Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][N:7]=[C:8]([C:17]1[O:21][N:20]=[C:19]([CH3:22])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O>C1C=CC=CC=1>[CH3:5][O:6][N:7]=[C:8]([C:17]1[O:21][N:20]=[C:19]([CH3:22])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: CON=C(c1cc(C)no1)c1ccccc1CO
Solvent: c1ccccc1
Product: CON=C(c1cc(C)no1)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Benzene (5 ml) and thionyl chloride (0.36 g, 3.0 mmol) were added to 2-hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.62 g, 2.5 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-chloromethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.26 g, yield: 39.3%) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39]>N1C=CC=CC=1>[CH:41]([O:40][C:38]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:39])([CH3:43])[CH3:42]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reactant: CC(C)OC(=O)Cl
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(=O)OC(C)C)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
100 mg of crude 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (see Example 1(f) above) was dissolved in pyridine (4 mL, dried over 4 Å molecular sieve) and cooled on ice. Pyrrolidinopyridine (39.5 mg, 0.266 mmol) and iso-propyl chloroformate (1M in toluene, 2.66 mL, 2.66 mmol) were then added to the mixture. The mixture was stirred overnight under N2 atmosphere at 50° C. Evaporation and co-evaporation with acetonitrile to remove the solvents, followed by purification using preparative LC/MS (30% acetonitrile to pure acetonitrile, reverse phase) gave the title compound (52.6 mg, 0.114 mmol).
Reaction SMILES: [C:1]([N:8]([CH3:27])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(B(O)O)ccc2F)CC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)CC1

Procedure:
The title compound was prepared from boronic acid (247) (600 mg, 1.58 mmol) and 1-(4-bromophenyl)-2,2,2-trifluoroethanone (400 mg, 1.58 mmol) in accordance with Method A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC.Cl.[CH3:30][O:31][NH:32][CH3:33]>C(Cl)Cl>[CH3:30][O:31][N:32]([CH3:33])[C:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CNOC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (11.93 g, 55.42 mmol) and DCM (70 mL) cooled to −15° C. was added a solution of NMM (5.79 g, 57.3 mmol), ethyl carbonochloridate (12.03 g, 110.8 mmol) and DCM (50 mL) and the mixture was stirred for 15 min. Additional NMM (11.59 g, 114.5 mmol) was added followed by portion wise addition of O,N-dimethylhydroxylamine hydrochloride (10.81 g, 110.8 mmol). The reaction was stirred at RT for 18 h. The reaction was poured onto water and extracted with DCM. The organic layer was dried, filtered, and concentrated and the crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane (1:1) to afford 9.74 g (68.03%) of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (74).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Cl:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([O:16][C:7]2[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:14]([Cl:15])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH:19]=1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1C=CCCC1
Temperature: 110 °C

Procedure:
A mixture of 2.5 g methyl 4-acetylamino-5chlorosalicylate, 2 g of 3-bromocyclohexene, 2 g K2CO3 and 30 ml DMF are combined and heated at 110° C. overnight. The reaction mixture is then poured into water, filtered, dried and then extracted into ether. The ether solution is treated with charcoal, filtered and evaporated to dryness to obtain methyl 2-(cyclohexen -3-yloxy)-4-acetylamino-5-chlorobenzoate. This is then purified by recrystallization from ether/hexane. (M.P. 100°-102° C.)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][C@@H:17](O)[CH2:18][CH:19]=[CH2:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N/C(OCC)=O>C1COCC1>[CH3:20][C@H:19]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13])[CH2:18][CH:17]=[CH2:16]
Reactant: C=CC[C@@H](C)O
Reactant: COC(=O)c1ccc2ccccc2c1O
Agent: CCOC(=O)/N=N\C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1c(C(=O)OC)ccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A mixture of methyl 1-hydroxy-2-naphthoate (500 mg, 2.473 mmol), (R)-pent-4-en-2-ol (0.382 mL, 3.71 mmol), triphenylphosphine (1297 mg, 4.95 mmol) and (Z)-diethyl diazene-1,2-dicarboxylate (0.836 mL, 4.95 mmol) in THF (20 mL) was stirred at rt for 3 h. It was then concentrated and the residue was purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-methyl 1-(pent-4-en-2-yloxy)-2-naphthoate (500 mg, 74.8%) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.41-8.27 (m, 1H), 7.96-7.81 (m, 2H), 7.69-7.45 (m, 3H), 5.89 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.22-5.04 (m, 2H), 4.49-4.29 (m, 1H), 3.99 (s, 3H), 2.66-2.57 (m, 1H), 2.55-2.46 (m, 1H), 1.28 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([S:6]([Cl:9])(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N:18]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C@H](C)CCCS(O)(=O)=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N:18]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C@H:4]([CH3:5])[CH2:3][CH2:2][CH2:1][S:6]([Cl:9])(=[O:8])=[O:7]
Reactant: CCCCCS(=O)(=O)Cl
Reactant: C[C@H](CCCS(=O)(=O)O)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: C[C@H](CCCS(=O)(=O)Cl)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 88 %

