Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:14][CH2:15][CH3:16].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30](O)([CH3:32])[CH3:31].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([O:8][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:7])=[CH:4][C:3]=1[O:14][CH2:15][CH3:16]
Reactant: CC(C)(C)O
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1Br
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-Bromo-3,5-diethoxybenzoic acid (2.8 g) in DMF (25 ml) was added CDI (1.8 g) at room temperature and the mixture was stirred at 40° C. for 2 h. To the reaction mixture, t-BuOH (1.85 ml) and DBU (1.752 ml) were added and further stirred at 40° C. for over night. After cooling to room temperature, the mixture was poured into ice-H2O and extracted with EtOAc. The organic layer was washed with H2O, brine and dried over sodium sulphate. After filtration and concentration, the residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:18])(=[O:17])[CH2:3]1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH3:1][C:2]1([CH3:19])[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH2:25][CH3:26])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:18])(=[O:17])[CH2:3]1
Reactant: Cc1c(C(=O)O)ccc2c1C(O)C(C)(C)CS2(=O)=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(c1C)C(O)C(C)(C)CS2(=O)=O
Yield: 51 %

Procedure:
7.4 Grams (26 mmol) of 3,3,5-trimethyl-4-hydroxy-6-carboxythiochroman-1,1-dioxide was dissolved in 70 ml of ethanol, and 1 ml of sulfuric acid was added. The mixture was refluxed for 18 hours. The reaction mixture was concentrated, and the residue was dissolved in 300 ml of ethyl acetate and washed with 50 ml of water, with 200 ml of a 2 wt % sodium hydroxide aqueous solution and with 50 ml of water in this order. An organic layer was dried over sodium sulfate, and the solvent was distilled off. The resultant brown oil was purified by column chromatography (silica gel/ethyl acetate+hexane=1:1) to give 4.1 g (yield 51%) of a brownish oil.
Reaction SMILES: CC1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9]([O:12][C:13](=[O:15])[CH3:14])(=O)C.[Mn]([O-])(=O)(=O)=O.[K+]>O1CCCC1>[NH2:8][C:6]1[N:7]=[C:14]([C:13]([O:12][CH3:9])=[O:15])[CH:3]=[CH:4][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)n1
Temperature: 75 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
A solution of 6-methylpyridin-2-amine (25 g, 231 mmol) and acetic anhydride (44 mL, 465 mmol) in tetrahydrofuran (188 mL) was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Water (350 mL) was added to the obtained crystals, and the mixture was heated to 75° C., and potassium permanganate (87.1 g, 551 mmol) was gradually added over 45 min. The mixture was stirred for 3 hr, and filtered through celite, and the filtrate was concentrated. Hydrochloric acid/methanol solution (Tokyo Chemical Industry Co., Ltd., 350 mL) was added, and the mixture was heated under reflux for 24 hr. The reaction solution was concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate. The obtained organic layers were mixed, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.28 g, yield 18%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 92 %

Procedure:
Into the same device as used in Example 1 were placed 9.66 g (0.050 mole) of 4'-methylbiphenyl-2-carbonitrile, 6.50 g (0.100 mole) of sodium azide, 13.77 g (0.100 mole) of triethylamine hydrochloride and 96.6 ml of toluene. The mixture was reacted for 48 hours in the same manner as in Example 1, giving 10.85 g (0.046 mole) of 5-(4'-methylbiphenyl-2-yl)-1H-tetrazole (yield 91.9% based on 4'-methylbiphenyl-2-carbonitrile). The reaction is illustrated below with chemical formulas: ##STR26##
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[S:27]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:28])=[O:29]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.5 mmol) to obtain 5-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.1 (s, 3H), 3.6 (s, 3H), 5.8 (s, 1H), 5.95 (dt, 1H), 7.0 (q, 1H), 7.2 (d, 1H), 7.3 (m, 2H), 7.4 (dd, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH:5]1([C:8]2[N:13]=[C:12]([C:14]([NH:16][C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[C:19](O)=[O:20])=[O:15])[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1>>[N:1]1([C:19]([C:18]2[CH:22]=[CH:23][N:24]=[CH:25][C:17]=2[NH:16][C:14]([C:12]2[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=[C:8]([CH:5]3[CH2:7][CH2:6]3)[N:13]=2)=[O:15])=[O:20])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(Nc1cnccc1C(=O)N1CCC1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 60 %

