Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH:24][CH3:23])=[O:21])[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCC(CCN3C(=O)COC3=O)CC2)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2cccc(C)n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.841 g (2.77 mmol) of 3-{2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 4.3, and 6.9 ml (13.86 mmol) of a solution (2M) of methylamine in tetrahydrofuran, 0.598 g of pure product is obtained in the form of an oil, after chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. This oily residue is then taken up with a solution of hydrochloric acid (5N) in isopropanol and the salt formed is filtered off and then washed successively with acetone and then with ether.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.C1C=CN=C(C2C=CC=CN=2)C=1>C(Cl)(Cl)Cl>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[N+:9]=1[O-:23]
Reactant: Cc1cccc(-c2cccc(C)n2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1ccc(-c2ccccn2)nc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2cccc(C)[n+]2[O-])n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6,6'-Dimethyl-2,2'-bipyridine (1.97 g, 0.0107 moles, Example 1) was dissolved in chloroform (10 ml). m-Chloroperbenzoic acid (1.85 g, 0.0107 moles) was dissolved in chloroform (40 ml), and added slowly to the bipyridine solution at 0°-5° C. After stirring for two hours at room temperature the solution was extracted twice with saturated sodium hydrogen carbonate solution and three times with water. The chloroform phase was dried and evaporated. The product was purified by flash chromatography.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([CH:11]=O)[CH:4]=[N:3]1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].C(OCC)(=O)C.C(OCC)(=O)C.CCCCCCC>C1COCC1.[Cl-].[Na+].O.ClCCl>[CH3:13][C:14]([S@:17](/[N:19]=[CH:11]/[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([F:10])([F:9])[F:8])=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cn1ncc(C=O)c1C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cn1ncc(/C=N/[S@](=O)C(C)(C)C)c1C(F)(F)F
Temperature: 2.5 °C
Reaction time: 6 h

Procedure:
1-Methyl-5-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (1.0 g, 0.0056 mole) was dissolved in THF (20 ml) and Ti(OEt)4 (2.56 g, 0.011 mole) in THF (5 ml) added and the solution stirred under nitrogen. (R)-(+)-2-methyl-2-propanesulfinamide (680 mg, 0.0056 mole) was added in a single portion and the reaction stirred under reflux and nitrogen for 6 hours. The solution was cooled to 0-5° C. and added to a cooled mix of brine and ethyl acetate (1:1, 120 ml) with rapid stirring. The mixture was filtered through Celite and the solids washed with more ethyl acetate. The organic layer was separated and back-washed with brine (2×60 ml). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give a cloudy oil. Yield 1.7 g. The oil was dissolved in dichloromethane and purified using an ISCO Companion (40 g silica col., hexane to hexane:ethyl acetate 1:1). The appropriate fractions were combined and evaporated to give an oil, which solidified on standing. Yield 1.43 g, 90%. 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H) 8.02 (s, 1H) 4.07 (s, 3H) 1.25 (s, 9H). MS (ESI) m/z 282 (M+H)+. LC-MS ESLD 100% m/z 282 (M+H)+. TLC ethyl acetate:heptane 1:1 0.8 UV +ve. GC-MS Cl+ m/z 282 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:20]=1[C:19]1[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:22])([CH3:21])[C:13](=[O:23])[NH:12]3)[C:9](=[O:24])[O:8]2.[C:25](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:20]=1[C:19]1[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:22])([CH3:21])[C:13](=[O:23])[N:12]3[CH3:25])[C:9](=[O:24])[O:8]2
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2oc(=O)c3c4c(ccc3c12)NC(C)(C)C(=O)N4
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2oc(=O)c3c4c(ccc3c12)NC(C)(C)C(=O)N4C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of tetracyclic lactone ix (100 mg, 0.32 mmol) in DMF (5 mL) was added cesium carbonate (263 mg, 0.81 mmol) and methyl iodide (100 μL, 1.60 mmol). The mixture was stirred at 40° C. overnight, poured into water (30 mL) and extracted with EtOAc(3×30 mL). The combined extracts were washed with brine and dried (MgSO4), the solvent was removed under reduced pressure to yield a product that was used in the next step with no further purification. A small portion of the residue was purified by reverse phase preparative HPLC for characterization. 1H NMR (acetone-d6) δ 8.69 (d, J=8.4 Hz, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.31 (d, J=8.4, 1H), 7.02 (d, J=8.4, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.04 (br, 1H), 4.06 (s, 3H), 3.27 (s, 3H) 1.32 (s, 6H). Anal. Calcd for C19H18N2O4⅓CF3COOH⅓H2O: C, 61.78; H, 5.01; N, 7.33. Found: C, 61.64; H, 4.84; N, 7.51.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:7][CH2:1][CH:2]1[CH2:3][CH2:4][O:5][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6]1
Reactant: O=Cc1ccccc1
Reactant: OCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1CCOC(c2ccccc2)O1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture of 1,2,4-butanetriol (3.0 g, 28.3 mmol) and benzaldehyde (11.48 ml, 113 mmol) in dry toluene (50 mL) with p-toluenesulfonic acid monohydrate (0.269 g, 1.413 mmol) was heated under reflux in a Dean-Stark apparatus. After ˜1 h, the solution was washed with sat. aq NaHCO3, dried and concentrated under high vac to remove most of the benzaldehyde. Chromatography gave syrupy title compound (2.88 g, 14.83 mmol, 52.5% yield). The NMR's were the same as reported (Tetrahedron Asymm. 1996, 7, 3209-3246).
Reaction SMILES: [H-].[Na+].[C:3]1([PH:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CN(C)C=O>[C:3]1([P:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[P:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:16])=[O:16])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)[C@@H]1CCCC[C@H]1P(=O)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 138.5 %

