Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([O:17][C:18](=O)[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:20]=O)C>CC(O)=O>[C:1]([N:5]1[C:9]2[NH:10][C:18](=[O:17])[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Reactant: CCOC(=O)C(C=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2cc(-c3ccccc3)c(=O)[nH]c21
Temperature: 110 °C
Yield: 0.9 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (1.0 g, 5.2 mmol) in AcOH (5 mL) was added 3-oxo-2-phenyl-propionic acid ethyl ester (1.0 g, 5.2 mmol). The reaction was then heated to 110° C. for 18 hr, at which time the reaction was cooled to room temperature, concentrated under reduced pressure to remove HOAc, diluted with EtOAc, and quenched with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography with a Biotage® 35L column (A Dynax Corp., Charlottesville, Va.), eluting with a gradient of 5%, 10%, 20% EtOAc/hexanes. The product was collected and concentrated under reduced pressure to give the title compound (15 mg, 9% yield). LRMS m/z (APCl) 322 (M+1).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][C:12]1[O:16][C:15]([C:17]([CH:20]2[CH2:24][CH2:23][C:22]([CH3:27])([CH:25]=[CH2:26])[O:21]2)(O)[CH3:18])=[CH:14][CH:13]=1>C(OCC)C>[CH3:11][C:12]1[O:16][C:15]([CH:17]([CH:20]2[CH2:24][CH2:23][C:22]([CH3:27])([CH:25]=[CH2:26])[O:21]2)[CH3:18])=[CH:14][CH:13]=1
Reactant: C=CC1(C)CCC(C(C)(O)c2ccc(C)o2)O1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: C=CC1(C)CCC(C(C)c2ccc(C)o2)O1
Yield: 45.1 %

Procedure:
52.5 g of aluminum trichloride were progressively added to 200 ml of anhydrous diethyl ether, followed by 7.5 g of lithium-aluminum hydride. The above mixture was then cooled to 0° and 35 g of crude 1-(5-methyl-fur-2-yl)-1-(5-methyl-5-vinyl-tetrahydrofur-2-yl)-ethanol -- see letter (a) -- were then added dropwise, under vigourous stirring. 30 min. after addition of the reactants, the obtained mixture was poured onto crushed ice and the organic layer extracted with ether, washed with a saturated aqueous solution of NaHCO3, then dried and evaporated in accordance with the usual techniques, to afford 28.9 g of raw material. The thus obtained residue was finally purified by means of a column chromatography (Silicagel - hexane/ether 9:1) followed by a fractional distillation, b.p. 49°-51°/0.001 Torr, of the eluate. 14.7 g (54%) of 1-(5-methyl-fur-2-yl)-1-(5-methyl-5-vinyl-tetra-hydrofur-2-yl-)-ethane were thus isolated, as a mixture of 4 isomers according to a vapor phase chromatography analysis (CARBOWAX 20 M - 5m -- ca. 200°C.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]CC3C=CC=CC=3)=[O:16])[CH:13]=2)[C:8]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])=[C:7]1[CH2:30][CH2:31][CH3:32])=[O:5]>CO.[Pd]>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[C:8]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])=[C:7]1[CH2:30][CH2:31][CH3:32])=[O:5]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OCc3ccccc3)cc2n1C(=O)c1ccccc1Cl
Agent: [Pd]
Solvent: CO
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)O)cc2n1C(=O)c1ccccc1Cl
Yield: 75.8 %

Procedure:
A solution of benzyl 1-(2-chlorobenzoyl)-3-isobutyryl-2-propylindole-6-carboxylate (304 mg) in methanol (6 ml) was hydrogenated over 10% palladium on carbon at 20° C. for 9 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of methanol and chloroform (1:30) to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1-(2-chlorobenzoyl)-3-isobutyryl-2-propylindole-6-carboxylic acid (189 mg) as colorless crystals.
