Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 4-(difluoromethoxy)benzaldehyde (10 g, 58 mmol) and (S)-2-methylpropane-2-sulfinamide (13 g, 105 mmol) in THF (50 mL) was added Ti(OEt)4 (43 mL, 209 mmol) and the reaction was stirred at RT overnight. The mixture was poured into brine (400 mL) and stirred for 10 min, filtered, and the filtered solids rinsed with additional THF/EtOAc. The organic layer was separated, and the aqueous layer extracted with additional EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was dry loaded and passed through a SiO2 plug eluting with a EtOAc/hexane gradient (10 to 15% EtOAc) to afford 16 g (100%) of (S,E)-N-(4-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (378) as pale yellow liquid.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:26]C(=O)C)([CH2:24][CH3:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)(=O)C.C(OC(=O)C(CC)C(OCC)=O)C>>[NH2:26][C:6]([CH2:24][CH3:25])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[CH2:5][OH:4]
Reactant: CCCCCCCC(=O)c1ccc(CCC(CC)(COC(C)=O)NC(C)=O)cc1
Agent: CCOC(=O)C(CC)C(=O)OCC
Product: CCCCCCCCc1ccc(CCC(N)(CC)CO)cc1

Procedure:
In working example 77, 2-acetamido-2-ethyl-4-(4-octanoylphenyl)butyl acetate obtained by using ethylmalonic acid diethyl ester instead of propylmalonic acid diethyl ester, is subjected to reduction in the same manner as working example 2 (7) and then hydrolysis in the same manner as working example 78 to give the subject compound.
Reaction SMILES: [Si]([O:8][C:9]([C:18]1[CH:55]=[CH:54][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:52])[NH:39][C@@H:40]4[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41]4)=[C:33]([F:53])[CH:32]=3)=[O:30])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])(C(C)(C)C)(C)C.[F-].[K+]>O1CCCC1>[F:53][C:33]1[CH:32]=[C:31]([C:29]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:54]=[CH:55][C:18]([C:9]([OH:8])([C:10]([F:13])([F:11])[F:12])[C:14]([F:15])([F:16])[F:17])=[CH:19][CH:20]=3)[CH2:24][CH2:25]2)=[O:30])[CH:36]=[CH:35][C:34]=1[NH:37][C:38](=[O:52])[NH:39][C@@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)C1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)C1
Temperature: 80 °C
Yield: 81.6 %

Procedure:
To a stirring solution of (R)-tert-butyl 3-(3-(4-(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)piperazine-1-carbonyl)-2-fluorophenyl)ureido)-pyrrolidine-1-carboxylate (0.372 mmol, 300 mg) in tetrahydrofuran (10 mL) was added potassium fluoride (50% weight on celite) (3.72 mmol, 433 mg). The resulting suspension was heated to 80° C. for 16 hours. The reaction mixture was filtered through celite and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (eluting with dichloromethane—5% methanol/95% dichloromethane gradient) to afford the title compound (210 mg). MS (ESI) m/z 692.3 [M+H]+
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[Br:14][C:15]1[CH:24]=[CH:23][C:18]2[C:19](=O)[CH2:20][O:21][C:17]=2[CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:24]=[CH:23][C:18]2[C:19]([CH2:5][C:3]#[N:4])=[CH:20][O:21][C:17]=2[CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1COc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1coc2cc(Br)ccc12
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.7 g, 0.0173 mol) was washed with hexanes then suspended in THF (8 mL). Diethyl cyanomethylphosphonate (3.07 g, 0.0173 mol) was added dropwise and stirred 10 minutes to give clear yellow solution. A solution of 11-5 (3.38 g, 0.0158 mol) in THF (20 mL) was added dropwise, the solution stirred for 0.5 hour, then heated to reflux for 0.5 hour. A solution of 6N HCL (3.4 mL) was added and the THF was removed under vacuum. The concentrated solution was diluted with Et2O and washed with 4×30 mL 6N HCl, the ether layer was dried (MgSO4), filtered and evaporated. The residue was chromatographed (20% EtOAc/Hexanes) to give 11-6 as an orange solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl[C:11]([O:13][CH3:14])=[O:12]>C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C@@H:3]([CH3:9])[C@H:4]([NH:5][C:11]([O:13][CH3:14])=[O:12])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)Cl
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
A solution of allo-O-methyl-L-threonine (519 mg, 3.90 mmol) in saturated sodium bicarbonate solution (47.6 mL) was treated dropwise with methyl chloroformate (453 μL, 553 mg, 5.85 mmol) followed by stirring at RT for 18 h. The mixture was extracted with ether and the aqueous phase was cooled to 0° C. and acidified to pH 2-3 by addition of concentrated hydrochloric acid solution. The mixture was extracted with ethyl acetate (3×). The combined organic layers were extracted with saturated sodium chloride solution and dried (Na2SO4). Concentration in vacuo afforded the title compound (640 mg, 86%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.48 (d, J=7.8 Hz, 1H), 4.52 (d, J=4.7 Hz, 1H), 3.71 (s, 3H), 3.39 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]3[CH2:18][C@@H:17]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[O:11])[N:7]([CH2:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:6]=2[CH:44]=1.C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]3[CH2:18][C@@H:17]([C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[O:20])[CH2:16][NH:15][CH2:14]3)=[O:11])[N:7]([CH2:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:6]=2[CH:44]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl (3S,5R)-3-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to give the object product (567 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:13]1[CH2:12][C:11]2([CH2:24][CH2:25][N:8]([C:6](=[O:7])[C:5]3[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:14]1=[O:23])(=[O:37])[CH3:36]
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CC(=O)Cl
Product: CC(=O)N1CC2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N(c2ccccc2C)C1=O

