Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:28])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (2.00 g, 6.40 mmol) in methylene chloride (100 mL) was cooled in an ice/salt bath and a solution of diethylaminosulfur trifluoride (1.24 g, 7.68 mmol) in methylene chloride (10 mL) added drop-wise over 1 hour. The resulting solution was then stirred for 14 hours during which time it slowly warmed to room temperature. After this time the reaction was quenched by the cautious addition of saturated sodium bicarbonate (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organics dried over magnesium sulfate. Subsequent filtration and concentration under reduced pressure afforded crude tert-butyl 4-(4-chlorophenyl)-4-fluoropiperidine-1-carboxylate as a viscous yellow oil. This material was immediately dissolved in 10% methanolic hydrogen chloride (100 mL) and the resulting yellow solution stirred at room temperature for 64 hours then concentrated under reduced pressure. The resulting dark yellow oil was triturated with ethyl acetate (100 mL) for 4 hours after which time a white crystalline solid resulted. This material was isolated by filtration and vacuum dried for 3 hours to afford 4-(4-chlorophenyl)-4-fluoropiperidine hydrochloride in 73% overall yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:44][OH:45]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([NH:44][OH:45])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(N(C)C)c3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(N(C)C)c3C2=O)ccc1OC
Yield: 87.3 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-dimethylaminophthalimido)-propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-dimethylaminophthalimido)propanoic acid (0.31 g, 0.75 mmol), carbonyldiimidazole (140 mg, 0.86 mmol) and hydroxylamine hydrochloride (66 mg, 0.95 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-dimethylaminophthalimido)propionamide as a yellow solid (280 mg, 87% yield): mp, 187.0-188.6° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=7.0 Hz, 3H, CH3), 3.01 (s, 6H, CH3), 3.08 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.63 (t, J=7.9 Hz, 1H, NCH), 6.88 (br s, 2H, Ar), 7.00 (br s, 1H, Ar), 7.19 (m, 2H, Ar), 7.57 (dd, J=7.1, 8.3 Hz, 1H, Ar), 8.78 (br s, 1H, OH), 10.57 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.66, 34.42, 42.96, 49.88, 55.45, 63.72, 111.75, 112.41, 112.71, 113.74, 119.63, 122.32, 131.61, 133.94, 134.92, 147.60, 148.43, 149.75, 166.11, 166.76, 167.56; Anal Calcd for C22H25N3O6: C, 61.82; H, 5.89; N, 9.83. Found: C, 61.79; H, 5.90; N, 9.58.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[C:3]=1[Cl:12].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)c(Cl)c1N
Yield: 96.3 %

Procedure:
To a stirred solution of 4-bromo-3-chloro-2-nitroaniline (0.200 g, 0.797 mmol) in EtOH (100 mL), was added SnCl2-2H2O (0.9 g, 3.985 mmol). The reaction mixture was heated to reflux for 3.5 h. The cooled solution (to rt) was diluted with H2O and the pH was adjusted to ca. 10 with Na2CO3. Extraction with CHCl3 (×3), was followed by washing with brine, drying over Na2SO4, and filtration. Concentration afforded an orange solid that was dried under vacuum to obtain 0.17 g product: 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J=8.4 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 3.90 (s, 2H), 3.40 (s, 2H); MS (ESI) m/z 223 (M+1).
Reaction SMILES: [H-].[Na+].C1[O:28][C:6]([O:25][CH2:26][CH3:27])([CH2:7][CH2:8][C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])OC1.[CH:29](OCC)=[O:30]>>[O:24]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][CH:7]([CH:29]=[O:30])[C:6]([O:25][CH2:26][CH3:27])=[O:28]
Reactant: CCCCCCCCCCCCCCC(=O)CCC1(OCC)OCCO1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCC(=O)CC(C=O)C(=O)OCC
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To 20 ml of an ethereal suspension of 1.20 g (30 mmol) of 60% sodium hydride was added dropwise 20 ml of an ethereal solution of 7.42 g (20 mmol) of ethyl γ-ketooctadecanoate ethylene ketal prepared in Synthetic Example 3 and 1.93 g (26 mmol) of ethyl formate under stirring at room temperature. The mixture was stirred at room temperature for 18 hours. Then, 0.70 g (17 mmol) of 60% sodium hydride and 1.00 g (13 mmol) of ethyl formate were further added to the mixture and the whole was stirred at the room temperature for 50 hours. The reaction was terminated by adding diluted hydrochloric acid and the resulting mixture was extracted with ether. A residue obtained by removing the solvent from the extract under reduced pressure was treated with 30 ml of concentrated hydrochloric acid under vigorous stirring for 1.5 hours. The resulting mixture was extracted with ether, washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the solvent under a reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to obtain 3.63 g (51% yield) of ethyl γ-keto-α-formyloctadecanoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[O:3]1.[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].Cl>O1CCCC1.O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:12]3=[N:13][CH:14]=2)[O:5]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnc3c(ccn3COCC[Si](C)(C)C)c2)OC1(C)C

