Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)[C:12](O)=[O:13])=[CH:4][CH:3]=1.[Cl-].ClC=[N+](C)C.[CH2:42]([SH:44])[CH3:43].[OH-].[Na+]>C(OCC)(=O)C.P([O-])([O-])([O-])=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:29][CH:30]=3)=[CH:20][CH:21]=2)[C:12](=[O:13])[S:44][CH2:42][CH3:43])=[CH:4][CH:3]=1
Reactant: CCS
Reactant: CS(=O)(=O)Oc1ccc(OCCc2ccc(CC(SCCc3ccc(O)cc3)C(=O)O)cc2)cc1
Agent: C[N+](C)=CCl
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CCSC(=O)C(Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)SCCc1ccc(O)cc1
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 80.3 %

Procedure:
A solution of racemic 2-{[2-(4-hydroxyphenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoic acid (45 g @ 80% strength, containing 8% wt/wt benzoic acid, 70 mmol) in ethyl acetate (225 mL, 5 vol) was cooled to 0-5° C. Solid chloromethylene-dimethylammonium chloride (Vilsmeier reagent @ 95% strength, 20.6 g, 161 mmol, 2.3 eq) was added in 4 equal portions over 1.5 hours maintaining a temperature of 0-5° C. The resulting turbid mixture was stirred at the same temperature for 2.5 hours and was subsequently added dropwise to an ice-cold vigorously stirred solution of ethanethiol (7.8 mL, 105 mmol, 1.5 eq.) in aqueous phosphate buffer (pH 7,200 mL). The pH was constantly monitored and kept between 6 and 7.5 by simultaneous addition of 32% NaOH solution. After 30 minutes at low temperature, the batch was allowed to warm to ambient temperature overnight. The organic phase was separated, dried (MgSO4) and concentrated in vacuo to give the crude product as brown oil (43.82 g, 114%). The crude compound was purified by flash chromatography (20:80 to 50:50 EtOAc:iso-hexane; silica) to yield the title compound as a pale yellow oil (31.5 g, 81%). HPLC (Rt 11.6 min); m.p. oil; 1H NMR (400 MHz, d6-DMSO) δ 9.19 (1H, s), 7.18-7.28 (4H, m), 7.14 (2H, d, J=8.1 Hz), 7.00-6.94 (4H, m), 6.65 (2H, d, J=8.4 Hz), 4.15 (2H, t, J=6.8 Hz), 3.87-3.83 (1H, m), 3.29 (3H, s), 3.08 (1H, dd, J=14.0, 8.4 Hz) 2.98 (2H, t, J=6.8 Hz), 2.87 (1H, dd, J=14.0, 7.0 Hz), 2.80-2.67 (4H, m), 2.66-2.60 (2H, m), 1.08 (3H, t, J=7.2 Hz); 13C NMR (100.6 MHz, d6-DMSO) δ 198.14, 157.15, 155.73, 142.45, 136.37, 135.52, 130.14, 129.34, 129.22, 129.07, 123.28, 115.39, 115.04, 68.51, 55.29, 37.14, 36.88, 34.41, 34.34, 32.78, 22.98 and 14.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]([OH:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[C:9]2=[O:18])=[N:6][CH:7]=1.Cl.Cl[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>C(N(CC)CC)C>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:18][CH:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16](=[O:17])[C:15]3[N:14]=[CH:13][CH:12]=[N:11][C:10]2=3)=[O:22])[CH2:24][CH2:25]1
Reactant: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1

Procedure:
reacting 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine with 1-chlorocarbonyl-4-methylpiperazine hydrochloride in an organic solvent in presence of triethyl amine along with a catalytic amount of an acylation catalyst to obtain racemic zopiclone;