Reaction SMILES: [OH-].[K+].C([N:6]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][N:13]=2)[CH2:8][CH2:7]1)(=O)C>CO>[CH3:15][C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][NH:6]2
Reactant: CC(=O)N1CCc2c(C)ccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccnc2c1CCN2
Temperature: 55 °C

Procedure:
Potassium hydroxide (1 M, 5 mL) was added to a stirred solution of N-acetyl-4-methyl-7-azaindoline (0.78 g, 4.75 mmol) in methanol (10 mL) and the resulting mixture was heated to 55° C. for 4 h. The mixture was cooled and partitioned between methylene chloride and dilute ammonium hydroxide solution. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a yellow solid:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:36]=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[BH4-].[Na+].CCCCCC>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:36][C:35]1[CH:38]=[CH:39][C:40]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[C:33]([O:32][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCCCCCCCC=CCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCC=CCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(CNCCCCNC(=O)OC(C)(C)C)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
To a vigorously stirred solution of the amine 9 (0.071 g, 0.38 mmol, 1.2 equiv) in CH2Cl2/MeOH (3:1, 5 mL) was added a solution of the aldehyde 8a (0.20 g, 0.33 mmol) in CH2Cl2/MeOH (3:1, 5 mL), dropwise over 20 minutes. The resulting mixture was stirred at it under an atmosphere of nitrogen overnight. 1H NMR showed the reaction to be complete when there was no aldehyde peak present. The solvent was removed in vacuo and the crude imine dissolved in CH2Cl2/MeOH (1:1, 10 mL). The solution was cooled to 0° C. and NaBH4 (60 mg, 1.58 mmol) was added in 15 mg portions over 30 minutes. TLC (10% EtAc/hexane) showed the reaction to be complete after stirring overnight. The solvent was removed in vacuo and the crude oil dissolved in CH2Cl2 (50 mL) and washed with sodium carbonate (10% aq, 3×40 mL). The CH2Cl2 layer was dried over Na2CO3, filtered, the solvent removed in vacuo and the oily residue purified by flash column chromatography (4% MeOH/CHCl3) to give the product 15 as a clear oil (0.18 g, 78%), Rf=0.2 (3% MeOH/CHCl3). 1H NMR (500 MHz, CDCl3) d 6.85 (s, 1H, aryl), 6.80 (m, 2H, aryl), 5.34 (t, 4H, olefinic), 4.78 (br s, 1H, NHCO), 3.97 (q, 4H, OCH2), 3.69 (s, 2H, benzylic), 3.13 (m, 2H, CH2) 2.63 (t, 2H, CH2NH), 2.01 (m, 8H, CH2C═C), 1.80 (m, 4H, CH2CH2O), 1.55 (m, 4H), 1.49-1.12 (m, 57H, 24×CH2, 3×CH3), 0.89 (t, 6H, CH3); 13C NMR (CDCl3) d 156.17, 149.34, 148.29, 133.15, 130.11, 130.00, 120.67, 114.18, 114.08, 79.23, 69.69, 69.52, 54.12, 49.22, 40.80, 32.28, 30.16, 29.92, 29.82, 29.71, 29.67, 28.81, 28.27, 27.68, 27.60, 26.44, 23.09, 14.54; Anal. (C52H94N2O4): C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: NCCc1ccccn1
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCCc3ccccn3)nc21

Procedure:
This compound was prepared by a procedure similar to that described in Example 49 starting with 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.00 g (8.20 mmol) of 2-(2-aminoethyl)-pyridine yielding 0.082 g of pure product; mp 173°-174° C.
