Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:4]([C@@H:23]2[CH2:31][CH2:30][CH2:29][C:28]3[N:27]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[N:26]=[CH:25][C:24]2=3)[N:3]=1.CC1(C)C(C)(C)OB([C:50]2[CH:68]=[CH:67][C:53]([C:54]([NH:56][C:57]3[CH:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][N:58]=3)=[O:55])=[CH:52][CH:51]=2)O1.C([O-])([O-])=O.[K+].[K+].O>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>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:23]3[CH2:31][CH2:30][CH2:29][C:28]4[N:27]([S:32]([C:35]5[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=5)(=[O:33])=[O:34])[N:26]=[CH:25][C:24]3=4)[N:3]=[C:2]([C:50]3[CH:68]=[CH:67][C:53]([C:54]([NH:56][C:57]4[CH:62]=[C:61]([C:63]([F:64])([F:65])[F:66])[CH:60]=[CH:59][N:58]=4)=[O:55])=[CH:52][CH:51]=3)[C:10]=12
Reactant: COc1ccc(CNc2ncnc3c2c(Br)nn3[C@@H]2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncnc3c2c(-c2ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc2)nn3[C@@H]2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
The mixture of (R)-3-bromo-N-(2,4-dimethoxybenzyl)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.125 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (59 mg, 0.150 mmol), Pd(PPh3)2Cl2 (9.2 mg, 0.0125 mmol) and K2CO3 (43 mg, 0.313 mmol) in dioxane/H2O (3 mL/0.3 mL) was stirred for 2 h at 90° C. under nitrogen atmosphere. Then the mixture was added water and extracted with DCM. The combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. Concentrated in vacuo and the residue was purified with silica gel chromatography with PE/EA=1/1 to give (R)-4-(4-((2,4-dimethoxybenzyl)amino)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (90 mg, yield 87.2%) as yellow solid.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:17][CH:16]=[CH:15][CH2:14][N:13]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:12]1[C:29](=[O:45])[NH:30][O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O)C1C=CC=CC=1.[Li+].[OH-]>C1COCC1.O>[CH:32]([O:31][N:30]1[C:9](=[O:8])[CH:11]2[CH:12]([N:13]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH:15]=[CH:16][CH2:17]2)[C:29]1=[O:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CC=CCC3C(=O)N(OC(c4ccccc4)c4ccccc4)C(=O)C32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-benzhydryloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-3-carboxylic acid benzyl ester (430 mg, 0.69 mmoL) was dissolved in a THF:H2O (1:1, 10 mL) mixture and was then treated with LiOH (35 mg, 0.82 mmoL). This solution was stirred overnight at ambient temperature. The THF was removed in vacuo and the resulting mixture was acidified with 2 M aqueous citric acid. The product was extracted into diethyl ether, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 10% methanol in chloroform) to give 7-benzhydryloxy-1-(4-methoxybenzenesulfonyl)-2,5,5a,8a-tetrahydro-1H-pyrrolo[3,4-b]azepine-6,8-dione; MS: (M+H)+ 519.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[C:3]1[CH3:19].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([CH3:26])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:19])=[C:4]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cccc(-c2c(C)n(C)c3ccc(O)cc23)c1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(C)c1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 1,2-dimethyl-3-(3-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][OH:24])[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][O:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[O:33][C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1-c1nc2ccccc2o1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCOc1ccccc1-c1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol (1.00 g, 3.11 mmol), 2-(2-hydroxyphenyl)benzoxazole (986 mg, 4.67 mmol) and triphenylphosphine (1.22 g, 4.67 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.18 g, 4.67 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give the object compound as an oily substance. 950 mg (yield: 59.4%)
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.[F:12][C:13]([F:27])([F:26])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][N:4]1[C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:6][C:2]([O:1][CH2:14][C:13]([F:27])([F:26])[F:12])=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: COC(=O)c1cc(O)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(F)(F)F)nn1C
Temperature: 100 °C

