Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:37])[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:25]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)=[CH:24][CH:23]=[CH:22][C:21]=3[CH:33]3[CH2:35][CH2:34]3)=[C:14]([CH3:36])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.O1CCCC1.CO.[OH-].[Li+]>O>[CH:33]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([N:26]3[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]3)[C:20]=2[CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:37])[N:8]=3)=[CH:13][C:14]=2[CH3:36])[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1c(C)c(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2nn(C)c(C(=O)O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Yield: 98.3 %

Procedure:
At room temperature, the mixture of 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester (Present compound 48) 1.4 g, tetrahydrofuran 40 ml, methanol 10 ml, water 10 ml and lithium hydroxide 0.2 g was stirred for twelve hours. The resulting mixture was concentrated under reduced pressure and was acidified with 10% hydrochloric acid solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure to give 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid 1.3 g.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:34][O:35][C:36]1[S:37][C:38]([CH3:44])=[CH:39][C:40]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:40]3[CH:39]=[C:38]([CH3:44])[S:37][C:36]=3[O:35][CH3:34])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1sc(C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1sc(C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Intermediate 21, 13 mg; 0.0219 mmol) was treated with (2-methoxy-5-methyl-3-thienyl)boronic acid (Step C, 10.4 mg; 0.0657 mmol), tetrakis(triphenylphosphine)palladium (0) (3 mg; 0.0026 mmol), and sodium carbonate (20 mg) as described in Example 291 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a yellow glass. LCMS=598.2 (M+1)+. 1H NMR (benzene-d6, 500 MHz): δ 7.75 (s, 1 H), 7.57 (s, 1 H), 7.31-29 (m, 1H), 7.24 (s, 2 H), 7.12-7.10 (m, 1 H), 6.14 (s, 1 H), 4.96 (d, J=16 Hz, 1 H), 4.57 (d, J=8 Hz, 1 H), 3.99 (d, J=15.8 Hz, 1 H), 3.30 (s, 3 H), 2.95-2.92 (m, 1 H), 2.05 (s, 3 H), −0.28 (d, J=6.7 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH:19]=O.[BH4-].[Na+].O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH2:19][NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Commercially available 3,4-dimethoxy-phenyl-amine (1.74 g, 11.3 mmoles) and 3,5-dichloro-pyridine-4-carbaldehyde (2.0 g, 11.3 mmoles) were dissolved in toluene (40 mL) under nitrogen atmosphere. Molecular sieves (4A, 1 g) were added, and the mixture was heated to reflux. Reaction monitoring was performed by TLC analysis (petroleum ether/AcOEt 7/3): formation of the imine intermediate was completed after 3 hours. Molecular sieves were removed by filtration and the solvent was evaporated. The residue was dissolved in ethanol (99%, 40 mL). The solution was cooled to 0° C. and NaBH4 (559 mg, 14.7 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours, then water was added (50 mL), and the mixture was extracted AcOEt (3×60 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3). The title compound was obtained as a yellow solid (3.04 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([CH3:11])[C:5]=1[CH3:12])[CH3:2].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:11][C:6]1[C:5]([CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc[n+]([O-])c(C)c1C
Product: CCOc1ccnc(COC(C)=O)c1C
Yield: 98.4 %

Procedure:
To 22.9 g of 4-ethoxy-2,3-dimethylpyridine-1-oxide, 55.0 g (5.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 6 hours at 90 to 100° C. The acetic anhydride was distilled off, and the resulting concentrated residue was purified on a silica gel column, to obtain 28.2 g of 2-acetoxymethyl-3-methyl-4-ethoxy-pyridine as an oily matter.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=O)[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15]>N1C=CC=CC=1>[CH2:1]([CH:3]1[C:8](=[S:15])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC1Oc2ccccc2NC1=O
Solvent: c1ccncc1
Product: CCC1Oc2ccccc2NC1=S
Yield: 532.7 %

Procedure:
0.25 g of 2-ethyl-1,4-benzoxazin-3-one is stirred in 2 ml of pyridine with 95 mg of phosphorus pentasulfide. The reaction is completed by reflux-boiling. It is poured onto water, extracted with ethyl acetate, and the organic phase is washed with brine. It is dried with magnesium sulfate and concentrated by evaporation. After column chromatography with hexane/ethyl acetate, 220 mg of product results.
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20].C([N-]C(C)C)(C)C.[Li+]>>[CH3:21][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32]([CH:15]1[CH2:16][CH2:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]1=[O:18])=[O:33])[CH3:20]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCN1CCC(C(=O)Nc2c(C(C)C)cccc2C(C)C)C1=O