Reaction SMILES: [CH3:1][C:2]1[CH2:8][CH:7]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:33])[CH2:16][CH2:17][C@@H:18]4[C@@:23]5([CH3:31])[C:24]([CH2:26][C@H:27]([OH:30])[C@H:28]([OH:29])[C@@:22]65[O:32][C@@H:21]6[CH2:20][C@H:19]4[C@@H:14]3[CH2:13][CH2:12]2)=[O:25])[CH3:10])[O:6][C:4](=[O:5])[C:3]=1[CH2:34][O:35][C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.CC1C[C@H]([C@H]([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)[C@@H](O)C[C@H](O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@H](O)[C@@]65O[C@@H]6C[C@H]4[C@@H]3CC2O)C)OC(=O)C=1CO>>[CH3:1][C:2]1[CH2:8][C@H:7]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:33])[CH2:16][CH2:17][C@@H:18]4[C@@:23]5([CH3:31])[C:24]([CH2:26][C@H:27]([OH:30])[C@H:28]([OH:29])[C@@:22]65[O:32][C@@H:21]6[CH2:20][C@H:19]4[C@@H:14]3[CH2:13][CH2:12]2)=[O:25])[CH3:10])[O:6][C:4](=[O:5])[C:3]=1[CH2:34][OH:35]
Reactant: CC1=C(CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C(=O)OC([C@@H](C)[C@H]2CC[C@H]3[C@@H]4C[C@H]5O[C@]56[C@@H](O)[C@@H](O)CC(=O)[C@]6(C)[C@H]4CC[C@]23C)C1
Agent: CC1=C(CO)C(=O)O[C@@H]([C@@H](C)[C@H]2C(O)C[C@H]3[C@@H]4C[C@H]5O[C@]56[C@@H](O)[C@@H](O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)C[C@H](O)[C@]6(C)[C@H]4CC[C@]23C)C1
Product: CC1=C(CO)C(=O)O[C@@H]([C@@H](C)[C@H]2CC[C@H]3[C@@H]4C[C@H]5O[C@]56[C@@H](O)[C@@H](O)CC(=O)[C@]6(C)[C@H]4CC[C@]23C)C1
Yield: 28 %

Procedure:
Isolation of withanolides. The combined crude extract from PhytoMyco Research Corporation (4 g) was stirred with n-hexane (500 mL) and filtered. The hexane insoluble portion (3.2 g) was chromatographed on MPLC using CHCl3 and MeOH (v/v) under gradient condition. The fractions collected were I (600 mg CHCl3:MeOH, 9:1), II (500 mg, CHCl3:MeOH, 8:2), III (1.2 g, CHCl3:MeOH, 7:3), and IV (200 mg, CHCl3:MeOH, 1:1). Repeated MPLC of fraction I using hexane-EtOAc (1:1, v/v) yielded pure compounds 6 (120 mg, 0.078%), 7 (50 mg, 0.032%) and a fraction 1 (4.0 mg). This fraction was further purified by PTLC (hexane-EtOAc, 6:4, v/v) to yield the pure compound 9 (2.1 mg, 0.0014%). Purification of fraction II by preparative HPLC using MeOH—H2O (1:1, v/v) afforded compound 10 (20 mg, 0.013%) at 19.5 min and fraction 2 (50 mg) at 24.2-28.1 min. It was further purified on HPLC by using MeOH—H2O (4:6, v/v) and gave compound 11 (40 mg, 0.026%) at 32.96 min. Similarly, fraction III was purified by Prep. HPLC (MeOH—H2O, 6:4, v/v) and yield pure compound 12 (15 mg, 0.0097%) at 112 min and fractions 3 (950 mg) at 20-45 min and 4 (16 mg) at 140-160 min. Fraction 3 was further purified by HPLC (MeOH—H2O, 6:4, v/v) to afford compounds 8 (200 mg, 0.13%) and 5 (10 mg, 0.0065%) at 66.8 and 78.6 min, respectively, and 700 mg of sucrose at 132 min. Fraction 4 was subjected to HPLC (MeOH—H2O, 7:3, v/v) yielded compound 2 (12 mg, 0.0078%) at 81 min. The fraction IV was purified by HPLC (MeOH—H2O, 7:3) and collected fractions 5 (13 mg) at 20-30 min and fraction 6 (30 mg) at 30.1-66 min. The fraction 6 was purified by HPLC (MeOH—H2O, 7:3, v/v) to yield compound 3 (8.5 mg, 0.0055%) at 57.9 min. Fraction 5 was further purified by HPLC using MeOH—H2O (6:4, v/v) and afforded pure compound 1 (10.5 mg, 0.0068%) at 59.3 min and a mixture of compounds 4 and 12 at 96.4 min (5.0 mg, 0.0032%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][C:29]([NH:31][CH3:32])=O)[CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH:31][CH3:32])[CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)c1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
