Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.FC(F)(F)[C:13]([O:15][C:16](=O)C(F)(F)F)=[O:14].O>CN(C=O)C>[CH3:16][O:15][C:13]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 mL) was treated at 0° C. with trifluoroacetic anhydride (6.1 mL, 42.6 mmol). After 30 min, the reaction was poured into water and the resulting precipitate collected by filtration, washed with water, then dried in vacuo. The solid was then dissolved in 10% aqueous NaOH (200 mL) and heated at reflux for 1 h. The reaction mixture was cooled to RT, washed with DCM and acidified with aqueous HCl. The resulting white precipitate was collected by filtration, washed with water, taken up in DCM, washed with water, dried (MgSO4) and evaporated in vacuo. The resulting material (5 g, 75%) was dissolved in methanol (80 mL) and treated with concentrated sulfuric acid (2 mL) then heated at reflux overnight. The reaction was cooled and the resulting precipitate collected, washed with water and concentrated in vacuo to give 5-fluoro-1H-indole-3-carboxylic acid methyl ester as a peach-coloured solid (4.5 g, 83%).
Reaction SMILES: O.O.O.O.O.[C:6]([CH2:9][O:10][CH:11]([CH2:15][C:16]([O-:18])=[O:17])[C:12]([O-:14])=[O:13])([OH:8])=[O:7].[Na+].[Na+].[Na+]>Cl>[C:6]([CH2:9][O:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])([OH:8])=[O:7]
Reactant: O=C([O-])CC(OCC(=O)O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)COC(CC(=O)O)C(=O)O

Procedure:
One hundred grams (0.29 mole) of trisodium carboxymethyloxysuccinate pentahydrate is placed in a flask and acidified with 90 mls of 37% hydrochloric acid while stirring and cooling the mixture in an ice bath. The reaction mixture is then evaporated to dryness in vacuo. The evaporation residue is then taken up in about 150 ml acetone and filtered to remove sodium chloride. The acetone filtrate is next evaporated to dryness to give essentially pure carboxymethyloxysuccinic acid as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.Cl.C1C[O:24]CC1>>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:24]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: O=Cc1ccc(O)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
After 2-chloro-4-hydroxy-benzonitrile (2 g, 0.013 mol) was dissolved in anhydrous THF (40 mL), DIBAL-H 1M hexane solution (21.7 mL, 0.032 mol) was added thereto at −78° C., and the mixture was stirred for 1 hour, and then stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with 1M HCl at 0° C. and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([CH:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]2C(OCC2C=CC=CC=2)=O)=[N:12][C:11]=1[C:37]([O:39][CH3:40])=[O:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:18]1[C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:11]([C:37]([O:39][CH3:40])=[O:38])[N:12]=1
Reactant: COC(=O)c1nc(C2Cc3ccccc3N2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2Cc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1

Procedure:
Benzyl 2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]indoline-1-carboxylate was dissolved in EtOAc and hydrogenated at atmospheric pressure on 10% Pd/C overnight. The crude title product was obtained after filtration and evaporation
Reaction SMILES: Cl[C:2]([F:6])=[C:3]([F:5])[F:4].C([Li])CCC.Cl[Si:13]([CH3:16])([CH3:15])[CH3:14]>>[F:4][C:3]([F:5])=[C:2]([F:6])[Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: FC(F)=C(F)Cl
Agent: [Li]CCCC
Product: C[Si](C)(C)C(F)=C(F)F

Procedure:
Chlorotrifluoroethylene of the formula (7) is treated with n-butyl lithium and then reacted with chlorotrimethylsilane of the-formula (8) to obtain 1,1,2-trifluoro-2-trimethylsilylethylene of the formula (9). Then, without isolation, this compound (9) is reacted further with a lithium compound of the formula (10) to obtain a difluoroethylene compound of the formula (11).