Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH:12]([O:16][C:17]([NH:19][C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)C>[Pd].C(O)C>[CH3:14][CH:13]([CH3:15])[CH:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:16][C:17]([NH:19][C:20]1([C:23]([OH:25])=[O:24])[CH2:21][CH2:22]1)=[O:18]
Reactant: CC(C)C(OC(=O)/C=C/c1ccccc1)OC(=O)NC1(C(=O)O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C(OC(=O)CCc1ccccc1)OC(=O)NC1(C(=O)O)CC1

Procedure:
A dry 100 mL round-bottomed flask equipped with a magnetic stir bar and a rubber septum was charged with 1-{[1-((2E)-3-phenylprop-2-enoyloxy)-2-methylpropoxy]carbonylamino}cyclopropanecarboxylic acid (18) (0.62 g, 1.8 mmols) and 10% palladium on carbon in a 1:1 mixture of ethylacetate and ethanol. The reaction was done at 1 atm pressure under a hydrogen balloon at ca. room temperature. After the reaction was complete, the solution was filtered through Celite and the solvents removed in vacuo using a rotary evaporator. The dry, crude residue was dissolved in a small amount of a mixture of 60% (v/v) acetonitrile/water (ca. 10 mL), and the solution filtered through a 0.2 μm nylon syringe filter. Final purification was achieved by mass-guided preparative HPLC. After lyophilization of the solvents, the title compound (19) was obtained as a yellow semisolid (70% yield). 1H NMR (CDCl3, 400 MHz): δ=7.33 (t, 2H), 7.20 (m, 3H), 6.61 (d, 1H), 6.05 (s, 0.35H), 5.35 (s, 0.65H), 2.98 (t, 2H), 2.71 (m, 2H), 2.01 (m, 1H), 1.65 (m, 2H), 1.36 (m, 2H), 0.98 (d, 6H). MS (ESI) m/z 371.92 (M+Na)+; 348.01 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:17](OCCC(C)C)=[O:18].CCOC(C)=O>C1COCC1.C1CCCCC1>[C:1]([C:5]1[NH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[C:8]([N:17]=[O:18])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cnc(C(C)(C)C)[nH]2)cc1
Reactant: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N=O)cc1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A yellow solution of Intermediate 51a (390 mg, 1.82 mmol) and isopentyl nitrite (0.294 mL, 2.18 mmol) in THF (10 mL) was stirred at 50° C. for 8 h, then cooled to RT and concentrated in vacuo to leave a dark green oil. FCC, using 0-25% EtOAc in cyclohexane, gave the title compound as a green solid (154 mg, 35%). LCMS (Method 3): Rt 3.82 min, m/z 244 [MH+].
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].O.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([O:23][C:27](=[O:29])[CH3:28])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@@H]1CC2

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-triene-17β-ol (0.95 g, 2.8 mM) in 20 ml of acetic anhydride and 5 ml of pyridine is heated on a steam bath for 1 hr. The resulting yellow solution is cooled and poured into 300 ml of cold H2O. The suspension is filtered, and the resulting white solid is recrystallized from methanol-H2O to give 1,17β-diacetoxy-3-methoxyestra-1,3,5(10)-triene as a white solid, yield 0.75 g (70%); m.p. 120°-121°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[C:15](#[N:18])[CH:16]=[CH2:17]>C(O)(=O)C>[C:15]([CH2:16][CH2:17][S:11]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])#[N:18]
Reactant: C=CC#N
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(=O)(=O)CCC#N)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 19.9 g (0.1 mol) of p-acetamidobenzenesulfinic acid (Organic Synthesis, Coll. Vol. I, page 7), 100 ml of water, 40 ml of acetic acid and 6.6 ml (0.1 mole) of acrylonitrile was heated on a steam bath for 2 hours. The resulting slurry was cooled to room temperature, filtered, washed with water and air dried to give 17.1 g (68 percent) of white solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH:11]([NH:12]C(OC(C)(C)C)=O)[CH2:10][CH2:9][CH2:8][N:7]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[N+:2]=[N-:3].[ClH:30].O1CCOCC1>CO>[ClH:30].[NH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][N:7]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH:6]1[CH2:5][CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCN=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: [N-]=[N+]=NCCC1C(N)CCCN1C(=O)OCc1ccccc1