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.01 g) was dissolved in tetrahydrofuran (10 ml). After the atmosphere was replaced with nitrogen, the solution was ice-cooled. 55% Sodium hydride (216 mg) was added and the mixture was stirred under ice-cooling for 20 minutes. Then, [2-(chloromethoxy)ethyl](trimethyl)silane (875 μl) was added and the mixture was stirred at room temperature for 15.5 hours. The reaction solution was diluted by adding water thereto, neutralized with 1 N hydrochloric acid (0.85 ml) and extracted with ethyl acetate three times. The organic layer was washed with water once and then with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The brown oil was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (691 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[SH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][S:16][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:19])[CH3:22]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CSc1c(C(=O)OCC)[nH]c2ccccc12
Yield: 21 %

Procedure:
To a solution of ethyl 3-bromoindole-2-carboxylate (1.34 g) and ethyl 2-mercaptoacetate (0.96 ml) in acetone (15 ml) was added potassium carbonate (1.38 g) and the resulting mixture was heated at reflux under argon for 18 hours. The cooled mixture was poured into water and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated to a gum which was purified by column chromatography using iso-hexane:ethyl acetate (1:4) to give the desired product (331 mg, 21%) NMR d (CDCl3) 1.05 (t, 3H), 1.45 (t, 3H), 3.6 (s, 2H), 4.0 (q, 2H), 4.5 (q, 2H), 7.2-7.4 (m, 3H), 7.9 (d, 1H), 9.2 (brs, 1H); M/z (+) 308.3 (MH30).
Reaction SMILES: Cl.Cl[CH:3]([C:17]1[CH:18]=[CH:19][C:20]([CH3:27])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][N:5]1[CH2:4][CH:3]1[C:17]1[CH:18]=[CH:19][C:20]([CH3:27])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1
Reactant: COc1ccccc1OCCNCC(Cl)c1ccc(C)c(S(N)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Yield: 88.3 %

Procedure:
In 50 ml of ethyl acetate was suspended 4.35 g (0.01 mole) of 5-{1-chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide hydrochloride and then 50 ml of an aqueous 10% sodium carbonate solution was added to the suspension with stirring. After further stirring overnight vigorously, the reaction mixture was recovered by decantation. After removing inorganic materials by passing the ethyl acetate layer thus recovered through a silica gel column (50 ml of silica gel), the reaction product was evaporated to dryness to provide 3.2 g (88%) of colorless resinous 5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide.
Reaction SMILES: Cl[C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([NH:22][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1)[CH3:21]
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Reactant: CCN
Product: CCNc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12

Procedure:
4-Chloro-N(1H-tetrazol-5-yl)quinaldamide (1 g) and aqueous ethylamine (20 ml., 70% w/w) were heated to 100° in an autoclave for 10 hours. The mixture was evaporated, the residue was dissolved in water (10 ml) and the solution was acidified with hydrochloric acid to pH 1. The solid was collected and dissolved in aqueous dimethylaminoethanol (20 ml., 5%) and the solution was warmed to 60° and acidified with dilute hydrochloric acid. 4-Ethylamino-N(1H-tetrazol-5-yl)quinaldamide was collected and dried, m.p. 237° (d).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3]
Reactant: N#Cc1c(OCC2CCNC2)cccc1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Yield: 100 %

Procedure:
Prepared as in Example 176b from 2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example 196d) and butyryl chloride in 100% yield as an orange solid. MS 318 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([OH:21])[C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH3:10])(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:12]1[O:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:21]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)C(O)c1nc2ncccc2o1
Reaction time: 1 h

Procedure:
(S)-[1-(Hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbamic acid tert-butyl ester (311 mg, 1 mmol) and MeCl2 (5 ml) were mixed and TFA (1 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 355 mg of 2-Amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-ol TFA salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([S:17]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH3:21])(=[O:19])=[O:18])=[C:4]([F:30])[CH:3]=1.BrC1[C:33]([Cl:39])=[CH:34][C:35]([CH3:38])=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:37]=[N:36][C:35]([CH3:38])=[CH:34][C:33]=2[Cl:39])=[CH:6][C:5]([S:17]([N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH3:21])(=[O:19])=[O:18])=[C:4]([F:30])[CH:3]=1
Reactant: COc1ccccc1N(C)S(=O)(=O)c1cc(C2OC(C)(C)C(C)(C)O2)c(Cl)cc1F
Reactant: Cc1cc(Cl)c(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1N(C)S(=O)(=O)c1cc(-c2cnc(C)cc2Cl)c(Cl)cc1F
Temperature: 85 °C