To a solution of 1-(3-t-butyl-1-(3-(2-(methylamino)-2-oxoethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (0.071 g, 0.15 mmol) in THF (2 mL) was added a solution of 1M BH3-THF (1 mL, 1 mmol) at 0° C. under Ar. After stirring the mixtureat 60° C. for 24 h, it was cooled to 0° C., and 3M HCl was added slowly. The mixture was heated to 60° C. for 30 min, cooled to 0° C., and basified with 20% NaOH solution. The product was extracted with CHCl3 (3×25 mL). The combined organic extracts were washed with H2O (1×30 mL), brine, dried (Na2SO4) and concentrated. The resultant residue was dissolved in CH2Cl2 (2 mL) and 3M HCl/EtOAc solution (1 mL) was added and stirred for 10 min to yield (0.025 g, 36%) 1-(3-t-butyl-1-(3-(2-(methylamino)ethyl)phenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea as a solid. 1H NMR (300 MHz, DMSO-d6): □ 9.52 (s, 1H), 8.92 (s, 1H), 8.70-8.66 (brs, 2H), 8.05 (dd, J=6.0 Hz, 4.0 Hz, 1H), 7.51-7.42 (m, 3H), 7.34-7.28 (m, 3H), 6.39 (s, 1H), 3.24-3.17 (m, 2H), 3.02-2.98 (m, 2H), 2.58-2.55 (m, 3H), 1.28 (s, 9H). MS (ESI) m/z: 460.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[C:15]([F:25])=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[I-].O[PH2]=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[C:15]([F:25])=[C:16]4[C:21](=[CH:22][C:23]=3[F:24])[N:20]=[CH:19][CH:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: O=[PH2]O
Agent: [I-]
Solvent: CC(=O)O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(5,7-difluoro-quinolin-6-yl)-ethanol (Intermediate D, 23.2 g, 63.7 mmol was dissolved in acetic acid (317 mL) and introduced in 23 microwave reactor-vials. Iodide (2.11 g×23, 191 mmol), followed by H3PO2 50% (2.28 mL×23, 464 mmol) were then added into each vial. Then they were submitted to microwave irradiations 5 min at 150° C. The combined RMs were concentrated in vacuo and the residue was diluted with water, basified by a 4 M NaOH solution and extracted with EtOAc (3×). The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was triturated with diisopropyl ether. The precipitate formed was filtered off to give a beige solid (tR 3.60 min (conditions 1), tR 9.76/10.87 min (conditions 2), MH+=345, 1H-NMR in DMSO-d6: 8.93 (d, 1H); 8.43 (d, 1H); 8.16 (d, 1H); 7.93 (s, 1H); 7.67 (d, 1H); 7.58 (m, 1H); 7.25 (d, 1H); 5.06 (q, 1H); 1.88 (d, 3H)).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: NCCc1cccc(F)c1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2cccc(F)c2)S/C1=C\c1ccc2ncncc2c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 2-(3-fluoro-phenyl)-ethylamine and DIEA to give 2-[2-(3-fluoro-phenyl)-ethylamino]-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 379 (MH+).