Procedure:
(4R)-4-[N-[2,5-difluorophenyl][(4-chlorophenyl)sulfonyl]amino]pentylsulfonyl chloride was prepared analogous to (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride by reacting (4R)-4-[N-[2,5-difluorophenyl][(4-chlorophenyl)sulfonyl]amino]pentylsulfonic acid with phosphorus pentachloride. Yield=88%; MS (ESI) 434 (M+1).
Reaction SMILES: CC1C=CC(S([CH2:11][N:12]=[CH2:13])(=O)=O)=CC=1.[C:14]([O:24][CH3:25])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1CCCC1.[H-].[Na+]>O>[C:17]1([C:16]2[C:15]([C:14]([O:24][CH3:25])=[O:23])=[CH:11][NH:12][CH:13]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C=Cc1ccccc1
Reactant: C=NCS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c[nH]cc1-c1ccccc1
Temperature: 25 °C

Procedure:
p-Tosylmethyl isocyanide (1 g., 5 mmoles) and methyl cinnamate (0.8 g., 5 mmoles) were combined in 50 ml. of tetrahydrofuran and dissolved by stirring at room temperature. The solution was cooled to -50° C. and sodium hydride (57% dispersion in oil, 210 mg., 5 mmoles) added. After stirring for 15 minutes at -50° C., the reaction was warmed to room temperature and stirred for approximately 16 hour. Water (20 ml.) was added and the product extracted into 35 ml. ether. The ether was back-washed with 20 ml. of water, evaporated to dryness, the residue triturated with ether and methyl 4-phenylpyrrole-3-carboxylate (230 mg., m.p. 182°-185° C., m/e 201) recovered by filtration. The product was recrystallized from acetone/hexane (210 mg., m.p. 184°-187° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]1)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=C1NCCc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CN2CCc3cc(Cl)ccc3C2=O)CC1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A room temperature solution of 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (0.100 g) in N,N-dimethylformamide (3 mL) was treated with sodium hydride (95% dispersion in mineral oil, 0.028 g) and stirred for 20 minutes. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (0.184 g) was added and the reaction was stirred at 40° C. overnight. The mixture was diluted with diethyl ether and washed sequentially with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=47:3) to obtain the title compound (0.188 g) having the following physical data.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>O1CCCC1>[CH3:22][O:21][C:19](=[C:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[O:20][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(O[Si](C)(C)C)=C1CCOCC1
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (5.2 mL, 37 mmol) in tetrahydrofuran (15 mL) was added dropwise n-butyllithium (1.6 M in hexane, 21 mL, 34 mmol) at 0° C. and stirred for 20 min. A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (4.5 g, 31 mmol) and trimethylsilyl chloride (4.3 mL, 34 mmol) was added to the mixture at −40° C., then trimethylsilyl chloride (0.4 mL, 0.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The volatile components were removed by evaporation and the residual mixture was filtered through a pad of celite washing with hexane. The filtrate was evaporated to give 6.9 g (quant.) of the title compound as a clear yellow oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:5]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2.Cl[CH:23]([F:25])[F:24].Cl>O.C(O)(C)C>[Cl:3][C:4]1[N:5]([C:13]2[CH:18]=[C:17]([O:19][CH:23]([F:25])[F:24])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: FC(F)Cl
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Fc1cc(Cl)c(OC(F)F)cc1-n1nc2c(c1Cl)CCCC2
Reaction time: 1 h