Procedure:
The compound 15 (125 mg), methanol (0.5 mL) and 4N hydrogen chloride-dioxane solution (2 mL) were stirred at room temperature for 1 hour. The reaction solution was concentrated and obtained the title compound (118 mg) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:8][N:9]2[CH3:12])=[CH:5][C:4]=1[C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CCO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:25]2[CH2:24][CH2:23][CH:22]([C:20]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][C:3]=3[O:2][CH3:1])[N:9]([CH3:12])[CH:8]=[C:7]4[C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[O:21])[CH2:27][CH2:26]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1cc2c(cc1C(=O)C1CCNCC1)c(C(=O)C(=O)N(C)C)cn2C
Solvent: CCO
Product: COc1cc2c(cc1C(=O)C1CCN(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2C
Temperature: 25 °C
Yield: 71.1 %

Procedure:
144 mg of 2-[6-Methoxy-1-methyl-5-(piperidine-4-carbonyl)-1H-indol-3-yl]-N,N-dimethyl-2-oxo-acetamide (0.39 mMol) is dissolved in 10 ml EtOH followed by the addition of 0.05 ml of 4-fluorobenzyl bromide (0.4 mMol). The reaction mixture is stirred at room temperature over night. After removing the solvent, residue is taken up in CH2Cl2 and washed with H2O, brine, dried over anhydrous sodium sulfate and concentrated. Silica gel column separation (2% MeOH in CH2Cl2) then gives 133 mg of product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:36])([CH3:35])[CH:30]=[C:31]([F:34])[CH2:32]O)=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:32][C:31]([F:34])=[CH:30][C:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)([CH3:36])[CH3:35]
Reactant: BrBr
Reactant: CC(C)(C=C(F)CO)c1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C=C(F)CBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
Under a nitrogen atmosphere, a solution of triphenyl phosphine (0.96 g, 4.25 mmol) in carbon tetrachloride at −5° C. is treated dropwise with a solution of bromine (0.679 g, 4.25 mmol) in carbon tetrachloride, warmed to and stirred at room temperature for 45 minutes, treated with a solution of 4-(p-chlorophenyl)-2-fluoro-4-methyl-2-penten-1-ol, (Z)—(0.81 g, 3.54 mmol) in carbon tetrachloride, refluxed for 2 hours, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered through diatomaceous earth. The filtrate is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a colorless oil (0.736 g, 71% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:25])=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]=[C:16]([CH3:25])[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(F)cc1)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=Cc1ccc(F)cc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl)-4-fluorobenzene, the title compound was synthesized according to Reference Example 17b. Yield: 52%. Melting point: 164-165° C. (Ethyl acetate-hexane)
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[ClH:14].N([O-])=O.[Na+]>O1CCOCC1.O.[Cu]Cl>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([Cl:14])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cl
Reactant: COC(=O)c1cc(N)c(C)cc1Br
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Cl)c(C)cc1Br
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a cooled solution (15° C.) of methyl 5-amino-2-bromo-4-methylbenzoate (122 g, 0.5 mol) in 1,4-dioxane (633 mL), was added conc. hydrochloric acid (550 mL). After the mixture was cooled to 5° C., a solution of sodium nitrite (35.53 g, 0.515 mol) in 83 mL of H2O was added dropwise at such a rate that the reaction temperature was kept below 0° C. After being stirred at 0° C. for 2 hours, the reaction mixture was added slowly to a flask containing copper (I) chloride (59.4 g, 0.6 mol) and conc. hydrochloric acid (275 mL). It was stirred for 40 min, at which time TLC demonstrated that the reaction was complete. The reaction mixture was poured over ice water (2 L) and then filtered. The filter cake was dissolved in ethyl acetate (1.5 L). The organic layer was washed with brine (3×500 mL), dried over anhydrous Na2SO4. Concentration under reduced pressure provided the title compound as light yellow crystals. Yield: 120 g (92.6%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (s, 1H), 7.54 (s, 1H), 3.92 (s, 3H), 2.38 (s, 3H); MS ESI (m/z) 262 (M)+, calc. 262.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C1C=C(O)C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[F:30])[O:31][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: Oc1ccc(F)c(Cl)c1
Agent: Oc1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc(F)cnc1Oc1ccc(F)c(Cl)c1

