Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].CON(C)[C:5](=[O:16])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[F:15].Cl.[CH3:19]C(OC)(C)C>C1COCC1>[F:15][C:8]1[C:9]([F:14])=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[CH2:6][C:5](=[O:16])[CH3:19]
Reactant: CON(C)C(=O)Cc1c(F)ccc(F)c1F
Reactant: COC(C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)Cc1c(F)ccc(F)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of CeCl3 (438 g, 1779 mmol) and THF (12 L) was heated at 40° C. for about 2 h then cooled to 5° C. Methylmagensium chloride in THF (3 M, 3.4 L) was charged at 5-9° C. and then it was warmed up to 16° C. and held for 1 h. The suspension was re-cooled to −10 to −15° C. A solution of 17 (1.19 kg) in THF (2.4 L) was charged into the suspension over 15 min. After confirmation of completion of the reaction, the reaction mixture was transferred to a cold solution of hydrochloric acid (2 N, 8.4 L) and MTBE (5 L) in 5-10° C. The aqueous phase was separated and the organic layer was washed with aqueous 5% K2CO3 (6 L) and then 10% aqueous NaCl (5 L). The organic layer was dried over Na2SO4, concentrated to give crude 18 (917 g, >99 wt %) in 95% yield. The crude 18 was used in the next step without further purification. Analytically pure 18 was obtained by silica gel column.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].Br[C:64]1[CH:65]=[C:66]([C:70]([F:73])([F:72])[F:71])[CH:67]=[CH:68][CH:69]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:71][C:70]([F:73])([F:72])[C:66]1[CH:65]=[C:64]([C:48]2([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]2=[O:62])[CH:69]=[CH:68][CH:67]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C=C1CCC(C)(c2cccc(C(F)(F)F)c2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 60.1 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (11.5 mg, 0.0125 mmol, 5 mol % Pd), (S)-BINAP (31.4 mg, 0.05 mmol, 10 mol %) and 2-methyl-5-(N-methyl-anilinomethylene) cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 3-bromobenzotrifluoride (225 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 108 mg (60%) of the title compound. The ee was determined to be 75% by chiral HPLC analysis.
Reaction SMILES: [CH3:1][Sn:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][C:5]([NH:7][NH2:8])=[O:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([CH:11]=[N:8][NH:7][C:5](=[O:6])[CH2:4][CH2:3][Sn:2]([CH3:10])([CH3:9])[CH3:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Sn](C)(C)CCC(=O)NN
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: C[Sn](C)(C)CCC(=O)NN=Cc1ccccc1
Yield: 88.5 %

Procedure:
In the manner described in Example 2, 3.0 g (0.012 mole) of 3-trimethylstannylpropionic acid hydrazide was reacted with 1.5 ml (0.015 mole) of benzaldehyde in 2.0 ml of ethanol. Recrystallization of the solid product from 95% ethanol gave 3.6 g of 3-trimethylstannylpropionic acid phenylmethylenehydrazide, Compound 3 of Table I. The infrared spectrum (KBr disc) showed N--H absorptions at 3100 cm-1 and a carbonyl band at 1670 cm-1. The carbon-tin bond gave characteristic absorptions at 770, 540, 520 and 505 cm-1. NMR spectroscopy (CDCl3) showed the following: the singlet at 10.43 delta (1H, N--H); a broadened singlet at 7.87 delta (1H, -N=CHPh); the aromatic protons formed two complex bands, 2H ortho centered at 7.64 delta and 3H meta and para centered at 7.38 delta; a triplet centered at 2.99 delta (2H, COCH2); a triplet centered at 1.11 delta (2H, SnCH2); and a singlet at the 0.14 delta (9H, Sn(CH3)3) flanked by the J(117/119Sn--CH3) doublets.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[OH:15].C(N(CC)C(C)C)(C)C.Cl[CH2:26][O:27][CH3:28]>C1COCC1>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:26][O:27][CH3:28]
Reactant: COc1ccc2c(O)c(Br)c(C)cc2c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Temperature: 0 °C
Yield: 79.6 %