Reaction SMILES: C(C1C=CC=CC=1O)C.C1(O)C=CC=CC=1.C(C1C=C(O)C=CC=1)C.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH3:27].C(C1C=CC=CC=1O)C.C1C=CC=CC=1.O>C1C=CC=CC=1>[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[CH2:27]
Reactant: CCc1ccc(O)cc1
Agent: CCc1cccc(O)c1
Agent: CCc1ccccc1O
Solvent: O
Solvent: Oc1ccccc1
Solvent: c1ccccc1
Product: C=Cc1ccc(O)cc1

Procedure:
Crude ethylphenol consisting of 1.1% phenol and m- and p-cresols, 0.1% o-ethylphenol, 0.5% m-ethylphenol and 98.3% p-ethylphenol was dissolved in benzene, and dehydrogenated at a temperature of 600° C. and LHSV of 1.0 hr-1 under atmospheric pressure using the same catalyst as in Example 1, with the ethylphenol/benzene/water molar ratio being about 1/1/12. The resulting product was allowed to stand at room temperature followed by separating the water. The crude vinylphenol so separated consisted of 40.2% benzene, 6.9% phenol and m- and p-cresols, traces of o-ethylphenol, 0.2% m-ethylphenol, 24.4% p-ethylphenol, traces of o-vinylphenol, 0.2% m-vinylphenol, 22.2% p-vinylphenol, 1.6% oligomers of vinylphenols and 4.3% water with the vinylphenols/ethylphenols molar ratio being 0.93. The crude vinylphenol was directly placed in a three necked glass reactor equipped with a stirrer, and heat polymerized at 140° C. for 5 hours while removing the benzene and water to obtain a crude p-vinylphenol polymer consisting of 3.6% oligomers of vinylphenols, 12.2 % phenol and m- and p-cresols, 44.3% unreacted ethylphenols, 39.5% p-vinylphenol polymer, a trace of o-vinylphenol and 0.4% m-vinylphenol. The crude polymer was pre-heated to about 50° C., and fed into a film evaporator at a feed rate of 7 l/hr under a pressure of 8 mmHg while maintaining the heat transfer medium at a temperature of 270° C. Otherwise, the conditions were the same as in Example 1. A purified p-vinyl-phenol polymer having a weight average molecular weight of 6,524 and containing 0.3% ethylphenols and o- and m-vinylphenol and 1.5% oligomers of vinylphenols was obtained almost quantitatively.
Reaction SMILES: ClCCl.[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:12][NH:13][C:14](=[O:26])[C:15]=3[CH:16]=[C:17]3[CH:25]=[CH:24][C:23]4[O:22][CH2:21][O:20][C:19]=4[C:18]=23)=[CH:6][CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>O>[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:12][NH+:13]([O-:35])[C:14](=[O:26])[C:15]=3[CH:16]=[C:17]3[CH:25]=[CH:24][C:23]4[O:22][CH2:21][O:20][C:19]=4[C:18]=23)=[CH:6][CH:5]=1
Reactant: O=C1NCc2c1cc1ccc3c(c1c2-c1ccncc1)OCO3
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=C1c2cc3ccc4c(c3c(-c3ccncc3)c2C[NH+]1[O-])OCO4
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a dichloromethane (100 ml) solution of 8,9-dihydro-10-(4-pyridyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one (200 mg) was added MCPBA (350 mg) and stirred for 2 hours at room temperature. To the reaction mixture was added water. The organic layer was taken and washed with sodium hydrogencarbonate solution and water. The mixture was dried with magnesium sulfate and concentrated to give the entitled compound (84 mg).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.O>C(O)(C)C>[S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)([O-:16])(=[O:15])=[O:14].[CH3:1][S:2]([OH:5])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