Reaction SMILES: [F:1][C:2]1([F:21])[C@H:14]2[C@H:10]([N:11]=C(C3C=CC=CC=3)[O:13]2)[CH2:9][C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[ClH:22]>>[ClH:22].[NH2:11][C@@H:10]1[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]([F:1])([F:21])[C@@H:14]1[OH:13]
Reactant: FC1(F)c2ccccc2C[C@H]2N=C(c3ccccc3)O[C@H]21
Agent: Cl
Product: N[C@@H]1Cc2ccccc2C(F)(F)[C@@H]1O

Procedure:
A suspension of (±)-(3aR,9aR)-9,9-difluoro-3a,4,9,9a-tetrahydro-2-phenyl-naphth[2,3-d]oxazole (50 mg) in 2.5 N aqueous hydrochloric acid was refluxed overnight. The mixture was concentrated in vacuo and the residue was crystallized from water. Benzoic acid was filtered and the filtrate was concentrated to afford the crude product which was recrystallized from methanol/ethyl acetate affording the title compound (35 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]2)[CH2:5][CH2:4]1)[CH3:2].C(=O)(O)[O-].[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCC1CCC(n2cnc(CO)c2)CC1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](n2cnc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound (1.00 g) obtained in Step 1 of this Reference Example was dissolved in toluene (10 mL). To the solution, a solution of sodium bicarbonate (1.21 g) in water (6 mL), iodine (2.19 g), and 2,2,6,6-tetramethyl-1-piperidinyloxy (75 mg) were added in this order, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, saturated aqueous sodium thiosulfate was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=2/1-1/1) to obtain the title compound (468 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHCl3, 57.3 g (0.414 mol) of K2CO3 and 260 ml of water are placed in a one liter Erlenmeyer flask, 51.8 g (0.296 mol) of p-chlorobenzoyl chloride, dissolved in 50 ml of CHCl3, are added in the course of 15 minutes, whilst cooling with a bath of iced water. The mixture is stirred overnight at ambient temperature. The organic phase is decanted, the aqueous phase is extracted with CHCl3 and the CHCl3 extract is washed with water until the pH is 6-7. It is dried over MgSO4, filtered and concentrated. The product is recrystallised from ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C.CCOC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:19][C:13]1[CH:12]=[C:11]([CH:10]([C:9](=[O:23])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:24]=2)[O:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH3:38]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C(OCC)C(=O)NCc2ccc(C#N)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(3-hydroxy-4-methoxy-phenyl)-acetamide (0.158 g) at rt in DMF (1.5 ml) were added K2CO3 (0.067 g) and ethyl bromoacetate (0.081 g). The reaction mixture was then stirred at rt under an argon atmosphere for 24 h. The mixture was diluted with EtOAc (10 ml), washed with water (10 ml+10 ml) and brine (10 ml), dried (MgSO4), filtered and concentrated (rotavapor). The product was purified by chromatography (Silicagel (20 g) using a gradient profile: cyclohexane to cyclohexane/EtOAc 45:55) to give (RS)-{5-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester (0.160 g) as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[N:19]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1NS(C)(=O)=O
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCc2ccccc2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Benzyl 4-methoxy-3-(methylsulfonamido)benzoate (1.5 g, 4.47 mmol, Compound 144 may be prepared in analogous manner as described in Scheme 19, Step 1 and 2) was dissolved in DMF (10 ml), then 4-(2-chloroethyl)morpholine (6.69 g, 44.7 mmol) and K2CO3 (1.23 g, 8.94 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction was quenched with water, and the product was extracted with EtOAc. The organic phase was washed with water (3×), then dried over Na2SO4 and evaporated under vacuum to yield 1.5 g of crude.