Procedure:
To an ice-water cooled solution of 2-bromo-3-methyl-6-(methyloxy)-1-naphthalenol (13) (6.8 g, 25.5 mmol) in THF (70 mL) was slowly added N,N-diisopropylethylamine (7 mL, 5.19 g, 40 mmol, 1.58 eq) followed by the slow addition of chloromethylmethyl ether (3.2 mL, 3.39 g, 42.1 mmol, 1.65 eq) between 0-5° C. with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was diluted with Et2O (400 mL), washed with H2O (2×250 mL) followed by 1 N HCl (2×250 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as a dark orange oil. The crude product was partially purified by flash chromatography over SiO2 with hexanes:EtOAc (12:1 to 9:1) to give 6.32 g of the impure title compound. The impure compound was purified by flash chromatography over SiO2 with hexanes:EtOAc (15:1) to give 4.8 g (60%) of compound 14 as a pale yellow oil. 1H NMR (400 MHz; DMSO-d6): δ 3.59 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 7.17 (dd, J=2.5 Hz, 9.3 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.95 (d, J=9.2 Hz, 1H). 1H NMR (400 MHz; CDCl3): δ 2.54 (s, 3H), 3.72 (s, 3H), 3.90 (s, 3H), 5.24 (s, 2H), 7.02 (d, J=2.4 Hz, 1H), 7.12 (dd, J=2.6 Hz, 9.2 Hz, 1H), 7.42 (s, 1H), 8.03 (d, J=9.1 Hz, 1H). (Note: In DMSO-d6, the 3-methyl group is coincident with the DMSO peak.) HRMS (EI+) calcd for C14H15BrO3: 310.0205 (M•+). Found: 310.0196.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:19]([CH3:28])=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=2)[C:21](O)=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][CH2:31][C:32]1[C:37](=[O:38])[CH:36]=[C:35]([CH3:39])[NH:34][C:33]=1[CH3:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>O.CN(C)C=O>[Cl:27][C:25]1[CH:24]=[C:20]([C:21](=[O:22])[NH:30][CH2:31][C:32]2[C:37](=[O:38])[CH:36]=[C:35]([CH3:39])[NH:34][C:33]=2[CH3:40])[C:19]([CH3:28])=[C:18]([CH:26]=1)[O:17][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1c(OC2CCN(C(=O)OCc3ccccc3)CC2)cc(Cl)cc1C(=O)O
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCN(C(=O)OCc4ccccc4)CC3)c2C)c(C)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.4 %

Procedure:
A 20 mL vial containing 3-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxy)-5-chloro -2-methylbenzoic acid (35.0 mg, 0.087 mmol) was charged with 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one hydrochloride (17.98 mg, 0.095 mmol), EDC (24.92 mg, 0.130 mmol), HOAt (20.04 mg, 0.130 mmol), N,N-dimethylformamide (1 mL), N-methylmorpholine (0.143 mL, 1.300 mmol) and a magnetic stir bar. The vial was capped and the reaction was stirred at room temperature for 3 days, at which time it was dripped into a stirred solution of saturated NaHCO3 (20 mL) and water (5 mL). The suspension was stirred at room temperature for 20 min and the solid was collected via vacuum filtration and dried under high vacuum. Purification of the solid by reverse phase HPLC (Column: Phenomenex Gemini-NX axia, 30×100, 5μ, C18. Eluent:10-80% acetonitrile/0.1% formic acid in water, 7 min gradient) gave benzyl 4-(5-chloro-3-(((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenoxy)piperidine-1-carboxylate (30 mg, 0.056 mmol, 64.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.21 (t, J=5.05 Hz, 1H), 7.26-7.44 (m, 5H), 7.15 (d, J=2.02 Hz, 1H), 6.81 (d, J=2.02 Hz, 1H), 5.87 (s, 1H), 5.09 (s, 2H), 4.70 (br. s., 1H), 4.19 (d, J=5.05 Hz, 2H), 3.63 (br. s., 2H), 3.36-3.45 (m, 2H), 2.31 (s, 3H), 2.15 (s, 3H), 2.06 (s, 3H), 1.90 (d, J=12.88 Hz, 2H), 1.49-1.67 (m, 2H). MS(ES) [M+H]+ 538.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9]O)=[C:4]([F:11])[CH:3]=1.[Br:12]P(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][Br:12])=[C:4]([F:11])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1c(F)cc(Br)cc1F
Solvent: ClCCl
Product: Fc1cc(Br)cc(F)c1CBr
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To a solution of (4-bromo-2,6-difluorophenyl)methanol (2 g, 8.97 mmol) in DCM (80 mL) was added tribromophosphine (2.91 g, 10.76 mmol) at 0° C. The resulting mixture was stirred at rt. After LCMS analysis showed the starting material had disappeared, the mixture was washed with aq NaHCO3 (40 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=5/1) to yield a colorless oil of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.48 mmol, 61.2% yield): 1H NMR (400 MHz, CD3OD) δ 7.12 (d, J=6.8 Hz, 2H), 4.47 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:27]2[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[CH:31][CH:32]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][N:42](C=O)C>C(OCC)C.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:26])=[CH:18][CH:19]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:41]#[N:42])[CH:28]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)C(=O)c1ccc(C2(c3cccc(OS(=O)(=O)C(F)(F)F)c3)CCN(Cc3ccccc3)CC2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(C#N)c3)CCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-[1-benzyl-4-(4-diethylcarbamoyl-phenyl)-piperidin-4-yl]-phenyl ester (1.82 g, 3.16 mmol) in DMF (14 mL) was added zinc cyanide (0.26 g, 2.21 mmol) and tetrakis triphenylphosphine palladium (0.73 g, 0.63 mmol). The reaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours. The mixture was cooled to room temperatures and it was diluted with diethyl ether (100 mL). The organic layer was washed with brine (5×10 mL), dried (MgSO4) and concentrated. Purification with hexanes/EtOAc (1:1) afforded 1.3 g (91% yield) of 4-[1-Benzyl-4-(3-cyano-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide. 1HNMR (400 MHz, CDCl3) δ 7.69-7.20 (comp, 13H), 3.55-3.43 (comp, 2H), 3.41 (s, 2H), 3.31-3.19 (comp, 2H), 2.6-2.25 (comp, 8H), 1.28-1.19 (comp, 3H), 1.17-1.08 (comp, 3H); MS (M+1) 452.2.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[C:8]([O:20][CH3:21])[CH:7]=1.[CH2:22]([N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31])[C:23]#[CH:24].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[O:31]=[C:26]1[CH2:27][CH2:28][C:29](=[O:30])[N:25]1[CH2:22][C:23]#[C:24][C:9]1[CH:10]=[CH:11][C:6]([CH:2]=[O:3])=[CH:7][C:8]=1[O:20][CH3:21]
Reactant: COc1cc(C2OCCO2)ccc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCN1C(=O)CCC1=O
Agent: [Cu]I
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1C#CCN1C(=O)CCC1=O

