Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].[CH:23]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:23]([N:36]1[CH2:41][CH2:40][N:39]([C:20](=[O:21])[CH2:19][N:3]2[CH2:4][CH2:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]2=[O:1])[CH2:38][C:37]1=[O:42])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=C1CNCCN1C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.18 g, 0.6 mmol) and the product from Example 28A (0.18 g, 0.6 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.6 mmol) and diisopropylethylamine (0.5 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.28 (m, 20H), 6.91 (s, 1H), 4.26 (d, J=21.70 Hz, 2H), 4.18 (d, J=12.88 Hz, 2H), 3.69 (m, 2H), 3.35 (m, 2H), 3.13 (m, 1H), 3.07 (m, 1H), 2.71 (m, 2H), 2.69 (s, 1H); MS (ESI+) m/z 544 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1.C1(C2[O:25]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([NH:5][C:6]2[N:11]=[C:10]([S:12]([CH3:13])=[O:25])[C:9]([C:14]([NH2:16])=[O:15])=[CH:8][N:7]=2)[CH2:4][CH2:3]1
Reactant: CSc1nc(NC2(C)CC2)ncc1C(N)=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(NC2(C)CC2)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a stirring solution of 2-(1-methylcyclopropylamino)-4-(methylthio)-pyrimidine-5-carboxamide (305 mg, 1.280 mmol) in chloroform (25.6 mL) was added portionwise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (502 mg, 1.920 mmol). The resulting pale yellow solution was stirred at ambient temperature overnight. The reaction solution was concentrated under reduced pressure to give crude product as a white solid. Ethyl acetate (10 mL) was added and the slurry was stirred at room temperature for 1 h, filtered, washed with ethyl acetate, and dried in a vacuum oven for a few hours to afford 2-(1-methylcyclopropylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (242 mg, 0.952 mmol, 74.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35-8.90 (m, 2H), 7.88-8.14 (m, 1H), 7.28-7.59 (m, 1H), 2.74 (s, 3H), 1.32-1.46 (m, 3H), 0.68-0.84 (m, 2H), 0.50-0.70 (m, 2H). MS (ESI) m/z 255.0 [M+1]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.C(OC)(OC)OC.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[OH-].[Na+]>CO>[CH3:38][C:34]1[S:33][CH:37]=[C:36]([N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[NH:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[C:9]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:6][CH2:7]2)[N:35]=1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: O=Cc1nccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC(OC)OC
Product: Cc1nc(N2CCC(c3[nH]nc(-c4ccc(Cl)cc4)c3-c3ccncc3)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) in 12 mL of MeOH was added trimethyl orthoformate (2.6 g, 24.4 mmol) and 2-thiazolecarboxaldehyde (1.4 g, 12.2 mmol). The suspension was stirred at room temperature for 2 h. To this mixture was added NaCNBH (1.5 g, 24.4 mmol) and the resulting suspension was stirred at room temperature for 7 days. The mixture was poured onto 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (1×100 mL), dried over Na2SO4, filtered and concentrated to leave a solid. This solid was triturated with ether and filtered to afford the title compound: MS (M+H): 436 (base peak).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].O>C1COCC1>[C@H:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:26][C:27]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1NC1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
(R)-Acenaphthen-1-yl-amine•hydrochloride (25 g) was dissolved in water (200 ml) and the mixture was alkalified with potassium carbonate and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained (R)-acenaphthen-1-yl-amine (21 g, 124 mmol) was dissolved in ethanol (200 ml). Potassium carbonate (2.5 g, 18 mmol) and 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g) dissolved in water (100 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)-1-(acenaphthen-1-yl)-piperidin-4-one (22 g) as a red-yellow oil. (4) A solution of (R)-1-(acenaphthen-1-yl)-piperidin-4-one (12.6 g, 50 mmol) and 1,2-phenylenediamine (10.8 g, 100 mmol) in THF (100 ml) was cooled to (0° C.), sodium triacetoxy borohydride (30 g) and acetic acid (12 ml) were added thereto, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was poured into water, and potassium carbonate was added for neutralization. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)—N-[1-(acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g) as yellow crystals. (5) (R)—N-[1-(Acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g, 26 mmol) was dissolved in THF (100 ml), and carbonyldiimidazole (5 g, 30 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (8.8 g) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:16][C:17]([O:19]CC)=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1.[Li+].[OH-].O>C1COCC1>[OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(N)CN(CC(=O)O)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Yield: 90.6 %