Procedure:
According to the general method described in step 3 of example 53, reaction of azetidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (60%) as amorphous yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[CH3:29][O:30][C:31](=[O:37])[C@H:32]([CH:34]([CH3:36])[CH3:35])[NH2:33].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:33][C@H:32]([C:31]([O:30][CH3:29])=[O:37])[CH:34]([CH3:36])[CH3:35])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3′-Fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-carboxylic acid (0.084 g, 0.22 mmol) and L-valine methyl ester hydrochloride (0.044 g, 0.26 mmol) were suspended in CH2Cl2 (5 mL), and triethylamine (0.04 mL, 0.26 mmol), 1-hydroxybenzotriazole (0.0296 g, 0.22 mmol), and N,N′-diisopropylcarbodiimide (0.030 mL, 0.22 mmol) were added. DMF (2.0 mL) was added to achieve dissolution, and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (50 mL) and was washed with water (2×50 mL) and brine (50 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (Biotage® system; 30-40% EtOAc/Hexanes gradient). This yielded 90.4 mg (83%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16]1)=[C:6]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc2c(=O)n(C)c(C3CCCN(C(=O)OCc4ccccc4)C3)c(-c3ccccc3)c2c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Reaction time: 4 h

Procedure:
To an ethanol (15 mL) solution of (±)-benzyl 3-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate (201 mg, 0.417 mmol) in a Parr hydrogenation jar was added 10% palladium on carbon catalyst (50 mg). The contents of the jar were hydrogenated at 60 psi for four hours. Filtration through celite followed by evaporation of the filtrate in vacuo gave the titled product as a white foam. Proton NMR for the product was consistent with the titled compound. ESI+MS: 349.2 [M+H]+.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[C:9]([S:12][CH2:13][C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][C:18]([Br:24])=[CH:19][CH:20]=2)[C:15]=1[CH3:25])(=[NH:11])[NH2:10].C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[Br:24][C:18]1[CH:17]=[C:16]2[C:21]([CH2:22][CH2:23][C@@H:14]3[CH2:13][S:12][C:9]([NH2:10])=[N:11][C@:15]32[CH3:25])=[CH:20][CH:19]=1
Reactant: CC1=C(CSC(=N)N)CCc2ccc(Br)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]12N=C(N)SC[C@H]1CCc1ccc(Br)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triflic acid (0.25 mL, 2.82 mmol) was added to flask charged with a stirred solution of (7-bromo-1-methyl-3,4-dihydronaphthalen-2-yl)methyl carbamimidothioate from step C3 (255 mg, 0.819 mmol) in TFA (2.5 mL) at 0° C. The resulting mixture was capped and left to stir at 0° C. for 2 h. The reaction contents were carefully added to a swirled mixture of ice and excess solid sodium bicarbonate. After gas evolution had ceased, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford rel-(4aS,10bR)-9-bromo-10b-methyl-4a,5,6,10b-tetrahydro-4H-naphtho[1,2-d][1,3]thiazin-2-amine as a white solid. The crude product was dissolved in THF (2.5 mL). Triethylamine (0.457 mL, 3.28 mmol), di-tert-butyl dicarbonate (0.571 mL, 2.458 mmol), and DMAP (5.00 mg, 0.041 mmol) were added to the crude product. After 16 h, the reaction mixture was concentrated in vacuo and purified using silica gel column chromatography (10:1 hexanes/EtOAc) to afford tert-butyl rel-((4aS,10bS)-9-bromo-10b-methyl-4a,5,6,10b-tetrahydro-4H-naphtho[1,2-d][1,3]thiazin-2-yl)carbamate (244 mg, 0.581 mmol, 71.0% yield) as a white solid. LCMS (M+H)+=225.0. 1H NMR (500 MHz, chloroform-d) δ 7.61 (br. s., 1H), 7.32 (dd, J=8.2, 1.8 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 3.04 (dd, J=12.9, 3.6 Hz, 1H), 2.88 (dd, J=13.0, 8.2 Hz, 1H), 2.83 (t, J=6.9 Hz, 2H), 2.36-2.20 (m, 1H), 2.19-2.08 (m, 1H), 2.04-1.95 (m, 1H), 1.62 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:27])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[C:24]([CH3:26])=[CH2:25])=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:27])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][C:12]=2[CH:24]([CH3:25])[CH3:26])=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N2CCOCC2)cc(C(C)C)c1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a stirred solution of N-[(4-fluorophenyl)-methyl]-2-isopropenyl-6-methyl-4-morpholin-4-yl-benzamide (0.23 g, 0.63 mmol) in ethanol (10 ml) is added 10% palladium on carbon (0.06 g). The reaction mixture is stirred under an atmosphere of hydrogen at RT for 2 h. After completion of reaction (monitored by TLC), the reaction mixture is filtered through a pad of celite, washed with ethanol and concentrated to get the crude product, which is purified by column chromatography (silica gel, 25% ethyl acetate/hexane) to afford N-[(4-fluorophenyl)-methyl]-2-isopropyl-6-methyl-4-morpholin-4-yl-benzamide (example 17) (0.16 g, 0.43 mmol, 69%). [M+H]+ 371.2.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=O)[CH2:5][O:4][CH2:3]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[CH3:1][C@@H:2]1[CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1COCCN1Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of (5R)-5-methyl-4-(phenylmethyl)-3-morpholinone (11.7 g, 57 mmol) in toluene (140 mL) at 0° C. was added sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) (35 mL, 3 mL/g of morpholinone) slowly via addition funnel, and the reaction mixture was stirred overnight at 60° C. The reaction was cooled down to 0° C. and quenched by dropwise addition of 1N aqueous NaOH (15 mL). The resulting mixture was partitioned between Et2O (100 mL) and of 1N aqueous NaOH (100 mL). The organic layer was separated, and the aqueous layer was further extracted with Et2O (50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting residue was azeotroped with CH3OH (50 mL) to afford the title compound (10.69 g) as a colorless oil. LC-MS (ES) m/z=192 [M+H]+
Reaction SMILES: [CH3:1][C:2]([O:11][CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([O:19]C2CCCCO2)[CH2:14]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[OH:19][C@H:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([CH2:12][O:11][C:2]([CH3:10])([CH3:1])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:14]1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](OC2CCCCO2)C1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](O)C1
Reaction time: 96 h