Procedure:
A mixture of 4.26 g (15 mmol) triflate (6.1b), 2.47 g (18 mmol) of 1-prop-2-ynyl-pyrrolidine-2,5-dione (7.4), 0.067 g (0.3 mmol) of [(C6H5)3P]2PdCl2, 0.143 g (0.75 mmol) CuI, 0.32 g (0.75 mmol) of 1,4-bis(diphenyl-phosphino)butane and 7 ml (50.5 mmol) of TEA in 40 ml DMF under nitrogen at 100° C. for 3 h. The inorganic salts are removed and DMF is evaporated. The residue is treated with water, extracted 3×50 ml of EtOAc, the collected organic phase is evaporated and purified by flash chromatography (toluene-MeOH 9:1). The desired intermediate 4.19 is 1.9 g (44%) of 4-[3-(2,5-dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzaldehyde, as a dark yellow solid. (M+H)+=272, Rt=2.15 min (A), purity: 98.9%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-])=O.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cn1ccc2c([N+](=O)[O-])cccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cn1ccc2c(N)cccc21

Procedure:
To a solution of crude methyl 2-(4-nitro-1H-indol-1-yl)acetate (obtained as reported in Example 15, Step 1, theoretical amount 3.08 mmol) in THF (15 ml), tin(II) chloride dihydrate (6.243 g, 27.7 mmol) was added, and the mixture was reacted at 50° C. for 5 hours and at room temperature overnight. A saturated solution of NaHCO3 (120 ml) was added to the cooled reaction mixture, and the resulting precipitate was filtered off on a celite pad. The filtrate was extracted with ethyl acetate (3×20 ml) and the combined organic layers were dried over sodium sulfate. After evaporation of the solvent, crude methyl 2-(4-amino-1H-indol-1-yl)acetate was obtained and used in the next step without any additional purification (810 mg). MS/ESI+ 205.0 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)(O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH2:9])[CH:3]=1
Reactant: COc1cccc(C(C)(O)c2cccc(Br)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(c1cccc(Br)c1)c1cccc(OC)c1

Procedure:
A solution of 1-(3-bromo-phenyl)-1-(3-methoxy-phenyl)-ethanol (31 g, ca. 100 mmol) in toluene (250 mL) was heated at reflux with para-toluenesulfonic acid (200 mg) in a Dean-Stark apparatus for 4 h. After TLC indicated complete conversion of starting material, the solution was left to cool, evaporated under reduced pressure and purified by flash chromatography (100 g silica gel, gradient cyclohexane 100% to 4% ethyl acetate in cyclohexane, eluant ca. 1 L, Rf 0.25 with 4% ethyl acetate in cyclohexane) to give a yellow oil (17.8 g, 62% over 2 steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[N:23])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccccc1COc1ccc(Br)nc1
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: [C-]#N
Product: N#Cc1ccc(OCc2ccccc2F)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a mixture of 2-bromo-5-(2-fluorobenzyloxy)pyridine (1.5 g, 5.3 mmol) and zinc cyanide (0.81 g, 6.9 mmol) in DMF (20 mL) was added Tetrakis(triphenylphosphine)palladium(0) (0.61 g, 0.53 mmol) at room temperature. After being stirred at 60° C. for 4 hours, sat. sodium bicarbonate aqueous solution was added to the mixture. The mixture was filtered off through a pad of Celite. The filtrate was extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 0.69 g (57% yield) of the title compound as a light yellow solid:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[N:16][C:15]=2[CH:26]=1)=O.O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:25][C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([CH2:9][OH:8])=[CH:26][C:15]=3[N:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc2oc(-c3cccc(F)c3)nc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2oc(-c3cccc(F)c3)nc2c1
Reaction time: 0.17 h