Procedure:
A solution of 200 mg (1.28 mmol) of methyl 3-hydroxy-1-methyl-5-pyrazolecarboxylate (for preparation see above) in 10 ml of N,N-dimethylformamide is admixed with 254 mg (2.56 mmol) of 2,2,2-trifluoroethyl-4-methylbenzenesulphonate and 138 mg (2.56 mmol) of potassium carbonate and the reaction mixture is heated at 100° C. for five hours and afterstirred at room temperature for two days. The reaction mixture is added to water and extracted several times with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation in vacuo on a rotary evaporator. This gives 500 mg of methyl 1-methyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate (50% strength, 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)[C:5]([F:25])=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:28]=1[NH2:29]>>[Cl:26][C:27]1[CH:33]=[C:32]([OH:34])[C:31]([CH3:35])=[CH:30][C:28]=1[NH:29][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)[C:5]([F:25])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OCCCN2CCOCC2)cc1
Reactant: Cc1cc(N)c(Cl)cc1O
Product: Cc1cc(Nc2ncc(F)c(Nc3ccc(OCCCN4CCOCC4)cc3)n2)c(Cl)cc1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineamine with 2-chloro-4-hydroxy-5-methylaniline gave N2-(2-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine. LCMS: retn, time: 15.19 min.; purity: 94%; MS (m/e): 488 (MH+); 1H NMR (CDCl3): δ 7.89 (1H, d, J=3.3 Hz), 7.52 (1H, d, J=2.5 Hz), 7.44 (2H, d, 8.7 Hz), 6.97 (1H, d, J=2.5 Hz), 6.91 (2H, d, 9 Hz), 6.71 (1H, s), 6.64 (1H, 2.5 Hz), 4.03 (2H, t, J=6.03 Hz), 3.74 (4H, t, J=4.65 Hz), 2.60-2.43 (6H, m), 2.23 (3H, s), 1.49 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][S:17](Cl)(=[O:19])=[O:18])=[O:15])[CH3:3].[CH:21]([NH2:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCOCC>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][S:17]([NH:34][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:19])=[O:18])=[O:15])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NS(=O)(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
A solution of [[[2,6-bis(1-methylethyl)phenyl]-amino]carbonyl]sulfamoyl chloride (1.0 g, 3.1 mmoles) in 60 mL Et2O was added dropwise to a solution of benzhydrylamine (0.56 g, 3.1 mmoles) and 0.5 mL triethylamine (3.4 mmoles) in 60 mL Et2O at -15° C. (acetone/ice bath) under an atmosphere of N2. The resulting suspension was warmed to 25° C. and stirred for 16 hours. This was then partitioned between 1N HCl and EtOAc. The EtOAc layer was dried with MgSO4, filtered, and evaporated to give an off-white solid. Chromatography (SiO2, 30% EtOAc/hexanes) gave 0.49 g (34%) of the title compound as a white solid, mp 182°-185° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>C1COCC1>[N+:22]([C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[O:10][CH2:9][CH2:8][N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)([O-:24])=[O:23]
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1OCCN1CCCC1

Procedure:
To a suspension of NaH (60%, 248 mg, 6.21 mmol) in dry THF was added 2-Pyrrolidin-1-yl-ethanol (0.68 mL, 5.74 mmol). Bubbling was observed. The reaction was stirred for 5 minutes, at which time 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (0.67 mL, 4.79 mmol) was added. The solution turned red, and LCMS indicated completion of the reaction. The reaction was quenched by addition of H2O, and the mixture was extracted with EtOAc, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=O)[CH3:17])=[CH:15][C:10]=2[N:9]=[CH:8]1.[BH4-].[Na+].[CH3:21][NH2:22]>CO>[CH3:21][NH:22][CH:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)[CH3:17]
Reactant: CC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(C)c1ccc2c(c1)ncn2C1CCCCO1
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 82 (1.2 g, 4.9 mmol) in 30% methanamine in MeOH (50 mL) was stirred at RT for 15 h. To the reaction mixture was added NaBH4 (186 mg, 4.9 mmol) at RT in several portions and stirred overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (100:1) followed by reverse phase chromatography on CombiFlash® eluting with 0.01% NH4OH ammonia in water (solvent A) and MeCN (solvent B) to afford 200 mg (15%) of (±)-N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanamine (84) as yellow oil: MS (ESI) m/z=260.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[S:14][CH3:13]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ccccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Yield: 17.9 %

Procedure:
A mixture of 2-amino-4-trifluoromethylphenol (1.00 g), 2-methylsulfanylbenzoic acid (0.95 g), WSC (1.41 g), and pyridine (10 ml) was stirred with heating at 80° C. for 2.5 hours. Into the reaction mixture cooled to room temperature, 1 mol/l of hydrochloric acid was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, sequentially, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of N-(2-hydroxy-5-trifluoromethylphenyl)-2-methylsulfanyl-benzamide (Compound (1B)-515).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:6][CH2:5]1.Cl[CH2:23][O:24][CH3:25].O>CN(C)C=O>[CH3:23][O:24][CH2:25][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:6][CH2:5][C:4]1=[O:3]
Reactant: O=C1CCN(c2ccccc2F)c2ccccc2N1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN1C(=O)CCN(c2ccccc2F)c2ccccc21
Reaction time: 1 h
Yield: 237.5 %

Procedure:
Under argon atmosphere, 60% sodium hydride (0.38 g) was suspended in N,N-dimethylformamide (5 ml), a solution of 2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.89 g) in N,N-dimethylformamide (15 ml) was added dropwise over 15 minutes under ice-cooling, the mixture was stirred for one hour at same temperature. Chloromethylmethyl ether (0.89 g) was added thereto, the resultant mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, extracted with chloroform, the organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 5.26 g of the titled compound as colorless amorphous (Yield: 98.4%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:32])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH:22]([OH:29])[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[CH:15][C:14]=2[O:30][CH3:31])[N:10]=1.[C:33](OC=C)(=[O:35])[CH3:34]>C1(C)C=CC=CC=1>[C:33]([O:29][C@H:22]([CH2:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:32])=[C:14]([O:30][CH3:31])[CH:15]=1)[C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])(=[O:35])[CH3:34]
Reactant: COc1cc(CCCC(O)C(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(CCC[C@@H](OC(C)=O)C(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A 3-L flask was successively charged with isopropyl (±)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxypentanoate (33.0 g), LIP-301 [immobilized lipase derived from Pseudomonas sp, TOYOBO CO., LTD] (16.5 g), molecular sieve 4A (33 g), toluene (1650 ml) and vinyl acetate (158 ml). The mixture was stirred for 4 hours at 23° C. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with isopropyl ether, was obtained isopropyl (R)-(+)-2-acetoxy-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]pentanoate (15.9 g). Chiral analysis of this compound by HPLC showed 96% ee.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]1.[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(C(C)=O)C(C)C>[OH:20][C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5]2([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[O:9][CH2:8][CH2:7][O:6]2)[CH2:23][CH2:22]1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1C1(CCCBr)OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1C1(CCCN2CCC(O)(c3cccc(C(F)(F)F)c3)CC2)OCCO1