Procedure:
Sodium hydride (0.34 g; 14.16 mmol) was added to a stirred solution of diphenylphosphine oxide (2.8 g; 13.86 mmol) in dimethylformamide (30 ml) at room temperature under argon. To the yellow solution was then added cyclohexane epoxide (0.68 g; 6.94 mmol) and the reaction mixture was warmed to 70° C. The yellow color slowly faded and after 2 hours a white precipitate had formed. The mixture was cooled, acidified with dilute HCl and the product extracted with chloroform. The removal of all solvents afforded, after recrystallization from chloroformdiethylether, trans-1,2-bis(diphenylphosphinyl)cyclohexane (3.10 g; 93% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1OC(OC1C=CC=C(C(C)(C)C)C=1)=S)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1([CH:59]=[CH:60][Sn](CCCC)(CCCC)CCCC)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[CH:60]=[CH:59][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COCCO[C@@H]1[C@H](OC(=S)Oc2cccc(C(C)(C)C)c2)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reactant: CCCC[Sn](C=Cc1ccccc1)(CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COCCO[C@@H]1[C@H](C=Cc2ccccc2)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 40 °C
Yield: 13.6 %

Procedure:
To a solution of 5′-O-(tert-butyldiphenylsilyl)-3′-O-(3-tert-butylphenoxythiocarbonyl)-2′-O-(2-methoxyethyl)-5-methyluridine (15.0 g, 20.0 mmol) in 150 mL of benzene was added PhCH═CHSnBu3 (18.7 g, 50 mmol). The resulting solution was degassed three times with argon at rt and 45° C. After AIBN (1.0 g, 6.1 mmol) was added, the resulting solution was refluxed for 2 h. Another portion of AIBN (1.0 g, 6.1 mmol) was added after cooling to about 40° C. and refluxed for 2 h. This procedure was repeated until the starting material disappeared. The solvent was evaporated and the residue was purified by flash chromatography on a silica gel column using 10:1 and 5:1 hexanes-EtOAc as eluent to give 1.74 g of 5′-O-(tert-butyldiphenylsilyl)-3′-deoxy-2′-O-(2-methoxyethyl)-3′-(2-phenylethenyl)5-methyluridine as a white foam.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([CH:24]=[CH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(C=Cc2ccccc2)c1
Temperature: 77.5 °C
Yield: 103.1 %

Procedure:
To a solution of 26 (60.0 mg; 0.13 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added aqueous sodium hydroxide (2 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white solid (59.2 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[C:23]([NH2:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.Cl.C(OCC)(=O)C.[Cu]I>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([NH:31][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: NC(=O)c1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)c3ccccc3)ccc2n1
Temperature: 150 °C
Yield: 12.3 %