Procedure:
2-(3-Chloro-4-fluoro-phenoxy)-5-fluoro-nicotinic acid was prepared in analogy to Example 1, Step 1, replacing 2-chloro-nicotinic acid with 2-chloro-5-fluoro-nicotinic acid ([CAS RN 38186-88-8]) and 3-trifluoromethyl-phenol with 3-chloro-4-fluoro-phenol ([CAS RN 2613-23-2]). 1H NMR (400 MHz, DMSO): δ7.16-7.19 (m, 1H), 7.44-7.48 (m, 2H), 8.19 (dd, J=8.1 Hz, J=3.2 Hz, 1H), 8.35 (d, J=3.2 Hz, 1H), 13.60 (s, 1H). 19F NMR (376.5 MHz, DMSO): −121.6, −134.8. MS (ISN): 283.8 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[N:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:36][C:37]1[N:42]=[C:41]([C:20]2[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:22][CH:21]=2)[CH:40]=[CH:39][N:38]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccnc(Cl)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Yield: 62 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.03 mmol), 2,4-dichloropyrimidine (183.7 mg, 1.24 mmol), PdCl2(PPh3)2 (41.2 mg, 5.9%) and aqueous solution of Cs2CO3 (2 mol/L, 2 mL) in 1,4-dioxane (5 mL) was heated to reflux overnight. The reaction was quenched with water. The organic layer was separated, dried, and concentrated to give the residue, which was purified by column chromatography to give (R)-3-((S)-1-(4-(2-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (300 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[Li]CCCC.[CH2:15]=[CH:16][CH2:17][CH2:18][C:19](=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23]>C1COCC1>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]([OH:24])([CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCC(=O)CCC=C
Reactant: Fc1cccc(Br)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(O)(CCC=C)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In an oven-dried 250 mL round-bottomed flask (t=g) was added 1-Bromo-2,3-difluorobenzene (2.304 mL, 20.58 mmol) in THF (60 mL) to give a colorless solution. After cooling to −78° C., BuLi (8.23 mL, 20.58 mmol) was added dropwise via syringe. The mixture was stirred at −78° C. for 20 minutes, and nona-1,8-dien-5-one (2.37 g, 17.15 mmol) (azeotroped with dry benzene) was added dropwise via canuula (plus 6 ml THF rinse). The mixture was warmed up to room temperature over 1 hour. Quenched with water and the THF solvent was stripped off. The remaining mixture was extracted with EtOAc. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, and concentrated to a yellow oil. The residue was purified by FCC up to 35% Et2O/hexane. The desired fractions were pooled and concentrated to the product as a colorless oil (2.39 g, 55.3%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.22 (m, 1H), 7.10-7.03 (m, 2H), 5.82-5.70 (m, 2H), 4.97-4.85 (m, 4H), 2.20-2.00 (m, 4H), 2.00-1.75 (m, 4H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:39])[CH:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>CO.C1COCC1.O>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH:6]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:20]=1)[C:5]([OH:39])=[O:4])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (121 mg, 5 mmol) was added to a solution of 50.2 in MeOH/THF/H2O (1:1:1, 90 mL). The resulting mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure. The reaction mixture was extracted with dichloromethane (10 mL><3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (50% ethyl acetate in hexanes) to yield acid 50.3 (860 mg) MS ESI (pos.) m/e: 523 (M+Na). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.67 (1H, s); 7.59-7.47 (3H, m); 7.29-7.25 (2H, m); 6.98-6.97 (2H, m); 5.14 (2H, s); 4.04-4.0 (1H, m); 3.1-3.053 (1H, m); 2.64-2.60 (1H, m); 1.4 (9H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+].CCCC[CH2:25][CH3:26].[CH3:27][N:28](C=O)[CH3:29]>CCOC(C)=O>[CH3:27][N:28]([CH3:29])[CH2:25][CH2:26][O:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1)[NH2:1]
Reactant: CCCCCC
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cc(N)cc(C(F)(F)F)c1
Yield: 63 %

Procedure:
A mixture of 2-chloro-N1N-dimethylethanamine (0.355 g, 2.66 mmol), 3-nitro-5-(trifluoromethyl)phenol (0.500 g, 2.41 mmol) and Cs2CO3 (2.36 g, 7.24 mmol) in DMF (19 mL) was stirred at rt until reaction complete by TLC (1:1 EtOAc:Hexane). The mixture was diluted with EtOAc and washed with water. The organic solution was dried over Na2SO4, filtered, and concentrated to give the desired product as a brown oil (0.490 g, 63%). LCMS: (FA) ES+ 304.3 (M+1).
Reaction SMILES: [CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH:1]1([C:5]2[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2csc(C3CCC3)n2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(/C=C/c2csc(C3CCC3)n2)c1
Temperature: 0 °C
Yield: 111.7 %