Procedure:
To a solution of 36 ml of isopropanol, 21 ml of water and 6.0 ml of sodium hydroxide was added 5.28 g of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole II-2, and the resultant mixture was heated at 50° to 60° C. to give a solution. Excessive chlorodifluoromethane gas was introduced, and each 4.5 g of 50% aqueous sodium hydroxide was added 1.5 and 3 hours after starting the gas inlet and further said gas inlet was continued for additional one hour. After cooling, the reaction mixture was neutralized with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (4:1 v/v). The eluate was concentrated to give 5.24 g of the titled compound I-2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]3[CH:45]=[CH:46][C:36]([Cl:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(/C=C/c2ccc(Cl)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), (E)-4-chlorostyrylboronic acid (54.6 mg, 0.299 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-((E)-4-chlorostyryl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was diluted with dichloromethane (3.0 mL) and treated with TFA (3 mL) for 1.5 hours to remove the protecting groups. The volatiles were subsequently evaporated from the reaction mixture, and the residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with 20-60% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (42 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=15.66 Hz, 1H), 1.98-2.22 (m, 1H), 3.50-3.73 (m, 2H), 3.79-4.08 (m, 3H), 4.32-4.51 (m, 2H), 4.55 (br s, 1H), 7.17 (d, J=5.05 Hz, 1H), 7.50 (d, J=8.59 Hz, 2H), 7.55-7.73 (m, 2H), 7.92 (d, J=4.55 Hz, 3H), 8.22 (d, J=16.17 Hz, 1H), 8.53 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20ClFN4O2, 403. found, 403.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-].[Na+].Cl[CH2:15][CH2:16][OH:17]>O>[OH:17][CH2:16][CH2:15][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: OCCCl
Reactant: COc1cc(C=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCCO

Procedure:
Vanillin (15.2 g, 0.01 m), water (70 mL), and sodium hydroxide (5.0 g, 0.0125 m) are mixed and stirred for a few minutes until solution is completed. 2-Chloroethanol (9.7 g, 0.012 m) is added and the reaction mixture heated at reflux for 16 hours and then cooled. The solid product is collected by filtration, washed with water, dried, and finally recrystallized from toluene. The yield is 13.0 g (69.9% of the theoretical yield).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[CH:2].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:46][C:47]([F:77])([F:76])[C:48]1[CH:49]=[C:50]([C:58]([CH3:75])([CH3:74])[C:59]([N:61]([CH3:73])[C@H:62]2[C@H:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:65][NH:64][CH2:63]2)=[O:60])[CH:51]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:53]=1>C1COCC1>[F:76][C:47]([F:46])([F:77])[C:48]1[CH:49]=[C:50]([C:58]([CH3:74])([CH3:75])[C:59]([N:61]([C@H:62]2[C@H:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:65][N:64]([C:9]([CH:6]3[CH2:5][CH2:4][CH:3]([C:1]#[CH:2])[CH2:8][CH2:7]3)=[O:11])[CH2:63]2)[CH3:73])=[O:60])[CH:51]=[C:52]([C:54]([F:55])([F:56])[F:57])[CH:53]=1
Reactant: C#CC1CCC(C(=O)O)CC1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC1CCC(C(=O)N2C[C@@H](N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)CC1
Reaction time: 48 h
Yield: 54 %