Procedure:
Lithium aluminum hydride was added to 100 ml THF and stirred for 10 minutes and cooled in an ice bath. A solution of Compound 69A (9.06 g, 33.4 mmol) in 200 ml THF was added dropwise over ½ hr to the lithium aluminum hydride solution and stirred for 2 h. A saturated solution of water/sodium sulfate decahydrate was added until gas evolution ceased and a heavy white precipitate formed. The reaction was stirred for 30 minutes more and filtered through Celite®, extracted into 2×200 ml ethyl acetate, washed with 1×50 ml brine dried over anhydrous sodium sulfate, and filtered through silica. The product was eluted with 300 ml ethyl acetate and concentrated to give a cream colored solid. MS m/z 244 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.Cl[CH2:37][CH2:38][N:39]=[C:40]=[S:41]>C(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:40]2[S:41][CH2:37][CH2:38][N:39]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: S=C=NCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCNC2=NCCS2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g), triethylamine (0.3 ml) and 2-chloroethylisothiocyanate (0.16 ml) were dissolved in methylene chloride (5 ml) and the mixture was stirred at room temperature for 2 hours. The mixture was then washed with water (5 ml), dried, filtered and evaporated to give a gum. Chromatography of the gum on silica "Kieselgel 60H" (Trade Mark) eluting initially with toluene then with chloroform with a trace of methanol gave the title compound, which was recrystallised from ether, yield 0.102 g, m.p. 145°-147°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:22])[CH:19](C)[CH3:20])[CH:13]=1)([CH3:9])([CH3:8])[CH3:7]>ClCCl>[CH3:1][S:2]([O:22][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11](=[O:23])[NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:13]=1)[CH2:19][CH3:20])(=[O:4])=[O:3]
Reactant: CC(C)C(O)c1cccc(C(=O)NC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)c1cccc(C(=O)NC(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
A solution of methanesulfonyl chloride (165 mg, 1.44 mmol) in dichloromethane (2.0 mL) was added to a stirred solution of N-tert-butyl-3-(1-hydroxy-2-methylpropyl)benzamide (300 mg, 1.20 mmol) in dichloromethane (8.0 mL). After 1.5 hours stirring, the mixture was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the intermediate 1-(3-(tert-butylcarbamoyl)phenyl)propyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C=Nc2nccs2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(CNc2nccs2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-[(6-chloro-3-pyridinyl)methylene]-2-thiazolamine (i.e. the product of Step A) (0.55 g, 2.46 mmol) was added portionwise to a stirred excess of sodium borohydride (0.45 g, 11.8 mmol) in methanol (30 mL). Additional portions of sodium borohydride (2×1 equivalent) were added during the addition of the imine to maintain an exothermic reaction. After addition was complete, the reaction mixture was allowed to stir for 5 min at ambient temperature. The excess reducing agent was quenched by adding glacial acetic acid until gas evolution ceased. The clear reaction mixture was concentrated, and the resulting residue was partitioned between saturated aqueous sodium carbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×30 mL), and the combined organic phases were washed with brine, dried (MgSO4) and concentrated to give the title compound as a tan powder (0.55 g).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[CH:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.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>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1\[CH:9]=[C:8]([C:32]2[CH:33]=[CH:34][C:29]([CH:27]=[O:28])=[CH:30][CH:31]=2)[C:12]([CH3:14])([CH3:13])[O:11]\1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C=O)cc1
Temperature: 80 °C

Procedure:
To 10 mL of 1,4-dioxane was added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (85 mg, 0.25 mmol), 4-formylphenylboronic acid (45 mg, 0.30 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol), 2M Na2CO3 aqueous solution (0.5 mL, 10 mmol). The mixture was heated at 80° C. under N2 for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (80 mL). The EtOAc solution was washed with brine (2×50 mL), dried over Na2SO4, and concentrated to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde as the crude product, which was used in the next step without further purification.