Procedure:
29 g of tert-butyl 2-methyl-2-[(1R,3S)-3-(tetrahydropyran-2-yloxy)cyclohexylmethoxy]-propionate are dissolved in 150 ml of isopropanol, and 2.3 g of toluenesulfonic acid monohydrate are added. After the toluenesulfonic acid has completely dissolved, the solution is left to stand for 4 days and then mixed with saturated sodium bicarbonate solution and partly concentrated. The residue is taken up MTBE/water, the phases are separated, the aqueous phase is extracted with MTBE, and the combined organic phases are dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel with heptane/ethyl acetate 3:1, resulting in 13.8 g of tert-butyl 2-((1R,3S)-3-hydroxycyclohexylmethoxy)-2-methylpropionate as yellow oil.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=2)[CH:8]=[O:9])=[CH:14]1
Reactant: OB(O)c1ccoc1
Reactant: O=Cc1ccnc(Br)c1
Agent: OBO
Product: O=Cc1ccnc(-c2ccoc2)c1

Procedure:
2-(furan-3-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and furan-3-ylboronic acid (67 mg, 93.2 mg theoretical, 61.2%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[O:14][C:12](=O)[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([NH2:29])=O>>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:29][C:12](=[O:14])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21
Solvent: O
Product: O=C1NC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A suspension of 21.9 g (66.3 mmol) of 4,5-bis(anilino)phthalic anhydride in 60 ml of formamide under argon atmosphere is heated at 125°-130° for 5 hours. The reaction mixture is cooled to 70°, and 250 ml of water are slowly added. This mixture is cooled to 0° for 30 minutes, and the reddish crystals are filtered off, washed with water and dried. Recrystallization from DMF/water yields the title compound in the form of orange crystals, m.p. 205°-207° C., FAB-MS: 330 [M+ +H].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:22](Br)[CH:23]=[CH2:24]>O>[CH2:24]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(F)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a round bottom flask were added 5-fluorosalicylaldehyde (47c, 4.0 g, 28.5 mmol, 1.0 equiv.), potassium carbonate (4.92 g, 35.6 mmol, 1.25 equiv.), and DMF (20 mL). Allyl bromide (3.7 mL, 42.8 mmol, 1.5 equiv.) was added slowly to the mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×25 mL), 0.1M KOH (2×25 mL), water (2×25 mL), and brine (2×25 mL), dried over MgSO4, filtered, and concentrated to yield 53b (4.64 g, 90.2%) as a pale yellow liquid. 1H-NMR (500 MHz, CDCl3) δ 10.47 (d, 1H, J=3.0 Hz), 7.50 (dd, 1H, J=3.0, 8.0 Hz), 7.23 (ddd, 1H, J=3.0, 7.5, 11.0 Hz), 6.95 (dd, 1H, J=4.0, 9.0 Hz), 6.06 (tdd, 1H, J=5.0, 10.5, 17.5 Hz), 5.44 (qd, 1H, J=1.5, 17.0 Hz), 5.34 (ddd, 1H, J=1.5, 2.5, 10.5 Hz), 4.64 (td, 2H, J=1.5, 5.0 Hz). 13C-NMR (125 MHz, CDCl3) δ 188.8, 157.4 (d, JC-F=1.9 Hz), 157.2 (d, JC-F=240.5 Hz), 132.4, 126.1 (d, JC-F=5.9 Hz), 122.6 (d, JC-F=23.8 Hz), 118.5, 114.8 (d, JC-F=7.1 Hz), 114.2 (d, JC-F=23.1 Hz), 70.1. 19F-NMR (470 MHz, CDCl3) δ −125.5. HRMS (EI): 180.05789 (M+); calcd. for C10H9FO2: 180.05866.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1.CO[N-]C.C(O)C.[OH-].[Na+:39]>O>[Na+:39].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:28])=[O:27])=[CH:6][CH:7]=1
Reactant: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: C[N-]OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 16 h
Yield: 87 %