Procedure:
4-Chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-5-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-benzenesulfonamide (57 mg, 0.125 mmol), 5-bromo-4-chloro-2-methyl-pyridine (21 mg, 0.1 mmol), Pd(Ph3P)4 (12 mg, 0.01 mmol), K2CO3 (69 mg, 0.5 mmol) in a mixture of dioxane (1.5 mL) and water (0.15 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and heated at 85° C. for 14 hrs. After the filtration, the mixture was purified by prep. LCMS to afford 4-chloro-5-(4-chloro-6-methyl-pyridin-3-yl)-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzenesulfonamide 3-1. MS: 454.7 (M+H)+; tR=7.77 min (method 2). NMR (CDCl3), δ, 8.350 (1H, s), 7.549 (1H, d, J=6.9 Hz), 7.257-7.436 (5H, m), 6.932 (1H, m), 6.817 (1H, m), 3.513 (3H, s), 3.389 (3H, d, J=2.1 Hz), 2.656 (3H, s).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CCO>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][CH3:1])=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 94 %

Procedure:
A mixture of 4-hydroxypropiophenone (20 g), benzyl chloride (16.1 ml), K2CO3 (12.9 g) and KI (2.21 g) in EtOH (80 ml) and H2O (1 ml) was stirred under reflux condition for 4 hours. The reaction mixture was cooled and filtered. Appeared crystal was dissovled with EtOAc and water. Organic layer was separated and washed with water and brine, dried over MgSO4 and filtered. Filtrate was evaporated under reduced pressure to give 30.0 g (94%) of 1-[4-(benzyloxy)phenyl]-1-propanone as a crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH:14]=O)[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26].[CH3:28][NH2:29].[O-]S([O-])(=O)=O.[Na+].[Na+].[Na]>ClC(Cl)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][NH:29][CH3:28])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26]
Reactant: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCC(CNC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinic acid methyl ester (67 mg, 0.17 mmol) in dichloroethane (2 ml) was treated with methylamine, 1 drop of acetic acid, anhydrous Na2SO4 and sodium cyanoborohdride and stirred at rt. overnight. The mixture was quenched with water, extracted with methylene chloride. The organic layer was separated, dried, concentrated, and purified by silica gel Biotage using methylene chloride to 5% methanol in methylene chloride as eluent to give the title compound as an off-white solid. 1HNMR(CDCl3) 8.07(d, 1H), 7.02(s, 2H), 6.29(s, 1H), 3.87(s, 3H), 3.80(m, 1H), 2.88(m, 2H), 2.56(s, 3H), 2.11(s, 3H), 2.06(s, 6H), 1.63(m, 2H), 0.99(t, 3H)ppm
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC#N>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccnc1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of 3-bromopyridine (4.82 mL, 0.05 mol), palladium acetate (0.22 g, 0.02 equiv.), tri-(o-tolyl)-phosphine (0.61 g, 0.04 equiv.), methyl acrylate (9.01 mL, 2 equiv.), triethylamine (12.5 mL) and CH3CN (25 mL) was sealed in a bomb and heated to 100° C. for 3.5 hours. The mixture was cooled in an ice-bath, the bomb was vented and the reaction mixture was concentrated in vacuo. The residue was extracted with 0.5N HCl/Et2O (3×), the organic layer was backwashed with additional 0.5N HCl and the aqueous layers were combined, basified with saturated NaHCO3 and extracted with ether. The ether layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 7.89 g (97%) of methyl 3-(3-pyridyl)-2-propenoate.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Cl)=[CH:3][CH:2]=1.[NH2:9][CH:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([NH:9][CH:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: Cc1ccc(NC(Cc2c[nH]c3ccccc23)C(=O)O)cc1
Yield: 82 %

Procedure:
The same procedure is used as in Example 1, p-toluyl chloride and DL-tryptophane being used. Yield 82%. Melting point 217.5° to 218.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1.C([Li])CCC.C(O[B:41]1[O:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]1)(C)C>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([B:41]4[O:45][C:44]([CH3:47])([CH3:46])[C:43]([CH3:49])([CH3:48])[O:42]4)=[CH:7][C:6]=3[C:5]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:14]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.3 %