Procedure:
The title compound was prepared from 1-dodecyl-2-pyrrolidinone (5.0 g, 0.019 mol), 2,6-diisopropylphenyl isocyanate (4.01 g, 0.019 mol) and lithium diisopropylamide (0.019 mol) using the procedure described in Example 1.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].CN(C)/C=[CH:10]/[C:11]1[N:12]=[CH:13][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:15][CH:16]=1.C([O-])(O)=[O:26].[Na+].CCOC(C)=O>C1COCC1.O>[CH:10]([C:11]1[N:12]=[CH:13][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:15][CH:16]=1)=[O:26]
Reactant: O=C([O-])O
Reactant: CN(C)/C=C/c1cnc(C(=O)OC(C)(C)C)cn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc(C=O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium periodate (1.67 g) was added to a solution of t-butyl 5-((E)-2-dimethylamino-vinyl)-pyrazine-2-carboxylate (645 mg) in 50% THF-water (26 mL), and the mixture was stirred at RT for 4 h. A saturated NaHCO3 solution and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated NaCl solution and dried over anhydrous MgSO4. The insoluble matter was separated by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (249 mg). 1H-NMR (CDCl3) δ (ppm): 1.68 (s, 9H), 9.25 (d, J=1.2 Hz, 1H), 9.36 (d, J=1.6 Hz, 1H), 10.2 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: Fc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
6-Bromo-N-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and 4-fluoroaniline (84 mg, 0.76 mmol) in a similar manner as described in Example 13 to give 26 mg (19%) of an off-white solid. 1H-NMR (DMSO-d6): δ 811.07 (s, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.12 (dd, 1H), 6.92 (t, 2H), 6.70-6.68 (m, 2H), 5.89 (d, 1H), 4.73-4.71 (m, 1H), 2.68-2.53 (m, 2H), 1.99-1.73 (m, 4H); MS m/z (M−1) 357, 359.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.C(O[CH:14](OCC)[CH2:15][S:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)C.Cl>C(O)(C)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:14]=[C:15]2[S:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22]1
Reactant: CCOC(CSC1CCN(Cc2ccccc2)CC1)OCC
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Product: Clc1ccc2[nH]cc(SC3CCN(Cc4ccccc4)CC3)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 127.4 %

Procedure:
4-Chlorophenylhydrazine hydrochloride (1 g) and 4-[(2,2-diethoxyethyl)thio]-1-(phenylmethyl)piperidine (1.8 g, prepared in Example 13) in isopropanol (20 ml) are stirred at room temperature under nitrogen until a solution is formed. After cooling to 0° C., the solution is saturated with gaseous hydrogen chloride. After 4 hours, the precipitate is filtered off, taken up in sodium hydroxide and extracted with ether and then with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residual oil is taken up in a solution of hydrogen chloride in ether to give 5-chloro-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indole hydrochloride (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[NH:8][C:7]([C:3]4[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:6][NH:5][N:4]=4)=[N:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4NS(C)(=O)=O)[nH]c3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-methanesulfonamide was prepared using 2-(4-Amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and Methansulfonylchloride (30 μl, 0.39 mmol). The title compound was obtained as off-white powder (30 mg, 24%).
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH3:17])(=[O:3])[CH3:2].C(O)(=O)C.Br.C([O-])(O)=O.[Na+]>O>[C:1]([C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2nc(C)c(C(C)=O)[nH]2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1[nH]c(-c2ccc(O)cc2)nc1C
Yield: 98.3 %