Procedure:
E-(7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-[(3R,5S)-3,5-dihydroxy-hept-6-enoic acid])-N-methoxy-N-methyl-amide (3.0 g), ethyl alcohol (30.0 mL), and a solution of sodium hydroxide (0.4 g) in water (3.0 mL) were added to a reactor. The reaction mixture was stirred for 16 hours while maintaining the temperature of 20˜25° C. and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (10.0 mL) and then diethyl ether (100.0 mL) was added thereto. The reaction mixture was stirred for over 5 hours and then filtered under reduced pressure. The resulting white solid was dried under vacuum to obtain (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy hept-6-enoic acid sodium salt (2.4 g, yield 85%).
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:29])[CH2:15][CH2:16][CH2:17][C@@:18]1([CH3:28])[O:22][C@H:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][C:19]1=[O:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:29])[CH2:15][CH2:16][CH2:17][C@@:18]1([CH3:28])[O:22][C@H:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][C:19]1=[O:27]
Reactant: C[C@H](CCC[C@@]1(C)O[C@H](C(C)(C)C)OC1=O)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CCC[C@@]1(C)O[C@H](C(C)(C)C)OC1=O)[C@H]1CCC2C(O)CCC[C@@]21C
Reaction time: 0.25 h

Procedure:
A 913 mg amount of (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one was placed in a 100 ml eggplant-shaped flask and dissolved in 10 ml of tetrahydrofuran. A tetrahydrofuran solution (1M, 2.5 ml) of tetrabutylammonium fluoride was added under ice cooling, then the solution was stirred at the same temperature for 15 minutes, was returned to room temperature, then was stirred for 1 hour. Thereafter, 100 ml of ether and 20 ml of water for separation were added, extraction was performed from the aqueous layer by ether, then the organic layer was washed with saline and then was dried over anhydrous magnesium sulfate. Further, this was concentrated, then purified by a silica column (hexane/ethyl acetate=9/1 to 6/1) to obtain (5R,2S)-5-{(4R)-4-[(1R,7aR)-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]pentyl}-5-methyl-2-t-butyl-1,3-dioxolan-4-one in an amount of 764 mg (99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2([CH3:13])[CH3:12].B.CSC.O.C(Cl)Cl.C[N+]([O-])(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Agent: B
Agent: C[N+](C)(C)[O-]
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CNc2ccc(Br)cc21
Temperature: 25 °C
Yield: 8.8 %

Procedure:
To a solution of the 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.9 g, 3.7 mmol) in 20 mL THF at 0° C. was added a borane-methylsulfide complex (2M in THF, 38 mL, 75 mmol). The reaction mixture was warned to room temperature then brought to reflux for 4 hours. The mixture was cooled to room temperature and poured into H2O/CH2Cl2 and washed with 5% NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was extracted in MeOH, trimethylamine N-oxide (2.0 g, 26.6 mmol) was added, and the solution was brought to reflux for 2 hours. The reaction mixture was cooled, concentrated and the crude residue purified by column chromatography (SiO2, methylene chloride) to afford 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (0.074 g, 87%) as a yellow oil: 1H NMR (CDCl3) δ 1.29 (s, 6H), 3.30 (s, 2H), 3.5 (br s, 1H), 6.49 (d, J=8.8 Hz, 1H), 7.08-7.12 (mn, 2H); 13C-NMR (CDCl3) δ 27.69 (q), 42.21 (s), 62.01 (d), 110.38 (s), 111.09, 125.46, 130.09 (d), 141.03, 149.52 (s); MS (EI) m/z 225, 227 (M)+.