Procedure:
2,7-Dibromo-9,9-dioctylfluorene (2.00 g, 3.65 mmol, 1 eq.) was dissolved in diethyl ether (30 ml). The solution was cooled to −78° C. and n-butyllithium (2.4 mL of a 1.6 M solution in hexanes, 3.83 mmol, 1.1 eq.) was added drop wise with strong stirring. The resulted white suspension was allowed to warm to −10° C. until a clear-yellow solution 3 was formed. After stirring for another 10 min, the solution was cooled to −78° C. again and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.82 mL, 4.0 mmol, 1.1 eq.) was added in one time. The mixture was stirring for another 1 h at −78° C. and was allowed to warm to 25° C. and stirred for 24 h, and then the reaction was quenched by 10 mL of water. The organic layer was washed thoroughly by water and was dried by anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude oil was separated by column chromatography with hexane/dichloromethane=4/1 (v/v) as eluent to give 1.42 g of white powder (yield=65%). 1H NMR (500 MHz, CDCl3) δ (ppm): 7.80 (d, J=7.55 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J=7.55 Hz, 1H), 7.57 (d, J=7.80 Hz, 1H), 7.44 (m, 2H), 2.02-1.96 (m, 2H), 1.94-1.88 (m, 2H), 1.39 (s, 12H), 1.23-1.14 (m, 4H), 1.13-1.03 (m, 16H), 0.82 (t, J=7.15 Hz, 6H), 0.57 (m, 4H). 13C NMR (500 MHz, CDCl3) δ (ppm): 153.57, 149.50, 142.98, 139.97, 133.88, 129.89, 128.86, 126.23, 121.52, 121.44, 119.02, 83.78, 55.47, 53.41, 40.12, 31.77, 29.21, 29.18, 24.97, 23.61, 22.59, 14.06.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[N:9]([CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=3)[C:8]=2[CH2:7][CH2:6]1
Reactant: COC(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Reactant: Fc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Combine (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid methyl ester (460 mg, 1.7 mmol) and anhydrous dimethylformamide (15 mL) under nitrogen. Chill the mixture to 0° C. and add potassium bis(trimethylsilyl)amide (0.5M toluene solution, 3.4 mL, 1.7 mmol). Stir the resulting mixture for 30 minutes, then add 3-fluorobenzyl bromide (210 μL, 1.7 mmol) and stir the reaction mixture for 4 h allowing slow warming to room temperature. Quench the reaction with water (50 mL) and extract the product with ethyl acetate (2×50 mL). Dry the combined extracts with magnesium sulfate and concentrate in vacuo. Purify the product via flash chromatography (25% ethyl acetate/hexanes isocratic) to afford 475 mg (74%) of a white solid. LCMS (Method E): 100% (m/z) 378 (M+1, APCI-pos); 1H NMR (DMSO, 400 MHz): δ 11.33 (s, 1H), 7.85 (s, 1H), 7.46 (d, 1H, J=7.9 Hz), 7.39-7.27 (m, 7H), 5.03 (q, 2H, J=8.8 Hz), 3.87-3.75 (m, 1H), 3.87-3.75 (m, 1H), 2.96 (dd, 1H, J=15.2, 5.1 Hz), 2.85-2.77 (m, 2H), 2.55-2.49 (m, 1H), 2.07-1.97 (m, 1H), 1.85-1.71 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([NH:12][C:13]1[CH:19]=[CH:18][C:17](=[O:20])[C:16]([OH:21])=[CH:15][CH:14]=1)=[CH:6][C:7]([O:9]CC)=O)[CH3:2].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH2:1]([O:3][C:4]([C:5]1[NH:12][C:13]2[CH:14]=[CH:15][C:16](=[O:21])[C:17]([OH:20])=[CH:18][C:19]=2[C:7](=[O:9])[CH:6]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)C=C(Nc1ccc(O)c(=O)cc1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cc(=O)c2cc(O)c(=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
2-(4-Hydroxy-5-oxo-1,3,6-cycloheptatrien-1-ylamino)-2-butenedioic acid diethyl ester (100 g, described in Example 1) is added in portions over 5 minutes to diphenyl ether (1000 ml) at reflux temperature. The solution is refluxed for 25 minutes and cooled to room temperature. Hexane (2000 ml) is added and the crystalline precipitate is collected. The precipitate is crystallized from acetic acid to obtain crystals of the title compound, mp > 300° C. and ν max 3270, 3170, 3100, 1740, 1620 and 1575 cm-1.