To a 5-L 3-neck flask under an inert nitrogen atmosphere, 2.0 L of isopropanol (IPA) was charged. A slurry was prepared by adding 289 g of the amorphous free base of Compound 1 to the flask. A solution of p-toluenesulfonic acid hydrate (97.0 g) in IPA (400 mL) was then added to the slurry. The water content of the slurry supernatant was adjusted to 0.6 g/L with the addition of water (9 mL), and the slurry was stirred at 20-25° C. for 18 hours to produce a thick crystalline slurry. The slurry was filtered and washed with IPA (2×500 mL). Excess IPA was removed from the crystalline cake by blowing dry nitrogen through the cake for 24 hours. With the solids containing 3 weight-percent (wt %) of IPA, the cake was further dried by blowing humidified nitrogen through the cake at a relative humidity of 70-75% for 24 hours. The cake retained 0.9 wt % of IPA that was not further reduced by this method. Excess water was then removed from the cake by blowing dry nitrogen through the cake for 24 hours. The tosylate salt of Compound 1 was isolated as an orange powder (337 g). The isolated tosylate salt of Compound 1 was crystalline with only one observed form: a non-stoichiometric hemihydrate, as determined by x-ray powder diffraction (XPRD) and thermogravimetric (TG) analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: COc1cccc(CBr)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CC(C#N)(C#N)CCC(F)(F)F)c1OC
Yield: 83.7 %

Procedure:
Using 0.23 g of 2,3-dimethoxybenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.26 g of 2-(2,3-dimethoxybenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (40)).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1Cl)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C(O)C>[C:1]([N:4]([C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1[N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: CC(=O)N(C(C)=O)C1=C(N2CCN(c3ccc(F)cc3)CC2)C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1.66 g of 2-[N,N-diacetylamino]-3-chloro-1,4-naphthoquinone and 1.441 g of 1-(4-fluorophenyl)piperazine in 50 ml of ethanol was refluxed overnight, then evaporated in vacuo. The residue was dissolved in dichloromethane, filtered through silica gel and eluted with chloroform:methanol (100:2). The eluent was evaporated and the residue crystallized from dichloromethane/hexane, giving 800 ml of the desired product, mp 149-15°C.
Reaction SMILES: C([Li])CCC.[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])C=CC=CC=1.[CH3:32][O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([CH:42]=O)[CH2:38][CH2:37]1)=[O:35].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:32][O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([CH:42]=[CH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:38][CH2:37]1)=[O:35]
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CCC(C=O)CC1
Agent: [Cl-]
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C1CCC(C=CCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 74 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (2.5 mL) was added dropwise to a suspension of triphenyl-(3,3,3-trifluoro-propyl)-phosphonium iodide (1.90 g, 3.91 mmol) in tetrahydrofuran (14 mL) at 0° C. The mixture was stirred at 0° C. for 35 minutes, and a solution of 4-formyl-cyclohexanecarboxylic acid methyl ester (605 mg, 3.55 mmol) in tetrahydrofuran (8.0 mL) was then added dropwise to the reaction solution at −78° C. The mixture was stirred for 45 minutes, and a saturated aqueous ammonium chloride solution was then added, followed by extraction with tert-butyl methyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and washed with sodium sulfate. After concentration, the residue was purified by silica gel column chromatography to give 4-(4,4,4-trifluoro-but-1-enyl)-cyclohexanecarboxylic acid methyl ester (657 mg, 67%) as a colorless oily substance and geometric isomer mixture.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:23])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13]O.C(N(CC)CC)C.Br.[NH:32]1[CH2:36][CH2:35][C@H:34]([S:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)[CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClCCCl.O>[F:11][C:12]([F:23])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][N:32]1[CH2:36][CH2:35][C@H:34]([S:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)[CH2:33]1