Reaction SMILES: [O:1]=[C:2]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:3][NH:4][C:5](OCC)=[O:6].C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:6]=[C:5]1[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2](=[O:1])[NH:3][NH:4]1
Reactant: CCOC(=O)NNC(=O)NCCCCNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NCCCCn1c(=O)[nH][nH]c1=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To ethyl 4,11-dioxo-13-phenyl-12-oxa-2,3,5,10-tetraazatridecan-1-oate (I-9a: 965 mg, 2.74 mmol) in ethanol (11.000 mL) was added K2CO3 (1514 mg, 10.95 mmol). The mixture was stirred at 65° C. for 16 hours, cooled to room temperature, filtered, and then 4N HCl in dioxane was added up to a pH of approximately 4. The resultant white solid was filtered, rinsed with some methanol, and then concentrated in vacuo. The residue was purified by silica gel chromatography (40-100% ethyl acetate/heptane) giving benzyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)butylcarbamate (I-9b: 369 mg, 44%) as a white solid. LC-MS (M+1) 307.1, t=0.78 minute. 1H NMR (400 MHz, MeOD) δ ppm 1.40-1.58 (m, 2 H) 1.58-1.74 (m, 2 H) 3.15 (t, J=6.82 Hz, 2 H) 3.51 (t, J=6.95 Hz, 2 H) 5.06 (s, 2 H) 7.21-7.42 (m, 5 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:25][C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Reactant: O=C(CCl)N1CCOCC1
Product: O=C(COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1)N1CCOCC1

Procedure:
By conducting reactions and treatments in the same manner as in Examples 1-6, using 3-(4-fluorophenyl)-1-(3-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine and 4-chloroacetylmorpholine, there was obtained 4-{3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetyl}morpholine, m.p. 141°-143° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1.[Mg].[CH2:11]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>O1CCCC1>[CH2:6]1[O:5][CH:4]([CH2:3][CH2:2][CH:28]([OH:29])[CH:25]2[CH2:24][CH2:23][CH:22]([CH:19]3[CH2:20][CH2:21][CH:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]3)[CH2:27][CH2:26]2)[O:9][CH:8]1[CH3:7]
Reactant: BrCCC1OCCCO1
Reactant: CCCCCC1CCC(C2CCC(C=O)CC2)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(C(O)CCC3OCC(C)O3)CC2)CC1
Yield: 82.8 %

Procedure:
To Grignard reagent prepared from 33.7 g (173 mmol) of 2-(2-bromoethyl)-1,3-dioxane and magnesium in 300 ml of tetrahydrofuran (THF), a solution of 40.0 g (151 mmol) of 4-(4-pentylcyclohexyl) cyclohexane carbaldehyde (10) in 200 ml of THF was added dropwise, and the resultant solution was stirred for 3 hours. The reaction solution was added into 500 ml of 1N-hydrochloric acid, and the reaction product was extracted with 300 ml of toluene. The formed organic layer was sequentially washed with a saturated aqueous solution of hydrogen sodium carbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane) to obtain 47.5 g (125 mmol) of 4-hydroxy-4-(4-(4-pentylcyclohexyl) cyclohexyl)butanal propylene acetal (11) at a yield of 82.8 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CNc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (10.0 g, 53.9 mmol) and aniline (2.34 mL, 25.7 mmol) in ethanol (200 mL) was added acetic acid (7.35 mL, 128 mmol), followed by the portion-wise addition of sodium cyanoborohydride (4.84 g, 77 mmol). The resulting mixture was stirred at rt for 2.5 hrs and concentrated to vacuo. The residue was partitioned between ethyl acetate and saturated aq. NaHCO3, and the organic layer was dried over anhydrous Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo to give a crude product that was purified by column chromatography on silica gel using a solvent gradient of 0-1% methanol in dichloromethane to give the title compound (5.7 g, 85%).