Procedure:
The title compound, MS: m/e=528.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and acetyl chloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>O>[CH3:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[C:36]1[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(C)c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of methyl 2-trifluoromethanesulfonyloxy-3-methylbenzoate (900 g, in toluene), potassium carbonate (629.6 g), tetrahydrofuran (2700 mL) and deionized water (5400 mL) under nitrogen is added tetrakis (triphenylphosphine)palladium (0) (104.6 g). To this is added the above solution of p-trifluoromethylphenylboronic acid and the mixture is heated at reflux for 2 days. The reaction mixture is filtered and evaporated to dryness. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is separated and evaporated to dryness. The residue is taken up in heptane-ethyl acetate (9:1), the mixture is filtered and the filtrate is evaporated to dryness to give methyl 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylate as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[N:22]=[C:21]([NH2:23])[S:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:17][C:18]1[N:22]=[C:21]([NH:23][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])[CH:5]=[CH:4][N:3]=2)[S:20][N:19]=1
Reactant: N#Cc1ccccc1Oc1ccnc(Cl)c1
Reactant: Cc1nsc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nsc(Nc2cc(Oc3ccccc3C#N)ccn2)n1
Yield: 2.5 %

Procedure:
Using the method of Example 3, Step B, 2-(2-chloropyridin-4-yloxy)benzonitrile (0.330 g, 1.43 mmol), 3-methyl-1,2,4-thiadiazol-5-amine (3.26 mL, 1.30 mmol), potassium phosphate (0.304 g, 1.43 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0298 g, 0.0326 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0207 g, 0.0358 mmol) were reacted in toluene (5 mL) and water (1.5 mL) to afford 2-(2-(3-methyl-1,2,4-thiadiazol-5-ylamino)pyridin-4-yloxy)benzonitrile (10 mg) as off white solid. 1H NMR (CDCl3) δ 8.35 (d, 1H), 7.76 (dd, 1H), 7.66 (dt, 1H), 7.37 (dt, 1H), 7.19 (d, 1H), 6.63 (dd, 1H), 6.45 (d, 1H), 2.49 (s, 3H); Mass spectrum (esi) m/z=310 (100) (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][C:4]=1[O:12][CH3:13])#[N:2].[OH:14][CH2:15][C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:18](O)=[O:19])[NH2:17].[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[O:11]=[C:10]1[NH:17][C:16]([CH2:18][OH:19])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15](=[O:14])[N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:12][CH3:13])[CH:5]=1
Reactant: NC(CO)(C(=O)O)c1ccccc1
Reactant: COc1cc(N=C=O)ccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(N2C(=O)NC(CO)(c3ccccc3)C2=O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 384 mg of 4-cyano-3-methoxyphenyl isocyanate (prepared according to WO 2007/137874) in 8 mL dioxane is added to a solution of 200 mg of 2-hydroxymethyl-2-phenylglycine (prepared according to literature procedure) in an aqueous solution of 1.8 mL 1N sodium hydroxide in 2 mL of water. The mixture is stirred at room temperature overnight, acidified by adding 3 mL 12N HCl and heated at 110° C. for 2 hours. The solution is then treated with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried over sulfate magnesium, filtered, evaporated and purified over silica gel while eluting with 60/40 heptane/ethyl acetate mixture to give the expected product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(=O)(O)[O-].[Na+].[OH:19][C:20]1[CH:21]=[C:22]([S:26][CH2:27][C:28]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:29]=2[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH3:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:28]([CH2:27][S:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:3][C:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH:21]=2)[C:29]=1[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1cccc(CSc2cccc(O)c2)c1C(=O)OCC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc(CSc2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)OCC(C)C
Reaction time: 16 h