Procedure:
A solution of 45 (1.0 g, 0.004 mol), glacial acetic acid (5.33 ml) and 48% HBr (22 ml) was heated at reflux for 3 hours with stirring. The reaction was cooled in an ice bath and the yellow precipitate was collected and combined with the residue resulting from concentration of the mother liquor. The solid was suspended in H2O (15 ml) and saturated NaHCO3 solution (41 ml) and stirred at ambient temperature overnight. The solids were collected, washed with H2O, and dried to yield 850 mg (98.4%) of 46; m.p. 300° C.
Reaction SMILES: C([O:4][CH:5]([C:7]1[N:15]=[C:14]2[C:10]([NH:11][C:12](=[O:42])[N:13]2[C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]3[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([F:32])[C:25]=3[F:33])[C:19]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:18][C:17]=2[Cl:41])=[C:9]([O:43][CH3:44])[N:8]=1)[CH3:6])(=O)C.C(OC(C1N=C(Cl)C([N+]([O-])=O)=C(OC)N=1)C)(=O)C.NC1C(Cl)=CC(OCC(OCC)=O)=C(OCC2C(OC)=CC=C(F)C=2F)C=1.NC1C(Cl)=CC(OCC(OCC)=O)=C(OCC2C(OC)=CC=CC=2F)C=1.[O-]CC.[Na+].Cl>C(O)C.O1CCCC1>[Cl:41][C:17]1[CH:18]=[C:19]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:20]([O:22][CH2:23][C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]([F:32])[C:25]=2[F:33])=[CH:21][C:16]=1[N:13]1[C:12](=[O:42])[NH:11][C:10]2[C:14]1=[N:15][C:7]([CH:5]([OH:4])[CH3:6])=[N:8][C:9]=2[O:43][CH3:44]
Reactant: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(C)OC(C)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: CCOC(=O)COc1cc(Cl)c(N)cc1OCc1c(F)cccc1OC
Agent: CCOC(=O)COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(C)O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 2-(1-acetyloxyethyl)-9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (0.33 g), which was prepared in a similar manner to that described in Example 171 using 2-(1-acetyloxyethyl)-4-chloro-6-methoxy-5-nitropyrimidine and ethyl 2-[4-amino-5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)phenoxy]acetate instead of 4-chloro-6-methoxy-2-methoxymethyl-5-nitropyrimidine and ethyl 2-[4-amino-5-chloro-2-(2-fluoro-6-methoxy-benzyloxy)phenoxy]acetate, respectively, in ethanol (2 mL)-tetrahydrofuran (3 mL) was added sodium ethoxide (20% ethanol solution, 0.5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/9) to give the title compound (0.17 g)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([C:19](OCC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([CH2:19][OH:20])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (17.94 g, 51.85 mmol, e.g. which can optionally be as prepared in Intermediate 4) in dichloromethane (150 ml) was cooled to 0° C. under an atmosphere of nitrogen, and was treated with di-iso-butylaluminum hydride (100 ml of a 1.5 M solution in toluene, 150 mmol) added dropwise over 30 minutes, keeping the temperature steady at 0° C. The reaction was stirred at 0° C. for a further 30 minutes after completion of the addition. The reaction was quenched by the dropwise addition of saturated aqueous potassium sodium tartrate solution (120 ml), keeping the temperature below 5° C. The resulting mixture was diluted with ethyl acetate (300 ml) and the whole filtered through a pad of Celite, to form two layers. During this filtration the sinter funnel imploded. Material spilt on the fumehood floor was soaked up and recovered as much as possible. The organic layer was separated and dried (MgSO4), the drying agent was filtered off, and the filtrate evaporated to give a first batch of product. The aqueous layer and the celite were extracted with a larger amount of ethyl acetate to give a second batch of product after evaporation. The two batches of product were combined to give the title compound (14 g) as an off-white waxy solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][C:9]=2[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].CN(C=O)C.Cl[CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[CH:37][N:36]=1>O>[CH3:41][C:40]1[C:35]([CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[O:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:6][CH:7]=2)=[N:36][CH:37]=[C:38]([CH3:42])[CH:39]=1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Reactant: Cc1cnc(CCl)c(C)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(COc2ccc(C3=C(c4ccc(C#N)cc4)OC(C)(C)C3=O)cc2)c(C)c1
Temperature: 80 °C

Procedure:
4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.5 g, 4.9 mmol) was added to a mixture of carbonate (6.3 g, 19.6 mmol) and DMF (100 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3,5-dimethylpyridine (1.14 g, 7.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 22% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl) (0.70 g, 35%) as yellow solid. 1H NMR, 200 MHz, CDCl3: δ 7.45-6.8 (Ar, 11H), 4.9 (d, 1H), 4.6 (d, 1H), 3.75 (s, 3H), 3.2 (d, 2H) 3.1 (q, 1H), 2.5 (q, 1H) 0.95 (t, 6H). MS: [M+H]+: m/z=425.2. HPLC: (96.3%, Condition-A).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1.C(N(CC)CC)C.[C:21](OC=C)(=[O:23])[CH3:22].C(Cl)(Cl)Cl>COC(C)(C)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13][C:21](=[O:23])[CH3:22])[CH:10]=[CH:9]1
Reactant: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Reactant: C=COC(C)=O
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 44.9 %

