 ml), washed with water (10 ml) and saturated sodium chloride solution (8 ml), dried over sodium sulfate and concentrated. The crude product was employed in the next stage without further purification. Yield: 89%
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(=O)(=O)(O)O.[N:21]([O-:23])=[O:22].[Na+]>CO.O>[N:21]([O:23][CH3:1])=[O:22].[OH:22][N:21]=[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:12]#[N:13]
Reactant: O=N[O-]
Reactant: N#CCc1cccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=O
Product: N#CC(=NO)c1cccc2ccccc12
Reaction time: 4 h
Yield: 72.5 %

Procedure:
2-(1-naphthyl)acetonitrile (16.7 g.) was added to a solution of sodium hydroxide (4.2 g.) in methanol (80 ml.). Gaseous methyl nitrite, which was prepared by adding a solution of concentrated sulfuric acid (5 ml.) in water (10 ml.) to a solution of sodium nitrite (8.3 g.) in a mixture of methanol (5.5 ml.) and water, was introduced, under ice-cooling, The mixture was stirred for 4 hours at the same temperature and the reaction mixture was treated by a conventional method to give 2-hydroxyimino-2-(1-naphthyl)acetonitrile (7.1 g.), oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:18]=[N+:19]([CH3:21])[CH3:20].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([N:19]([CH3:21])[CH3:20])[C:8]2[C:7]3[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Reactant: CCc1cccc2cc[nH]c12
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccc(OC)c(OC)c3)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: C([Mg]Cl)(C)C.C(O[C:9]([C:11]1[C:12]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:10])C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1>[CH3:35][O:34][N:33]([CH3:32])[C:9]([C:11]1[C:12]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:10]
Reactant: CCOC(=O)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Yield: 14.8 %

Procedure:
Add 2M iso-propylmagnesium chloride (717 mL, 1.4 mol) to a −10° C. solution of 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl ester (175 g, 478 mmol) and N,O-dimethylhydroxylamine hydrochloride (56 g, 574 mmol) in THF (2 L). Stir the reaction for 45 min. and then slowly quench with a 1:1 mixture of sat. NH4Cl and water (750 mL). Extract the mixture with EtOAc (3×500 mL). Wash the organic phase with brine (1000 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 7:3 hexanes/EtOAc) gives the title compound (27 g, 52%). MS (m/e): 381 (M+H)+; m.p.=51–56° C.; 1H NMR (300 MHz, CDCl3) δ7.32–7.60 (m, 4H), 5.00 (d, J=14 Hz, 1H), 4.78–4.81 (m, 1H), 4.73 (d, J=14 Hz, 1H), 3.85–3.98 (m, 1H), 3.52–3.61 (m, 1H), 3.40 (s, 3H), 3.10–3.29 (m, 3H), 1.50–1.82 (m, 6H); HPLC >99%; TLC Rf=0.41 (1:1 Hexanes/EtOAc).
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[CH2:9]([N:11]=[C:12]=[O:13])[CH3:10].C([Sn]CC[CH2:21][CH3:22])CCC.C([CH:25](CCCC)[C:26]([O-])=[O:27])C>[Cu].C(N(CC)CC)C.COCCOC>[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[CH2:9]([N:11]([CH2:21][CH3:22])[C:12]([O:27][CH2:26][CH3:25])=[O:13])[CH3:10]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: CCCC[Sn]CCCC
Reactant: CCN=C=O
Agent: [Cu]
Agent: OCC#CC#CCO
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)N(CC)CC
Yield: 95 %

Procedure:
The monomer 2,4-hexadiyn-1,6-diol-bisethylurethane is synthesized in 95% yield by the reaction of 11.0 gm (0.10 mole) 2,4-hexadiyn-1,6-diol with 26.5 gm (0.37 mole) ethylisocyanate in the presence of 1,2-dimethoxyethane (50 ml), dibutyltin bis(2-ethylhexanoate (0.1 gm), and triethylamine (2 ml). The monomer is recrystallized as approximately 3 cm long needles by the slow cooling of a 10:90 acetone/petroleum either solution (75 ml) containing 0.2 sample, as described in Example 4. These crystals rapidly turn pink upon exposure to light. Polymerization proceeded quantitatively by 60Co γ-ray irradiation at a dose rate of 1 Mrad/hr and a total dosage of 60 Mrad. The resulting polymer fibers are copper-like in appearance and strongly dichroic, with dichroic axis in the fiber axis direction. The polymer fibers are monoclinic monocrystals in which the polymer chain axis, with repeat length 4.9 A is in a non-unique axis direction. The polymer fibers are annealed as described in Examples 4 and 5, in order to obtain reversible thermal-dimensional behavior. The annealed polymer fiber has a negative thermal expansion coefficient over the entire temperature range from -50° to 100° C. The average thermal expansion coefficient is -1.46×10-5 ° C.-1 between -50° and +100° C. and -1.31×10-5 ° C.-1 between -50° and +40° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1c(F)ccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)ccc(Br)c1Oc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
A solution of 1-bromo-2,4-difluoro-3-nitrobenzene (0.128 g, 0.538 mmol) [Combi-Blocks, AN-3334] and cesium carbonate (0.211 g, 0.646 mmol) in dimethyl sulfoxide (0.59 mL) was treated with phenol (0.0609 g, 0.647 mmol) and stirred at 20° C. for 3 h, after which time the reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude oil. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (57 mg, 34%) as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]([CH3:11])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[NH3:5].[CH:9]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([CH3:11])[CH3:8]
Reactant: OC1CCNCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCC(O)CC1
Product: N
Reaction time: 0.25 h