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH3:2].C(O)[C:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1.Cl.O1CCOCC1>>[CH2:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[C:2]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NN(Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCc1ccccc1)c1cc(O)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.9 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (1.5 g, 3.3 mmol) was dissolved in benzyl alcohol (20 mL, 100 mmol) and 4 M HCl in dioxane (10 mL, 40 mmol) was added. The mixture was stirred at room temperature for 6 hours. The mixture was evaporated under reduced pressure and purified (Interchim C18 reverse phase chromatography column, 30-95% MeCN in water with 0.05% TFA). The clean fractions were combined, lyophilized and purified to yield the title compound (688 mg; purity 98%). MS m/z [M+H]+ calc'd for C27H24ClN3O6, 522.14. found 522.2.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:35][S:34](=[O:37])(=[O:36])[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:11]=3[N:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([C:7]([C:9]2[C:10]3[CH2:35][S:34](=[O:37])(=[O:36])[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:11]=3[N:12]([CH2:14][CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1nn(CC2CCNCC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]methyl}piperidine-1-carboxylate (0.1 g, 0.21 mmol) in DCM (2.0 mL) is added TFA (0.119 g, 1.05 mmol, 5 Eq) and the reaction mixture is stirred at room temperature overnight. The crude reaction mixture is washed with sodium bicarbonate then brine and dried over MgSO4. The crude residue is purified by flash chromatography to afford the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.03-7.98 (m, 2H), 7.88 (t, J=7.5 Hz, 1H), 7.73-7.70 (m, 1H), 4.78 (s, 2H), 4.47 (t, J=7.1 Hz, 2H), 3.91 (s, 2H), 3.66-3.63 (m, 6H), 2.98-2.95 (m, 2H), 2.00 (brs, 1H), 1.75-1.69 (m, 1H), 1.48-1.40 (m, 2H), 1.24-1.17 (m, 3H). MS (ESI+): 431.0. HPLC (max plot) 97.2%; Rt 2.16 min.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1>CC(O)C.C1COCC1>[OH:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:12])[F:13])=[N:9][CH:10]=1
Reactant: COCOc1cnc(C(F)(F)F)cc1C(C)=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)c1cc(C(F)(F)F)ncc1O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanone (3.2 g, 13 mmol) and 5N (40 ml) in i-PrOH/THF (1:1, 40 ml) was stirred at 45° C. overnight. The mixture was cooled, concentrated, taken up in H2O, neutralized with saturated NaHCO3, and extracted with DCM (3×). The organic layers were combined, dried over Na2SO4, and concentrated to give the title compound as a tan solid. MS (m+1): 206.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:15][CH:16]([CH2:31][CH3:32])[C:17]([NH:19][C:20]1[S:21][C:22]([C:25]([CH3:30])([CH3:29])[CH2:26][CH:27]=[CH2:28])=[N:23][N:24]=1)=[O:18].C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O.C(=O)(O)[O-].[Na+].CCN(CC)CC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:15][C@@H:16]([CH2:31][CH3:32])[C:17]([NH:19][C:20]1[S:21][C:22]([C:25]([CH3:30])([CH3:29])[CH2:26][CH:27]=[CH2:28])=[N:23][N:24]=1)=[O:18])[CH2:6][CH2:5]2
Reactant: C=CCC(C)(C)c1nnc(NC(=O)C(N)CC)s1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: C=CCC(C)(C)c1nnc(NC(=O)[C@H](CC)NC2CCc3cc(F)cc(F)c3C2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (182 mg, 1 mmol), 2-amino-N-[5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-butyramide HCl (305 mg, 1.0 mmol), NEt3 (0.14 ml), acetic acid (0.27 ml, 4 mmol), sodium sulfate in methylene chloride was stirred at room temperature for 1 hr. 95% pure sodium triacetoxy borohydride (424 mg, 2.0 mmol) was added and the mixture was stirred at rt overnight. The mixture was diluted with dilute water, saturated sodium bicarbonate to pH 7-7.5 and extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified by silica gel column chromatography using methylene chloride to 10% methanol in methylene chloride as eluent to give the title compound as ayellow oil. LC-MS, RT=2.1 min, M+1=435.3. The corresponding HCl salt was prepared as a beige solid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1.[Cl:20][C:21]1[C:22]2[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=2[S:24][C:25]=1[C:26]([NH2:28])=O>C(Cl)Cl.O>[Cl:20][C:21]1[C:22]2[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=2[S:24][C:25]=1[C:26]#[N:28]
Reactant: NC(=O)c1sc2ccccc2c1Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1sc2ccccc2c1Cl
Temperature: 25 °C
Yield: 96.3 %

Procedure:
Trifluoroacetic anhydride (11.90 g, 56.6 mmol) is added dropwise to a mixture of pyridine (5.23 g, 66.1 mmol) and 3-chlorobenzo[b]thiophene-2-carboxamide (10.0 g, 47.2 mmol) in methylene chloride at 0° C. The reaction mixture is warmed to room temperature over one hour, diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, one molar hydrochloric acid and brine, dried over MgSO4 and concentrated in vacuo to obtain a yellow solid. The solid is recrystallized from ethyl acetate and hexane to give the title product as off-white needles (8.80 g, 96%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:13][CH2:14][C@:15]1([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([NH:13][CH2:14][C@:15]2([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[N:11]=1
Reactant: Clc1cc2ncccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To 5,7-dichloro-1,6-naphthyridine (5.01 g, 25.2 mmol) and 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (5.32 g, 22.90 mmol) in NMP (20 ml) was added DIPEA (8.00 ml, 45.8 mmol) and the mixture was stirred at 100° C. for 72 h under nitrogen. The reaction was cooled and partitioned between ethyl acetate and water (200 ml each). The aqueous was washed with ethyl acetate. The combined organics were washed with water and the solvent was removed. The residue was dissolved in DCM and loaded onto a 100 g silica SNAP column and purified on the SP4 eluting with 0-50% ethyl acetate in cyclohexane over 17 CVs. Appropriate fractions were combined and the solvent was removed to give the title compound as a pale orange solid which was dried under high vacuum for 2 h (7.61 g).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:14])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=O)[CH3:2].[N:15]1C=CC=CC=1>CN(C=O)C>[CH3:2][C:1]1[C:4]2[CH:12]=[CH:11][C:10]3[NH:9][C:8](=[O:13])[CH2:7][C:6]=3[C:5]=2[O:14][N:15]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1ccc2c(c1O)CC(=O)N2
Solvent: CN(C)C=O
Product: Cc1noc2c3c(ccc12)NC(=O)C3
Yield: 33.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (0.334 g, 1.35 mmol) and pyridine (0.55 mL, 6.75 mmol) in DMF (25 mL). After work-up, the residue was purified by silica gel flash chromatography (50→75% EtOAc-hexanes) to give the title compound (0.086 g, 34%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[O:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[OH:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C:2](=[O:22])[NH:1]3)[CH:19]=[CH:18][CH:17]=1
Reactant: CCO
Reactant: OCCOc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(OCCO)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To the suspension of 2-[3-(1H-indol-4-yl)-phenoxy]-ethanol (5.4 g, 21 mmol) in t-BuOH:ethanol:acetic acid (139.5 mL:84 mL:100.5 mL) was added pyridinium tribromide (21.21 g, 63 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (90 mL) and water (3 mL). Zinc dust (21 g) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with 1N HCl (3×), water (1×), brine (2×), dried over Na2SO4, concentrated. The residue was recrystallized to give 1.82 g (32%) of 4-[3-(2-hydroxy-ethoxy)-phenyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH:22]([C:24]3[C:32]4[C:28](=[CH:29][N:30](COCC[Si](C)(C)C)[N:31]=4)[CH:27]=[C:26]([C:41]([F:44])([F:43])[F:42])[CH:25]=3)[CH3:23])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:7]2([CH2:20][O:21][CH:22]([C:24]3[CH:25]=[C:26]([C:41]([F:42])([F:44])[F:43])[CH:27]=[C:28]4[C:32]=3[NH:31][N:30]=[CH:29]4)[CH3:23])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(±)-tert-Butyl 4-phenyl-4-((1-(5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (62 mg, 0.098 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1.5 mL) and stirred at room temperature for 3 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 41 mg (quant.). 1H-NMR (CDCl3, 500 MHz) δ 10.03 (bs, 1H), 8.08 (m, 1H), 7.95 (m, 1H), 7.32-7.55 (m, 5H), 7.26 (m, 1H), 4.66 (m, 1H), 3.54 (m, 2H), 3.36 (m, 2H), 2.72-3.06 (m, 4H), 2.36 (m, 1H), 2.16 (m, 1H), 1.97 (m, 1H), 1.85 (m, 1H), 1.49 (m, 3H); 13C-NMR (CDCl3, 126 MHz) δ 143.8, 138.1, 135.2, 128.8, 127.5, 127.1, 126.8, 124.7 (q, J=272 Hz), 123.3, 119.7 (q, J=3.8 Hz), 118.1 (q, J=3.8 Hz), 79.2, 78.3, 42.8, 42.6, 41.7, 33.8, 33.7, 22.2. Mass spec.: 404.19 (MH)+. Accurate mass spec.: m/z 404.1960 [MH]+, Δ=2.5 ppm.