Procedure:
Ethyl N-[(2-hydroxy-10-H-pyrimido[5,4-b][1,4]-benzothiazin-1-yl)acetyl]-N-(2-Boc-aminoethyl)glycinate (201 mg, 0.4 mmol) was dissolved in THF (10 mL) and LiOH (2M, aqueous, 1.0 mL) was added. After 15 minutes at room temperature water (10 mL) was added, the THF was evaporated in vacuo and HCl (2M, aqueous, 1.0 mL) was added with vigorous stirring. The solid yellow material was filtered off and dried in vacuo to give 173 mg (91%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.C([CH:48](O)[CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1)(C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:48][CH2:49][CH2:50][N:51]4[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1CCN(CCC(O)C(C)(C)C)CC1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 34 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 3-(4-methylpiperazin-1-yl)propan-1-ol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 34 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide 3-(3,5-difluorophenyl)-6-(3-(4-methylpiperazin-1-yl)propoxy)-2-(pyridin-3-yl)-1H-inden-1-one, which was treated with HCl/dioxane following the same procedure in Step 8 of Example 1 (50% for 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)CO.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([SH:31])[CH3:30]>C(O)(C)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:31][CH2:29][CH3:30])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Solvent: OCCO
Product: CCSc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Lit. Org. Lett. 2002, 4(20), 3517-3520. To a stirred suspension of 0.66 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 5 ml isopropanol were added 1.32 mmol ethylene glycol, 0.07 mmol copper(I) iodide, 1.32 mmol cesium carbonate, 0.13 mmol 1,20-phenanthroline and 3.29 mmol ethyl mercaptan and the reaction mixture was stirred at 120° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 260.0 ({37Cl}[M+H− Me2C═CH2]+, 42%), 258.1 ({35Cl}[M+H− Me2C═CH2]+, 100%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:31])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:28][C:27]2[C:22](=[CH:23][C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2cc(C)c(C)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2cc(C)c(C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (300 mg, 1.54 mmol), 2-amino-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (432 mg, 1.85 mmol), HATU 878 g, 2.31 mmol) in anhydrous DMF (10 mL) is added DIPEA (382 μL, 2.31 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-40% EtOAc in heptane) to give a pure product (90) as white solid (591 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10](C4C=CC=CC=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[F:29]C1C=CC=C2C=1NC(=O)C2=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]([F:29])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(F)cccc12
Yield: 10 %

Procedure:
This compound was synthesized according to the procedure described above for Compound 2, reacting 7-fluoroisatin (1.00 g, 6.06 mmol) with 3-(4-chlorophenyl)-2-oxopropyl acetate, Intermediate 2 (1.72 g, 7.57 mmol). The crude acid was purified as described above for Compound 3, then recrystallized from ethanol/benzene to give pure product as an off-white powder Compound 13 (0.206 g, 10% yield): 1H NMR (400 MHz, DMSO-D6) δ 4.34 (s, 2H) 7.37 (m, 5H) 7.55 (m, 1H) 8.34 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].[C:6]([N:10]=[N:11][C:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7].O>CCCCC>[C:6]([N:10]=[N:11][C:12]1([NH:18][C:19]([O:3][CH2:1][CH3:2])=[S:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Product: CCOC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 ml of ethanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The next morning the reaction mixture was poured into 200 ml water and the product extracted with 50 ml pentane. The pentane extract was washed twice with water, once with 10% NaHCO3, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a mushy solid. The solid was slurried in a small amount of cold pentane and filtered. The solids were air dried and weighed 7.1 grams (52% crude yield) and melted at 57°-62° C. The product had a strong broad band at 1515 cm-1 and a sharp NH band at 3300 cm-1 in its infrared spectrum.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]([C:18]([F:21])([F:20])[F:19])=[C:7]([Br:22])[N:6]=1)=[O:4].[OH-].[Na+].O.Cl>C1COCC1>[Br:22][C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(Br)nc1C(=O)O