Procedure:
A microwave tube containing 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (100 mg, 0.25 mmol), benzamide (30 mg, 0.25 mmol) and cesium carbonate (162 mg, 0.5 mmol) in DMF (1.2 mL) was evacuated and then back-filled with Ar several time and then sealed. The resulting mixture was heated to 150° C. in the microwave for 3 h and then additional benzamide (30 mg, 0.25 mmol) and CuI (5 mg, 0.025 mmol) added and the resulting mixture heated to 200° C. in the microwave (2×30 min). The resulting mixture was then poured into water and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a brown gum. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 25:75) afforded a solid that was then diluted with hydrochloric acid (1 N) and ethyl acetate. The precipitate was filtered off to afford the title compound (12.1 mg, 12%) which was obtained as a light yellow solid. MS: m/e=395.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20]C)[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41].O>CN(C)C=O>[CH3:43][O:42][C:40](=[O:41])[CH:39]([NH:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:19](=[O:22])[CH3:20])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1)[CH3:44]
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Nc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccccc3)C[C@@H]2C)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
(±)-Cis-2-{4-[4-(acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-phenylamino}-propionic acid methyl ester was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. A mixture of (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (210 mg, 0.53 mmol), potassium carbonate (123 mg, 0.89 mmol), and methyl 2-bromopropionate (70 uL, 0.63 mmol) in dry dimethylformamide (2 mL) was heated at 100° C. for 6 h, then cooled to room temperature and stirred with 20 ml water until all of the salts dissolved. The aqueous layer was separated and was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography, eluting with (97:3 methylene chloride/methanol) to afford the title compound (220 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:27])[CH2:18][O:19]CC3C=CC=CC=3)[CH:12]=2)[CH:7]=1)[CH3:5]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:27])[CH2:18][OH:19])[CH:12]=2)[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc2cc(OC(=O)COCc3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1ccc2cc(OC(=O)CO)ccc2c1
Reaction time: 4 h
Yield: 78.7 %

Procedure:
2-[6-(2-Benzyloxyacetoxy)naphthalen-2-yl]propionic acid methyl ester 99 (5 g, 13.22 mmol) was dissolved in ethyl acetate (50 ml) in a pressure vessel, palladium on carbon (5%, 3 g) added and the mixture stirred under a hydrogen atm. (3.5 Kg) for 4 hrs. The catalyst was removed by filtration and ethyl acetate distilled off under vacuum. Hexane was added to precipitate and filtered to give pure 100 (3 g, 78.9%) as off-white powder. M.p: 49.5-52° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH:10]([NH2:14])([CH2:12][CH3:13])[CH3:11]>>[CH3:11][CH:10]([NH:14][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:12][CH3:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCC(C)N
Product: CCC(C)NC(=O)C(F)(F)F

Procedure:
In a procedure similar to Example 6, ethyl trifluoroacetate (295 g, 2.07 m) was reacted with sec-butylamine. The resulting amide distilled at 72.5° C./8 mm Hg and amounted to 285 g.
Reaction SMILES: CC[O-].[Na+].C(OCC)(=O)[CH2:6][C:7]([O:9]CC)=[O:8].[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=2)[C:20]([Cl:33])=[CH:19][C:18]=1[CH2:34]Br>C(O)C>[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=2)[C:20]([Cl:33])=[CH:19][C:18]=1[CH2:34][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOc1ccc(Cc2cc(Br)c(CBr)cc2Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(Cc2cc(Br)c(CCC(=O)O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A solution of NaOEt (freshly prepared from 0.84 g Na and 10 mL of ethanol) was added to diethyl malonate (5.53 mL, 0.036 mol) in 10 mL of ethanol. After stirring for 1 h at room temperature, the resulting solution was added to a suspension of 1-bromo-2-(bromomethyl)-4-chloro-5-(4-ethoxybenzyl)benzene (BJ) (2.8 g, 0.0067 mol) in 10 mL of ethanol and heated to 80° C. overnight. The ethanol was removed by distillation. The remaining solution was cooled to 0° C., diluted with water, and acidified to pH 2 with conc. HCl. The aqueous solution was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over Na2SO4, concentrated, and the residue was taken up in 40 mL of ethanol and 50 mL of aqueous NaOH solution. The mixture was heated to reflux for 4 h, and then the ethanol was removed by distillation. The solution was cooled to 0° C., acidified with 50 mL of conc. HCl and then heated to reflux overnight. The solution was basified to pH 12 and extracted with ethyl acetate. The aqueous solution was acidified to pH 2 and the precipitate collected. The filter cake was washed with water and dried under vacuum to obtain 1.07 g of intermediate BK.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH3:19])O.Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[CH2:19]
Reactant: CC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 7-bromo-3-chloro-1-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (50 g, 145 mmol) in THF (300 mL) was added HCl in dioxane (4M, 19.95 mL, 80 mmol). The reaction was heated to 50° C. for 16 hours. The reaction was cooled to RT and K2CO3 (30.1 g, 218 mmol) was added. The reaction mixture was stirred for 30 minutes before filtering. The filtrate was concentrated under reduced pressure and the resulting crude material was washed with DCM. The solid was collected by filtration to afford 7-bromo-3-chloro-1-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine (33.0 g, 101 mmol, 69.6% yield).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([O:23][CH:24](OCC)[CH:25]=[CH2:26])[CH3:22].[OH-].[Na+]>O.C(#N)C>[CH2:21]([O:23][CH:24]1[CH2:25][CH2:26][C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2]1)[CH3:22]
Reactant: Oc1cccc(O)c1
Reactant: C=CC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCOC1CCc2ccc(O)cc2O1
Reaction time: 1 h
Yield: 62 %