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:48]=[CH:47][C:41]2[N:42]([CH3:46])[C:43](=[O:45])[S:44][C:40]=2[CH:39]=1>>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:38]2[CH:48]=[CH:47][C:41]3[N:42]([CH3:46])[C:43](=[O:45])[S:44][C:40]=3[CH:39]=2)=[CH:9][CH:10]=1
Reactant: Cn1c(=O)sc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Product: Cn1c(=O)sc2cc(-c3ccc(C[C@H](NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)C(N)=O)cc3)ccc21

Procedure:
The subtitle compound was prepared by the method of Example 96 step (a) using (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate and 6-bromo-3-methylbenzo[d]thiazol-2(3H)-one.
Reaction SMILES: [ClH:1].C([N:15]1[CH2:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])([CH3:19])[CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:1].[CH:21]([O:20][C:17]1([CH3:19])[CH2:18][NH:15][CH2:16]1)([CH3:23])[CH3:22]
Reactant: CC(C)OC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC(C)OC1(C)CNC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 1-benzhydryl-3-isopropoxy-3-methylazetidine hydrochloride (1.23 g, 3.71 mmol) in ethanol (30 ml) was added 10% Palladium hydroxide on carbon (200 mg) and the mixture degassed three times with nitrogen and three times with hydrogen. The mixture was then stirred under a hydrogen atmosphere at room temperature for a 12 h. The reaction was degassed with nitrogen and filtered through celite and concentrated. The compound was used crude in subsequent chemistry.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[C:13]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)[N:12]=[C:11]2[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3c(OC)cccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [5-methoxy-1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(4′-fluorobiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionate (915 mg), which is the product of Example 77, was reacted with aqueous sodium hydroxide solution (1N, 5.00 ml) and the reaction mixture was treated to give the title compound (866 mg) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])([O-])=O.O.NN>CO.C1COCC1.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH2:9]([N:8]([CH2:7][C:6]1[CH:5]=[C:4]([CH:17]=[CH:16][CH:15]=1)[NH2:1])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCCN(CCC)Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(CCC)Cc1cccc(N)c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
The compound (595 mg) obtained in Example 33-1 was dissolved in methanol (6.0 ml) and THF (3.0 ml). The solution was added with activated carbon (59.0 mg) and iron trichloride hexahydrate (manufactured by Kanto Kagaku) (5.90 mg), followed by thermal reflux for 30 minutes. After having been cooled to room temperature, the mixture was added with hydrazine monohydrate (0.43 ml) and then subjected to thermal reflux for 24 hours. After completion of the reaction, the mixture was subjected to Celite filtration and the solvent was then distilled off. The residue was added with water and then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and then solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (343.9 mg) as a yellow oily substance.
Reaction SMILES: C(=O)([O-])OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2CC)(=O)=O)=CC=1.ICC.[CH2:31]([C@@H:33]1[N:42]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)(=[O:45])=[O:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([F:53])[CH:40]=2)[N:35]([CH2:54][CH2:55]C)[C:34]1=[O:57])[CH3:32]>>[CH2:54]([N:35]1[C:36]2[C:41](=[CH:40][C:39]([F:53])=[CH:38][CH:37]=2)[N:42]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)(=[O:45])=[O:44])[C@@H:33]([CH2:31][CH3:32])[C:34]1=[O:57])[CH3:55]
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Agent: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Solvent: CCI
Product: CC[C@H]1C(=O)N(CC)c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1,3-diethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−7° (c=0.0077 G/ML, DMSO); MS (ESI) m/z 379 ([M+H]+); MS (ESI) m/z 377 ([M−H]−); HRMS: calcd for C18H19FN2O4S, 378.1050; found (ESI+), 379.11178.