Procedure:
To a stirred solution of 4-ethynyl-cyclohexanecarboxylic acid (commercially available) (6.5 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 13.7 mg (54%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:35])=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:16])=[CH:14][C:4]=2[O:3]1.C(O)(=O)C.[S:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][C:50](O)=[O:51])[CH2:43][CH2:42]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:36][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:35][C:50](=[O:51])[CH2:49][CH2:48][CH2:47][N:44]3[CH2:43][CH2:42][S:41][CH2:46][CH2:45]3)=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: O=C(O)CCCN1CCSCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
1,2-Dihydro-7-(2-eicosyl)-9-hydroxy-4-oxo-4H-thieno-[2,3-c][1]benzopyran is reacted with methyl magnesium bromide according to the procedure described hereinabove in Example 8 to give 1,2-dihydro-4,4-dimethyl-7-(2-eicosyl)-9-hydroxy-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with γ-thiomorpholinobutyric acid, acetate salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10]O)=[N:8][CH:9]=1)=[O:4].[ClH:13].S(Cl)([Cl:16])=O>C(OCC)(=O)C.CO>[ClH:16].[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10][Cl:13])=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnc(CO)n1C
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cnc(CCl)n1C
Reaction time: 0.5 h

Procedure:
A solution of 2-hydroxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.5 mmol) in ethyl acetate/methanol 6 ml, 1:1) was converted to the hydrochloride by usage of an excess of an etheral solution of hydrogen chloride. After evaporation, the light brown residue was treated with thionyl chloride (1.1 ml, 15 mmol) and stirred for 0.5 h. After evaporation, the title compound was obtained as brown solid (100% yield). MS: m/e=189(M+H+), mp 106-108° C.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=1>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH:17][C@@H:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=1)[OH:32]
Reactant: C#CC(C)(C)C
Reactant: Cc1ccc(C=O)cc1
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: Cc1ccc([C@@H](O)C=CC(C)(C)C)cc1
Yield: 86 %

Procedure:
The product was prepared by General procedure S using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.55 mL (1.1 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 59 μL (0.50 mmol) p-tolualdehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a white solid in 86% yield (88 mg, 0.43 mmol). m.p.: 38-40° C.; [α]D20=+52.7 (c=0.97, CHCl3, 95% ee); 1H NMR (CDCl3, 500 MHz): δ 0.95 (s, 9H), 1.83 (br s, 1H), 2.26 (s, 3H), 5.03 (d, 1H, J=6.7 Hz), 5.47 (dd, 1H, J=15.6, 6.8 Hz), 5.70 (d, 1H, J=15.6 Hz), 7.07 (d, 2H, J=7.7 Hz), and 7.17 (d, 2H, J=7.9 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 21.1, 29.4, 32.8, 75.2, 126.1, 127.2, 128.1, 137.1, 140.6, and 143.2 ppm; IR (film): 3346, 3023, 2959, 2865, 2361, 2334, 1655, 1613, 1513, 1478, 1461, 1416, 1388, 1362, and 1268 cm−1; HRMS-CI m/z 204.1509 [M+; calcd for C14H20O: 204.1514].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:28]3[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[C:31]([CH3:38])=[CH:30][CH:29]=3)=[C:18]5[CH:17]=[CH:16][C:15]4=[C:14]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:42]([CH3:49])=[CH:41][CH:40]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Br:50]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:50][C:21]1[C:22]2[C:27]3=[C:26]4[C:25](=[CH:24][CH:23]=2)[C:12]([C:5]2[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][C:14]([C:39]2[C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:42]([CH3:49])=[CH:41][CH:40]=2)=[C:15]4[CH:16]=[CH:17][C:18]3=[C:19]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH3:38])=[CH:30][CH:29]=2)[CH:20]=1
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)cc(-c5ccc(C)c6ccccc56)c5ccc2c3c45)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cc(Br)c3ccc4c(-c5ccc(C)c6ccccc56)cc(-c5ccc(C)c6ccccc56)c5ccc2c3c45)c2ccccc12
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixed solution of 1.9 g of the above-mentioned 1,3,6-tri(4-methylnaphthalene-1-yl)pyrene, 0.64 g of N-bromosuccinimide and 15 ml of dimethylformamide was stirred under nitrogen gas stream at a temperature of 60° C. for 6 hours. After cooling the mixed solution to room temperature, 50 ml of water was injected thereinto to extract therefrom with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography and thereafter vacuum dried under a temperature of 70° C. to obtain 1.5 g of 1-bromo-3,6,8-tri(4-methylnaphthalene-1-yl)pyrene as pale-yellow powder.