Procedure:
6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.9 g, 5.04 mmol) and 2M NaOH (2.52 ml, 5.04 mmol) in THF (10 ml) was stirred at RT for 1 hour. The reaction mixture was poured into water (50 ml) and the pH was adjusted to pH 4 by addition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the organic portion was washed with brine (30 ml), dried over MgSO4 (5 g), filtered and concentrated to give the title compound as a crystalline orange solid;
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])=[O:5]>O>[OH:5][CH:4]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])[CH3:1]
Reactant: C[Mg]Br
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To methylmagnesium bromide (2.0 M THF solution, 5.0 mL, 10.0 mmol) was added N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 1.91 mmol) obtained in Example 20 at 0° C. and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with water and 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 192 mg (yield: 19%) of the title compound as a low polarity isomer. Melting point: 147-148° C. (ethyl acetate-hexane).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[N:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0359 g, 0.108 mmol) in methanol (2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0166 g, 0.113 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0332 g, 67%).
Reaction SMILES: CN(OC)[C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.[H-].Cl.[OH2:21]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[O:6][C:5](/[CH:3]=[CH:3]/[C:5]([O:6][CH3:7])=[O:21])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C)cc2)o1
Reactant: O
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(-c2ccc(C)cc2)o1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a solution of N-methyl-N-methoxy-5-(4-methylphenyl)furan-2-carboxamide (2.5 g) in tetrahydrofuran (20 ml) was added duisobutylaluminum hydride (1.01M toluene solution) (15 ml) at -78° C., and the mixture was stirred at -78° C. for 10 minutes and then at 0° C. for 15 minutes. To the reaction mixture was added 1N hydrochloric acid to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:5→1:4) to give crude product (1.49 g). A solution of the crude aldehyde (1.49 g) and methyl (triphenylphosphoranilidene)acetate (2.67 g) in toluene (30 ml) was refluxed under nitrogen atmosphere for 1 hour and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9→1:5) to give methyl (E)-3-[5-(4-methylphenyl)furan-2-yl]acrylate (1.63 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1.O>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9])=[O:17]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1c(Cl)cncc1Cl)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-amino 3,5-dichloro pyridine in THF (0.5M) at 0° C. was added NaH (1.5 eq). The mixture was stirred at 0° C. for 30 min then 3-bromo benzoyl chloride (2.0 eq.) was added dropwise. The resulting mixture was stirred 12 hours at room temperature, poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2 SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:1) afforded the desired compound a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH2:21]([O:20][C:18]([CH:17]1[CH:10]2[CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]2=[O:14])=[O:19])[CH3:22]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1C=CCCN1Cc1ccccc1
Agent: [Mo]
Agent: [C-]#[O+]
Product: CCOC(=O)C1C2CCN(Cc3ccccc3)C(=O)C21

Procedure:
These compounds can be prepared from 1-benzyl-5,6-dihydro-2(1H)-pyridinone by reaction with ethyl diazoacetate with molybdenum hexacarbonyl catalyst to provide 3-benzyl-2-oxo-3-azabicyclo[4.1.0]heptane-7-carboxylic acid ethyl ester, which can be reduced with lithium aluminum hydride to provide 3-benzyl-7-hydroxymethyl-3-azabicyclo[4.1.0]heptane. Utilization of the methods in Section VIII then yields the desired 7-R7 -substituent.