Procedure:
A mixture of 4-hydroxypiperidine (10 g, 0.10 mol), acetone (21.8 mL, 0.30 mol), acetic acid (5.7 mL, 0.10 mol) and tetrahydrofuran (150 mL) was stirred in an ice bath for 15 minutes. Sodium triacetoxyborohydride (31.3 g, 0.15mol) was then added portionwise and the mixture was stirred for a further 10 minutes. The reaction mixture was then warmed and stirred at room temperature for 10 minutes and at 40° C. for 2.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in water (50 mL). The aqueous solution was basified to pH9 with 0.88 ammonia and the solution was stirred for 30 minutes. The reaction mixture was then extracted with diethyl ether (2×200 mL) and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 96:4:1 to 90:10:1, to afford the title product as a yellow oil in quantitative yield, 14.6 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1.[C:15]([S:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([S:19][C:20](=[O:25])[CH:21]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[C:22](=[O:24])[CH3:23])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Product: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 11a using 1-(4-bromomethylphenyl)-2,2-dimethylpropan-1-one and 3-oxothiobutyric acid S-tert-butyl ester
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:24])=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=1)[NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].[CH2:30]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32][CH2:31]1>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([N:6]([CH2:36][CH:33]1[CH2:34][CH2:35][CH2:30][CH2:31][CH2:32]1)[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([OH:24])=[C:18]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(NCc1cccnc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=CC1CCCCC1
Product: CCOC(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N(Cc1cccnc1)CC1CCCCC1

Procedure:
Synthesized as in Example 2 from Example 2 (0.418 g, 1.05 mmol) and cyclohexyl carboxaldehyde (384 μL, 3.10 mmol). This gave 0.120 g (24%) of product.
Reaction SMILES: [OH:1][CH:2]([C:7]1([CH2:11][CH2:12][CH3:13])[CH2:10][O:9][CH2:8]1)[C:3]([F:6])([F:5])[F:4].N1C=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O:22][CH2:23][CH3:24])C>>[C:23]([O:1][CH:2]([C:7]1([CH2:11][CH2:12][CH3:13])[CH2:8][O:9][CH2:10]1)[C:3]([F:4])([F:5])[F:6])(=[O:22])[CH2:24][CH2:18][CH2:17][C:16]#[CH:15]
Reactant: CCCC1(C(O)C(F)(F)F)COC1
Reactant: CCOCC
Reactant: c1ccncc1
Product: C#CCCCC(=O)OC(C(F)(F)F)C1(CCC)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of hex-5-ynoic acid (1 g) and thionyl chloride (1.95 ml) in benzene (25 ml) was heated at reflux for 2.5 hours. The resulting solution was cooled and then evaporated in vacuo. The acid chloride thus obtained was taken up in dry diethyl ether (5 ml) and added, dropwise, to a stirred solution of 3-(1-hydroxy-2,2,2-trifluoroethyl)-3-n-propyloxetane (1.77 g) (European Patent Application No. 211598) and pyridine (0.8 ml) in ether (20 ml). The reaction mixture was allowed to stir at room temperature overnight. After washing with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and brine, the organic phase was dried over anhydrous magnesium and then evaporated in vacuo. The residue was purified by chromatography on silica, pre-eluted with hexane containing 1% triethylamine. Gradient elution with hexane/ether mixtures gave 2,2,2-trifluoro-1-(3-propyloxetan-3-yl)ethyl hex-5-ynoate (1.2 g) as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[NH:43][C:42](=[O:44])[O:41][N:40]=3)=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(OCC)C.Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[NH:43][C:42](=[O:44])[O:41][N:40]=3)=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[CH:45][CH:46]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(-c3noc(=O)[nH]3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(-c3noc(=O)[nH]3)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 500 mg (0.81 mmol) of methyl 4-((3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-{2-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]ethyl}but-3-en-1-yl)benzoate in 5 ml of THF and 5 ml of water is mixed with 38.8 mg (1.62 mmol) of lithium hydroxide and stirred at 50° C. for 12 h. Cooling is followed by addition of water and extraction with diethyl ether. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with diethyl ether. The resulting organic phase is washed with sodium chloride solution, dried over sodium sulfate and concentrated. 420 mg (0.7 mmol, 79% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:41][CH2:42][CH2:43][N:44]1[CH2:50][CH:49]([OH:51])[C:46]2([CH2:48][CH2:47]2)[CH2:45]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:51][CH:49]1[C:46]2([CH2:48][CH2:47]2)[CH2:45][N:44]([CH2:43][CH2:42][CH2:41][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]5[C:23](=[O:35])[N:24]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:25]([CH3:28])[C:26]=5[CH3:27])=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:50]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.642 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (240 mg, 0.963 mmol) and Cs2CO3 (417 mg, 1.284 mmol). The reaction was stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the title compound as a white solid (259 mg, 65%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[CH2:16]([S:18][CH:19]=[C:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[CH3:17].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[CH2:16]([S:18][CH:19]=[C:20]1[S:24][C:23](=[O:25])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[C:21]1=[O:26])[CH3:17]
Reactant: ClCCCCSc1cccc2nccn12
Reactant: CCSC=C1SC(=O)NC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCSC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 601 mg (2.5 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 473 mg (2.5 mmol) of 5-(ethylthiomethylene)thiazolidine-2,4-dione in 5 ml of N,N-dimethylformamide, 0.37 ml (2.5 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 16 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/4→ethyl acetate) to yield 0.76 g (77.2%, light orange oily substance) of the desired product.
Reaction SMILES: C([O:3][C:4]([CH:6]=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CO.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.O>[OH:3][CH2:4][CH:6]=[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=CCO)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 19.901 g (73.888 mM) of tert-butyl 4-(ethoxycarbonylmethylene)piperidine-1-carboxylate in 100 ml of toluene was added 123 ml (185 mM) of 1.5 M diisobutylaluminum hydride-toluene at −78° C. and the mixture was stirred at −78° C. for 1 hour. Then, methanol was added at −78° C. and the mixture was stirred for 0.5 hour to decompose the excess diisobutylaluminum hydride. Then, water was added under ice-cooling and the mixture was stirred for 2 hours. The resulting precipitate was filtered off with the aid of celite and the celite was washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.BrC[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.O>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:5][CH2:4][C:3]([OH:11])=[O:10])([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccccc1[N+](=O)[O-]
Reaction time: 0.05 h
Yield: 56.9 %