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([F:14])[CH2:11][CH2:10][CH:9]1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])C1C=CC=CC=1>CO.[Pd]>[F:14][CH:12]1[CH2:13][NH:8][CH:9]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)=CN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCC(F)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above described tert-butyl (1-benzyl-5-fluoro-1,2,3,4-tetrahydropyridin-2-yl)methylcarbamate and 10% Pd/C in MeOH was stirred at rt under a hydrogen balloon overnight. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo to provide the desired product tert-butyl (5-fluoropiperidin-2-yl)methylcarbamate in quantitative yield which was used for next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 4.56-4.47 (m, 1H), 3.34-3.17 (m, 2H), 3.02-2.95 (m, 1H), 2.67-2.60 (m, 2H), 2.19-2.14 (m, 1H), 1.81-1.76 (m, 1H), 1.59-1.45 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:25])(=[O:24])[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN(P(N(C)C)(N(C)C)=O)C.[C:37](=[O:39])=[O:38]>C1COCC1>[CH2:15]([CH:14]([C:37]([OH:39])=[O:38])[C:13]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: CCCCCCCCC=CC(=O)O
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCCCCCCCC(C(=O)O)C(=O)O
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
An oven-dried 500 mL 2-neck flask equipped with magnetic stirbar and addition funnel was charged with diisopropylamine (12.8 mL, 91.1 mmol) and THF (180 mL) under nitrogen. The solution was chilled to −25° C. in a dry ice/water/ethanol bath, and n-butyllithium (34 mL of a 2.65 M solution in hexanes, 89.0 mmol) was added dropwise via addition funnel. The solution was stirred for 30 min, after which a degassed solution of undecenoic acid (8.0 g, 43.4 mmol) in THF (44 mL) was added dropwise via addition funnel, causing the solution to become turbid. HMPA (8 mL, 43.4 mmol) was added via addition funnel. The cooling bath was then removed to allow the solution to warm to room temperature over 30 min, during which time the solution turned clear and yellow. The solution was cooled again to −25° C. A second 500 mL 2-neck flask under N2(g) purge was charged with CO2(s) (200 g, 4.5 mol) and chilled to −25° C. The enolate solution was cannula transferred onto the CO2(s) under N2(g) purge, causing the solution to become clear and colorless. The solution was stirred at −25° C. for 30 minutes then the cooling bath was removed and stirring continued at 22° C. overnight, during which time the reaction gelled. The reaction was quenched by the addition of 10% HCl (aq) (100 mL), causing two layers to form. This biphasic mixture was transferred to a reparatory funnel, and the organic layer was collected and the aqueous layer was extracted with ether (3×75 mL). The combined organic layers were then washed successively with 2M HCl (aq) (3×50 mL), water (75 mL), saturated NaCl (aq) (75 mL), and then dried over anhydrous MgSO4 (s). The solvent was removed on a rotary evaporator to yield 9.5 g of white solid. The crude product was recrystallized from heptane to yield white crystals. Yield: 9.07 g (92% yield). 1H NMR (300 MHz, DMSO-d6, 22° C.): δ (ppm) 12.62 (s, 2H, CH(COOH)2), 5.78 (ddt, JH—H3=17.0, 10.3, 6.8 Hz, 1H, CH2═CHCH2), 4.98 (ddt, JH—H3=17.2, 1.6 Hz, JH—H32.2 Hz, 1H, CH2═CHCH2), 4.93 (ddt, JH—H3=10.2, 1.2 Hz, JH—H2=2.3 Hz, 1H, CH2═CHCH2), 3.17 (t, JH—H3=7.5 Hz, 1H, CH(COOH)2), 2.00 (dt, JH—H3=7.0, 6.8 Hz, 2H, CH2═CHCH2), 1.73-1.63 (m, 2H, CH2CH(COOH)2), 1.40-1.16 (m, 10H, CH2═CHCH2(CH2)5CH2CH(COOH)2). 13C NMR (75 MHz, DMSO-d6, 22° C.): δ (ppm) 170.90, 138.82, 114.64, 51.60, 33.18, 28.69, 28.64, 28.41, 28.24, 26.79. ESI-MS: calcd. for C12H20O4Na [M+Na]+251.1, found 251.1.
Reaction SMILES: FC1C2OC(CN)CNC=2C=CC=1.[Cl:14][C:15]1[C:24]2[O:23][CH:22]([C:25]([NH2:27])=O)[CH2:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:15]1[C:24]2[O:23][CH:22]([CH2:25][NH2:27])[CH2:21][NH:20][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)C1CNc2cccc(Cl)c2O1
Agent: NCC1CNc2cccc(F)c2O1
Product: NCC1CNc2cccc(Cl)c2O1

Procedure:
This compound is obtained following the same experimental conditions as those used for the synthesis of intermediate 2b but replacing 3,4-dihydro-8-fluoro-2H-1,4-benzoxazine-2-carboxamide (4b) with 3,4-dihydro-8-chloro-2H-1,4-benzoxazine-2-carboxamide (4d). The title compound of formula (2d) is obtained.