Procedure:
A mixture of 3.7 g of 4-bromo-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane, 2.5 g of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 1.4 g of anhydrous potassium carbonate, a catalytic amount of potassium iodide and 20 ml of methyl isobutyl ketone was heated at 80°-90° C for 2 hours. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extracts were washed with water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane as a residual oil.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[C:8]([O:12][C:13]([NH:15][CH2:16][C@@:17]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][C@H:22]2[C@@H:18]1[CH:19]=[C:20]([CH2:24][CH3:25])[CH2:21]2)=[O:14])([CH3:11])([CH3:10])[CH3:9].CI>O>[C:8]([O:12][C:13]([N:15]([CH2:16][C@@:17]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][C@H:22]2[C@@H:18]1[CH:19]=[C:20]([CH2:24][CH3:25])[CH2:21]2)[CH3:4])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C1CCOC1
Reactant: CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CNC(=O)OC(C)(C)C)CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Sodium hydride (63%, 2.48 g, 65.0 mmol) was added in small portions to a tetrahydrofuran solution (25 mL) of [(1S,5R,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (2.01 g, 6.50 mmol) and methyl iodide (4.05 mL, 65.0 mmol) with stirring at room temperature. The mixture was stirred at this temperature for 6 hours, and water (50 mL) was then added thereto while the reaction solution was cooled on ice, followed by washing with diethyl ether. The aqueous layer was made acidic using 1 M citric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (2.00 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(cc(F)cc2[N+](=O)[O-])C1=O
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 5-fluoro-1H-indole-2,3-dione (2.5 g, 15.0 mmol) in conc. H2SO4 (9 mL) was added very slowly fuming nitric acid (1.5 mL) at −5 to 0° C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured onto crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (3 g, 94.30%) which was used for the next step directly.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([O:20][CH3:21])[N:14]=3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.C(O)(=O)C.[Fe]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:8]([NH:10][C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([O:20][CH3:21])[N:14]=3)=[O:9])=[CH:23][CH:24]=1
Reactant: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc([N+](=O)[O-])cc3)sc2n1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(N)cc3)sc2n1

Procedure:
The title C compound, 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-(4-nitro-phenyl)-propionamide (12 g, 28.2 mmol) is diluted with 160 mL of ethanol and 150 mL acetic acid. 8 g of iron powder (325 mesh, 0.14 mol) is added and the mixture heated to reflux. Once reflux begins the mixture is stirred vigorously and then heating is discontinued and the mixture is allowed to cool slowly. The solvents are removed and the residue is treated with 250 mL of water. Saturated sodium bicarbonate is added carefully to bring the mixture to a pH of 8-9. The mixture is extracted with ethyl acetate, washed with brine, dried and evaporated to give an orange solid which is triturated from hexane. The resulting solid is collected by filtration to afford 2-(4-amino-phenyl)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide: 1H NMR (400 MHz, CDCl3) δ 1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.6 (t, 1H, J=7.8), 3.98 (s, 3H), 6.7 (d, 1H, J=8.8), 6.8 (d, 2H, J=8.6), 7.2 (d, 2H, J=8.6), 7.8 (d, 1H, J=8.8); LC/MS 397 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:18][C:19](Br)=[N:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24]1[C:27]2([CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[CH2:26][NH:25]1>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[S:18][C:19]([N:25]2[CH2:24][C:27]3([CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)[CH2:26]2)=[N:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1-c1nnc(Br)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(Br)cc3OCc3ccccc3)s1)C2
Temperature: 120 °C
Yield: 44.9 %

Procedure:
To a stirred suspension of 2-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-5-bromo-1,3,4-thiadiazole (252 mg, 0.567 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (179 mg, 0.681 mmol) in dioxane (2.8 mL) was added TEA (237 μL, 1.702 mmol) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to RT, diluted with water (20 mL), extracted with DCM (20 mL). The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue. The crude material was purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (150 mg, 45% yield). LC-MS: Rt 1.62 min; MS m/z 591.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.47 (m, 7H), 5.31 (s, 2H), 3.83 (s, 4H), 3.17-3.30 (m, 4H), 1.65-1.77 (m, 4H), 1.40 (s, 9H).