Procedure:
A mixture of 0.3 g of (E)-2-cyclobutyl-4-[2-(3-nitrophenyl)ethenyl]thiazole, 0.9 g of tin(II) chloride dihydrate and 50 ml of ethyl alcohol was heated to reflux for 16 hr. The mixture was then diluted with ice water and an excess of 3N sodium hydroxide. This mixture was extracted with methylene chloride and the combined extracts were washed with water followed with brine and then dried (MgSO4). Condensation in vacuo yielded 0.3 g of (E)-3-[2-[2-Cyclobutyl-4-thiazolyl]ethenyl]phenylamine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:30])[CH3:29])[CH2:24]2)=[C:19]([F:31])[CH:18]=1>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:29])[CH3:30])[CH2:24]3)=[C:19]([F:31])[CH:18]=2)=[O:12])=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C1CCN(c2ccc(N)cc2F)C1
Reactant: CCCCOc1ccc(C(=O)O)c(C)c1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)c(F)c2)c(C)c1

Procedure:
4-Butoxy-2-methylbenzoic acid was reacted with [1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]dimethylamine by method P. The product with the molecular weight of 413.54 (C24H32FN3O2) was obtained in this way; MS (ESI): 414 (M+H+).
Reaction SMILES: [C-:1]#[N:2].[K+].CO.Cl.CN([CH2:10][CH:11]1[CH2:16][S:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[C:12]1=[O:20])C>O>[O:20]=[C:12]1[CH:11]([CH2:10][C:1]#[N:2])[CH2:16][S:15][C:14]2[S:17][CH:18]=[CH:19][C:13]1=2
Reactant: CN(C)CC1CSc2sccc2C1=O
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CCC1CSc2sccc2C1=O
Yield: 86.1 %

Procedure:
To a solution of 25.3 g of potassium cyanide in 100 ml of water is added 400 ml of methanol and to the solution is added 41 g of 5-dimethylaminomethyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one hydrochloride with stirring. The mixture is stirred for 3 hours at 45°-50° C. and then concentrated under reduced pressure. To the residue is added water and the mixture is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and the chloroform is distilled off. The residue is subjected to chromatography on silica gel and eluted with chloroform to give 28 g of 4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetonitrile as pale brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:32]=[CH:31][C:20]([NH:21][C:22](=[O:30])[C:23]2[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:25])=[CH:19][CH:18]=1.[Cl:33]C1C=CC=CC=1Cl>CN(C)C1C=CN=CC=1>[C:20]1([NH:21][C:22](=[O:30])[C:23]2[CH:29]=[C:28]([Cl:33])[CH:27]=[CH:26][C:24]=2[O:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:31]=[CH:32][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Clc1ccccc1Cl
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccccc1O
Agent: CN(C)c1ccncc1
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C(=O)Nc3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 4′-chloro-salicylanilide (445 mg), and 4-dimethylaminopyridine (220 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (38 mg, yield 20%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC2CC2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC1CC1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (4.10 g, colorless oil) from 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanone (3.18 g, 15.5 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.82 g, 23.3 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]=[CH:4][CH2:3]1.N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.O.C(OCC)(=O)C>[C:25]([Si:12]([O:1][CH:2]1[CH2:6][CH:5]=[CH:4][CH2:3]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CC=CC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89679.5 %

Procedure:
To an ice-cooled solution of 4-hydroxycyclopentene (50.0 g, 0.594 mol) and imidazole (80.9 g, 1.19 mol) in N,N-dimethylformamide (300 mL) was slowly added tert-butyldiphenylsilyl chloride (180 g, 0.65 mmol). The reaction mixture was warmed to room temperature. After 16 h, the reaction mixture was diluted with water (1 L) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organics were washed sequentially with water (3×300 mL) and saturated aqueous sodium chloride solution (2×200 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (15:1 petroleum ether/ethyl acetate) provided tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane (188 g, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.69-7.66 (m, 4H), 7.43-7.38 (m, 6H), 5.63-5.60 (m, 2H), 4.58-4.53 (m, 1H), 2.46-2.38 (m, 4H), 1.61 (s, 9H).