Reactant: Oc1ccc(S[C@H]2CCNC2)cc1
Reactant: OCC(F)(F)CCc1ccccc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Oc1ccc(S[C@H]2CCN(CC(F)(F)CCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.8 %

Procedure:
To a −60° C. solution of oxalylchloride (0.21 ml, 2.42 mmol) in dry CH2Cl2 (4 ml) was added a solution of DMSO (0.34 ml, 4.84 mmol) in CH2Cl2 (2 ml). After 5 minutes stirring, a solution of 2,2-difluoro-4-phenyl-butan-1-ol (0.41 g, 2.2 mmol) in CH2Cl2 was added dropwise at −60° C. After 15 minutes stirring, triethylamine (1.54 ml, 11 mmol) was added dropwise, the reaction mixture was allowed to warm up to room temperature and H2O (10 ml) was added. The aqueous phase was extracted with CH2Cl2 (3×20 ml).The combined organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was dissolved in 1,2-dichloroethane (15 ml) and added to a suspension of (3S)-4-(pyrrolidin-3-ylsulfanyl)-phenol hydrobromide (0.68 g, 2.2 mmol), triethylamine (0.31 ml, 2.2 mmol) and sodium triacetoxyborohydride (0.74 g, 3.30 mmol) in 1,2-dichloroethane (45 ml). Mixture was stirred at 65° C. for 2 hours and overnight at room temperature. H2O (30 ml) was added. The aqueous phase was extracted with CH2Cl2 (3×20 ml).The combined organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 99:1 to 90:10) to provide (3S)-4-[1-(2,2-difluoro-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (0.55 g, 70%) as light yellow oil, MS: m/e=364.2(M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:32][C:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[C:36]([CH3:47])[NH:35][N:34]=1>>[CH3:32][C:33]1[C:37]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:31])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)=[C:36]([CH3:47])[NH:35][N:34]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6c(C)n[nH]c6C)ccn45)cccc32)n1

Procedure:
Prepared according to procedure of Example 68, using 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (CDCl3, δ) 9.55 (d, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.78 (d, 1H), 7.62 (s, 1H), 7.42 (t, 1H), 7.34 (t, 1H), 7.15 (d, 1H), 7.06 (t, 2H), 6.52 (d, 1H), 5.64 (s, 2H), 2.87 (s, 3H), 2.58 (s, 3 h), 2.40 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[OH-].[Na+].O.[CH2:13]([SH:16])[CH2:14][CH3:15]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([S:16][CH2:13][CH2:14][CH3:15])=[N:6][CH:7]=1
Reactant: CCCS
Reactant: Clc1cc(Br)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCSc1ncc(Br)cc1Cl
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2,3-dichloropyridine (4.47 g, 19.7 mmol) and NaOH (867 mg, 21.7 mmol) in DMSO (50 mL) was treated with sufficient H2O to effect dissolution. n-PrSH (1.96 mL, 21.7 mmol) was added, then the reaction was stirred at 20° C. for 4 h. The mixture was poured onto crushed ice (200 g) and then extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 extracts were washed with H2O (3×100 mL) and brine (3×100 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH) provided 5-bromo-3-chloro-2-propylsulfanylpyridine: m/z (ES+)=268.0 [M+H]+. Step 2: Reaction of this bromopyridine (2.73 g, 10.2 mmol) with (Z)-methyl 3-cyclopentyl-2-iodoacrylate (1.84 g, 6.6 mmol), according to the cross-coupling conditions described in Step 2 of Preparation 9, gave (E)-methyl 2-(5-chloro-6-propylsulfanylpyridin-3-yl)-3-cyclopentylacrylate: m/z (ES+)=340.1 [M+H]+. Step 3: Saponification of this ester (770 mg, 2.3 mmol), using a similar protocol to that described by Step 2 of Preparation 3, furnished the title compound: δH (CDCl3): 1.05 (t, 3H), 1.40-1.85 (m, 10H), 2.45-2.60 (m, 1H), 3.20 (t, 2H), 7.15 (d, 1H), 7.40 (d, 1H), 8.15 (d, 1H).