Procedure:
The free base of 2-(chloromethyl)quinoline hydrochloride (148 mg, 0.69 mmol) is prepard by partioning the material between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. This material is then dissolved with isobutyl 2-[3-(hydroxy)-phenylsulfanylmethyl]-6-methyl-benzoate (220 mg, 0.67 mmol, example 83) in DMF (2 mL) at 0° C. and sodium hydride (60%, 27 mg 0.67 mmol) is added. The reaction is allowed to stir 16 h and is then partitioned between ethyl acetate and water. The organic phase is washed with water (3×), dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 10% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H), 8.08 (d, 1H), 7.83 (d, 1H), 7.74 (t, 1H), 7.63 (d, 1H), 7.55 (t, 1H), 7.18–7.07 (m, 4H), 6.99 (d, 1H), 6.89 (d, 1H), 6.82 (dd, 1H), 5.33 (s, 2H), 4.18 (s, 2H), 4.10 (d, 2H), 2.36 (s, 3H), 2.07–2.01 (m, 1H), 0.98 (d, 6H); MS (ESI) 472 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:23]=[C:22]([CH3:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:25][CH3:26])[CH:20]=3)[N:15]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:26][O:25][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH:23]=[C:22]2[CH3:24]
Reactant: COc1ccc2nc(N[C@H]3CCN(Cc4ccccc4)C3)cc(C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(N[C@H]3CCNC3)cc(C)c2c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
To a mixture of 2-chloro-6-methoxy-4-methylquinoline (1.1 g), Pd2(dba)3 (0.242 g), (±)-BINAP (0.495 g), (S)-1-benzyl-3-aminopyrrolidine (1.1 g), and 1,4-dioxane (88 mL) was added sodium t-butoxide (1.65 g) under nitrogen atmosphere, and the mixture was stirred at 65° C. for 3 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=10:1) to obtain (S)-N-(1-benzylpyrrolidin-3-yl)-6-methoxy-4-methylquinolin-2-amine (1.1 g). (2) (S)-N-(1-Benzylpyrrolidin-3-yl)-6-methoxy-4-methylquinolin-2-amine (1.1 g) was dissolved in methanol (25 mL), followed by addition of 20% Pd(OH)2/C (0.20 g), and the mixture was stirred at 45° C. under hydrogen atmosphere for 5 h. The catalyst was removed by Celite filtration, and then the filtrate was concentrated under reduced pressure to obtain (S)-6-methoxy-4-methyl-N-(pyrrolidin-3-yl)quinolin-2-amine (0.81 g).
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:4][CH2:5][C@H:6]2[C@H:13]([OH:14])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]1[CH2:22][O:21][C:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:4][CH2:5][C@H:6]2[C@H:13]([O:14][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1
Reactant: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2O)OCCO1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC2CCCCO2)OCCO1

Procedure:
A solution of (1S,5R,6R,7R)-6-(3,3-ethylenedioxy-octyl)-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-one (6a) (4.70 g) in dichloromethane (200 ml) was cooled on ice and dihydropyran (2.41 g) and p-toluenesulfonic acid (0.23 g) were added thereto and the resultant mixture was stirred for 1,5 hours. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (59).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([OH:19])(=[O:18])[CH:12]=[CH:13][CH2:14][C:15]([OH:17])=[O:16]>OS(O)(=O)=O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH:13]([CH2:12][C:11]([OH:19])=[O:18])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: Sc1nc2ccccc2s1
Reactant: O=C(O)C=CCC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)CC(CC(=O)O)Sc1nc2ccccc2s1
Yield: 87 %