Procedure:
A 500-milliliter (ml) flask fitted with a dropping funnel was charged with 10.0 g of resorcinol, 0.2 g of p-toluenesulfonic acid monohydrate, and 100 ml of acetonitrile for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 11.1 ml of acrolein diethyl acetal under room temperature. After the dropwise addition, the mixture was stirred for 1 hour while being cooled with ice. After 5 ml of a 5% sodium hydroxide aqueous solution and 30 ml of water were added thereto, the acetonitrile was removed by distillation in vacuo (under vacuum pressure), and the residue was extracted three times with 50 ml of chloroform. Subsequently, the chloroform layer obtained was washed with 30 ml of water, the chloroform was then removed by distillation in vacuo, and the resulting residue was purified by distillation to obtain 10.9 g of a colorless liquid (yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].[Cl-].[Mg+2].[Cl-].Cl.[CH2:18]([NH2:20])[CH3:19].C(N(CC)CC)C>ClCCl>[CH2:18]([NH:20][C:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH3:19]
Reactant: CCN
Reactant: COC(=O)c1ccnc(C(=O)O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1cc(C(=O)OC)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
A mixture of 4-(methoxycarbonyl)picolinic acid (1.00 g, 5.12 mmol) and magnesium chloride (312 mg, 3.28 mmol) in dichloromethane (10 mL) is stirred at room temperature for 0.5 hour. Then, ethylamine hydrochloride (627 mg, 7.69 mmol) and triethylamine (1.07 mL, 7.69 mmol) are added. After stirring at room temperature for 20 hours, the mixture is poured onto water (50 mL). The aqueous phase is extracted with EtOAc (50 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (3:11:1) to give 525 mg (49% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:9])=[CH:4][CH:3]=1.C(NC(C1OC=CC=1C)=O)C1C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>>[Br:34][C:12]1[S:11][C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[O:9])=[C:14]([CH3:15])[CH:13]=1
Reactant: Cc1ccsc1C(=O)NCc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccoc1C(=O)NCc1ccccc1
Product: Cc1cc(Br)sc1C(=O)NCc1ccc(F)cc1
Yield: 87 %

Procedure:
Following the procedure as described in Preparation 19, making variations only as required to use N-(4-fluorobenzyl)-3-methylthiophene-2-carboxamide) in place of N-benzyl-3-methylfuran-2-carboxamide to react with N-bromosuccinimide, 5-bromo-N-(4-fluorobenzyl)-3-methylthiophene-2-carboxamide was obtained as a colorless solid in 87% yield: 1H NMR (300 MHz, CD3CN) δ 7.38-7.32 (m, 2H), 7.10-7.03 (m, 2H), 6.97 (s, 1H), 4.45 (d, J=6.1 Hz, 2H), 2.40 (s, 3H); MS (ES+) m/z 328.1 (M+1), 330.1 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[CH2:19]([OH:24])[CH2:20][CH2:21][CH:22]=[CH2:23].C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[CH3:1][Si:2]([CH3:18])([CH3:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][OH:24])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: C=CCCCO
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)Oc1ccc(-c2ccc(C=CCCCO)cc2)nc1
Yield: 88.6 %

Procedure:
6.0 g of 5-trimethylsilyloxy-2-(4-bromophenyl)pyridine, 2.5 g of 4-penten-1-ol, 4 g of sodium bicarbonate solution, 20 ml of N-methylpyrrolidone, 0.03 g of palladium(II) acetate and 0.11 g of triphenylphosphine were reacted in an analogous manner to Example 1(b) to give 5.4 g of 5-trimethylsilyloxy-2-(4-[5-hydroxy-1-pentenyl]phenyl)pyridine.