Procedure:
Sodium hydride (60% in paraffin oil, 1.0 g, 25 mmol) was added to a solution of diethyl malonate (3.2 g, 20 mmol) in DMF (20 ml) and the mixture was stirred for 3 min. 1-Bromomethyl-2-nitrobenzene (4.3 g, 20 mmol) was then added in portions during 5 min. The reaction mixture was stirred for 3 h, diluted with water, and extracted twice with ethyl acetate. The combined organic phases was washed with water and evaporated. The residue was suspended in acetic acid (40 ml) and 7.5 M HCl (10 ml) was added. The mixture was refluxed for 19 h, cooled and partitioned between diethyl ether and saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and then acidified with 2M HCl. The precipitate was collected by filtration and dried to give the title compound (2.22 g, 77%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].C(N(C(C)C)CC)(C)C.O([CH2:42][CH:43]([F:45])[F:44])S(C(F)(F)F)(=O)=O>C1COCC1>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:42][CH:43]([F:45])[F:44])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CC(F)F)CC1
Reaction time: 24 h

Procedure:
To a suspension of (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride (0.13 mmole) from experiment K4 in THF (2 ml) was added at 22° C. diisopropyl ethyl amine (0.75 mmole) and 2,2-difluoroethyl triflate (0.60 mmole) and stirring was continued at 60° C. for 24 h. The mixture was quenched with methanol, acidified with acetic acid and subjected to prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2,2-difluoro-ethyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 418.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17]C(COC3CCCCO3)=[CH:15][CH:14]=2)=[N:3]1.Cl.[C:29](=[O:32])([O-])O.[Na+].[CH3:34]O>>[CH3:27][C:2]1([CH3:1])[CH2:6][O:5][C:4]([C:7]2[C:12]([CH3:34])=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:29]([OH:32])=[CH:17][CH:18]=2)=[N:3]1
Reactant: CO
Reactant: CC1(C)COC(c2ccccc2-c2ccc(COC3CCCCO3)cc2)=N1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(-c2ccc(O)cc2)c1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4.0 g (10.9 mmol) of 4,4-dimethyl-2-(4'-tetrahydropyranyloxymethylbiphenyl-2-yl)oxazoline was dissolved in methanol (50 ml), and 6N hydrochloric acid (15 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 3.0 g of the title compound (yield 98%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.C1C(=O)N([Cl:19])C(=O)C1.Cl.O1CCOCC1>CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[N:8][OH:9])=[CH:5][CH:4]=1
Reactant: ON=Cc1ccc(CCl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: ON=C(Cl)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
4-(chloromethyl)benzaldehyde oxime 5 (15.8 g, 93.16 mmol) was dissolved in DMF (300 mL). NCS (13.69 g, 102.5 mmol) was added in portions and then HCl in dioxane (100 mL of 4 M, 400.0 mmol) was added slowly, cooling the mixture with an ice water bath to moderate the exotherm, keeping below 33° C. The mixture was stirred at room temperature for 1 hour. The solution was then partitioned between EtOAc and water. The combined organic extract was washed with water and brine (5×200 ml), dried over MgSO4 and concentrated under reduced pressure to give a colourless solid (21.65 g, 95%). 1H NMR (400 MHz, CDCl3) d 4.63 (2H, s), 7.45 (2H, d, J=8 Hz), 7.86 (2H, d, J=8 Hz), 8.36 (1H, s).