Procedure:
Cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (1.091 g, 5.92 mmol, prepared in example 6) is dissolved in tert-butyl methyl ether (8.6 mL, anhydrous). To the solution is added triethylamine (0.59 mL, 4.2 mmol), pancreatin (3.2 g, available from Sigma Chemical Company), and vinyl acetate (2.7 mL, 29 mmol). The reaction is allowed to stir for 7 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum. The products are separated by chromatography on silica gel (10% to 20% ethyl acetate/hexane) to provide (-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (B, 601 mg, 45% yield, 91% ee) [α]D =-19.8°,(c=1.00, chloroform) as a yellow oil and (-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (A, 560 mg, 50% yield, 94% ee), [α]D =-9.9°, (c=1.06, chloroform) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](N)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N(OCCC(C)C)=O>C1COCC1>[F:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(F)c2s1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Fc1cccc2ncsc12
Temperature: 25 °C

Procedure:
To a solution of 7-fluorobenzo[d]thiazol-2-amine 25C (1 g, 5.95 mmol) in THF (10 mL) was added isoamyl nitrite (1.51 g, 12.9 mmol) at room temperature. After refluxing for 3 hr, the reaction mixture was then allowed to cool to room temperature and poured into ice water (50 mL), and then extracted with EtOAc. The organic extract was washed with water and brine, dried and evaporated. The residue was chromatographed on silica gel to get the 7-fluorobenzo[d]thiazole as colorless oil. LC-MS: m/z 154.2 (M+H)+
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:23](OCC)=[O:24].[OH-].[Na+]>C(O)C.O>[O:24]=[C:23]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1][CH:8]([C:9]([OH:11])=[O:10])[CH2:14]1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CC(C(=O)O)Cc2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
100 mL (0.425 mol) of diethyl benzylmalonate were added dropwise to a stirred suspension of 28 g (0.7 mol) of NaH (60% dispersion in mineral oil) in 550 mL of absolute ethanol at room temperature. The reaction mixture was refluxed 2 h, then cooled to 50° C. and 47.1 mL (0.425 mol) of ethyl bromoacetate were added dropwise. The reaction mixture was refluxed 2 h, then quenched with 150 mL of water; a solution of 140 g (3.5 mol) of NaOH in 400 mL of water was added and the mixture was heated to reflux for 1 h. EtOH was removed in vacuo, the aqueous solution was washed with Et2O and then carefully brought to acidic pH with 350 mL of 37% HCl and extracted with AcOEt. The solvent was removed in vacuo and the resulting residue was heated to 180° C. for 30 min. After cooling to room temperature, 100 mL of 95% H2SO4 were added and the reaction mixture stirred for 2 h, then it was poured onto 500 g of crushed ice and extracted with Et2O. The organic phase was dried and the solvent removed in vacuo. The resulting residue was taken up in Et2O, washed with 40% NaOH solution then brought to acidic pH with 37% HCl and extracted with Et2O. The organic phase was dried and the solvent removed in vacuo. The resulting solid residue was triturated with Et2O, filtered and dried yielding 15 g of the title compound, used without further purification. m.p.=146-147° C. IR (cm−1): 2924, 1692, 1600; NMR (300 MHz, DMSO, δ ppm): 12.6-12.5 (bs, 1H); 7.9 (d, 1H); 7.6-7.5 (m, 1H); 7.4-7.3 (m, 2H); 3.3-3.1 (m, 3H); 2.7 (m, 2H). MS (m/z): 191.1 (MH+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[CH2:20][CH:19]3[CH:15]([CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([OH:28])[CH2:13]2)(=O)=O)=CC=1.[C-:36]#[N:37].[K+]>>[C:36]([CH2:11][CH:12]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[C:14]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([OH:28])[CH2:13]1)#[N:37]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)OC(C)(C)C)CC3C(O)(c3ccccc3)C2)cc1
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2CC(CC#N)CC(O)(c3ccccc3)C2C1
Yield: 134.3 %

Procedure:
The procedure is as described for Example 13 below, starting from 1.1 g of (3aRS,4RS,6RS,7aSR)-6-p-toluenesulphonyloxymethyl-4-phenyl-2-tert-butyloxycarbonylperhydroisoindol-4-ol and 0,214 g of potassium cyanide, and gives 1.05 g of (3aRS,4RS,6RS,7aSR)-6-cyanomethyl-4-phenyl-2-tert-butyloxycarbonylperhydroisoindol-4-ol in the form of a yellow oil.