Procedure:
16.8 g of 2-mercaptobenzothiazole are suspended in 50 ml of 70% H2SO4, and 13.7 g of glutaconic acid are added at 45°-50° in the course of 30 minutes, with stirring. The reaction mixture is stirred for a further 1.5 hours at 45°-50° and the product is isolated as described in Example 5. 26 g (88% of theory) of 3-(benzothiazol-2-ylthio)-glutaric acid, of melting point 153°-154°, are obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:25][C:26](O)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:25][C:26]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCCC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCC1)C2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine 0.43 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.49 g, and stirred at 0° C. for 45 min. Cyclopentyl acetic acid 0.36 ml and WSC 0.59 g were added therein, then the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with 10% sodium hydroxide and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-cyclopentylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.19 g and refluxed for 1.5 hours. The reaction mixture was cooled, then added ether, water and 10% aqueous sodium hydroxide thereto, and filtered the insoluble material. The filtrate was extracted with ether and dried by anhydrous sodium sulfate. After filtering the drying agent, a residue obtained by concentrating the filtrate in vacuo was purified by means of flash column chromatography (Merck, silica gel 60: 230-600 mesh, chloroform-chloroform:acetone=20:1) to obtain the product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH:14]1N=CN(C(N2C=NC=C2)=O)C=1.CO>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CCC(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CCc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
In a 100 mL round bottom flask, 3-(4-(methylthio)phenyl)propanoic acid (1.00 g, 5.10 mmol) was dissolved in DMF (17 mL) under N2(g). CDI (1.24 g, 7.65 mmol) was then added to the reaction mixture and the resulting mixture was allowed to stir at room temperature for ˜45 min. MeOH (6 mL) was then added in dropwise fashion to the reaction. The reaction was allowed to stir for an additional 1 h, after which time it was extracted with EtOAc (3×50 mL) and brine (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4(s), filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution mixture: 10% EtOAc in Hexanes to 0100% EtOAc) to give the title compound (0.771 g, 72%).
Reaction SMILES: CN1CCC(=[O:8])CC1.ClC1C=CC=CC=1C=O.[OH-].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[C:28]1[CH2:33][C:32](=[CH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[CH2:31][N:30]([CH3:42])[C:29]1=O>C(O)C>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[C:28]1[C:33](=[O:8])[C:32](=[CH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[CH2:31][N:30]([CH3:42])[CH2:29]1
Reactant: CN1CC(=Cc2ccccc2Cl)CC(=Cc2ccccc2Cl)C1=O
Reactant: CN1CCC(=O)CC1
Agent: O=Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CC(=Cc2ccccc2Cl)C(=O)C(=Cc2ccccc2Cl)C1
Reaction time: 0.03 h

Procedure:
A stirred solution of 11.3 g. (0.1 mole) of 1-methyl-4-piperidinone and 28 g. (0.2 mole) of o-chlorobenzaldehyde in 220 ml. of ethanol is treated with 11 g. (0.17 mole) of 85% KOH. The temperature rises to 34° and after approximately 2 minutes a solid begins to separate. After stirring for 30 minutes the yellow solid is filtered, washed with water, and air-dried to yield 31.6 g. of yellow, 3,5-bis[(2-chlorophenyl)methylene]-1-methyl-piperidinone; m.p. 148°-150°.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@H:3]([OH:20])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[C:24](=[O:25])([O:20][C@H:3]([CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1)[C:2]([CH3:22])([CH3:21])[CH3:1])[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](O)Cn1nccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)[C@@H](Cn1nccc1-c1ccc(C(F)(F)F)cc1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 90.7 %

Procedure:
To 562.0 mg (1.80 mmol) of (2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol in 18 mL of 1,2-dichloroethane at room temperature was added 544.1 mg (2.70 mmol) of 4-nitrophenyl chloroformate. Then, 291.1 μL (3.60 mmol) of pyridine was added, and the solution was heated at reflux for 16 h. Saturated aqueous sodium bicarbonate was added, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (3:7) to give 779.7 mg (91%) of 4-nitrophenyl (1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl carbonate. Rf=0.21 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.29 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 7.63 (s, 1H), 7.33 (d, J=9 Hz, 2H), 6.52 (s, 1H), 4.71 (d, J=9 Hz, 1H), 4.64 (d, J=15 Hz, 1H), 4.33 (dd, J=15 Hz, J=10 Hz, 1H), 0.89 (s, 9H); ES-LCMS m/z 478 (M+H).