Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=2)=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]([S:33]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:11](=[O:16])[N:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(Nc1nc(=O)[nH]cc1F)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
To a suspension of 4-chloro-N-(5-fluoro-2-oxo-1,2-dihydropyrimid-4-yl)benzamide (0.10 g, 0.37 mmol) in CH2Cl2 (4 mL) were added Et3N (0.08 g, 0.82 mmol) and 4-chlorobenzenesulfonyl chloride (0.087 g, 0.41 mmol) at 0° C., and the resulting mixture was warmed to room temperature and stirred for 3 h. The reaction was diluted with CH2Cl2 (10 mL) and washed with brine. The phases were separated and the organic phase was dried over sodium sulfate (Na2SO4), filtered, and concentrated to an amber oil (0.295 g). Purification by normal phase chromatography (12 g SiO2; gradient, 0 to 35% EtOAc/hexanes) afforded 4-chloro-N-[1-(4-chlorobenzenesulfonyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]benzamide (0.025 g, 26%) as a white solid: mp 169-172° C.; 1H NMR (300 MHz, CDCl3) δ 12.59 (s, 1H), 8.29-8.15 (m, 3H), 8.05 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H); ESIMS m/z 442 ([M+H]+), 440 ([M−H]−).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg+].[Br-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]([OH:13])[CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg+]
Reactant: O=Cc1sc2ccccc2c1-c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenylbenzo[b]thiophene-2-carbaldehyde (430 mg, 1.87 mmol) in THF (10 mL) cooled to −78° C. and under a nitrogen atmosphere was added 3.0M MeMgBr in diethyl ether (1.24 mL) and stirring was continued for 30 min. The reaction mixture was quenched with a saturated solution of NH4Cl (20 mL) and slowly warmed to RT. The mixture was extracted with EtOAc (×2) and the combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo affording 1-(3-phenylbenzo[b]thiophen-2-yl)ethanol as a white solid (472 mg, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.88-7.84 (1H, m), 7.52-7.28 (8H, m), 5.21 (1H, q, J=6.35 Hz), 2.03 (1H, s), 1.59 (3H, d, J=6.63 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[C:20](OS(C(F)(F)F)(=O)=O)=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=2.[O-]P([O-])([O-])=O.[K+].[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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:20]1[C:19]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]2[CH3:12])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=2)[N:21]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (2,4-difluorophenyl)boronic acid (218.9 mg, 1.39 mmol) in dioxane (5.0 mL) and water (3 drops) was added (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, 0.69 mmol), K3PO4 (293 mg, 1.38 mmol) and Pd(PPh3)4 (39.97 mg, 0.03 mmol) with stirring for 1 hour at 95° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (192.0 mg, 70%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]([O:31][CH3:32])=[O:33])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCNC(c2cccc(C(C)(C)C)c2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Methyl 2-(3-tert-butylphenyl)piperidine-4-carboxylate (2.56 g, 9.30 mmol) was dissolved in DCM (100 mL) and DIPEA (2.429 mL, 13.94 mmol) added followed by methyl carbonochloridate (0.9 mL, 11.43 mmol) at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture was washed with 1 M aq HCl (pH 4) followed by brine, satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-tert-butylphenyl)piperidine-1,4-dicarboxylate (3.17 g, quant.) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1ncccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ncccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (867 mg, 6.1 mmol) was dissolved in absolute ethanol (130 mL), and then triethylamine (3.75 mL, 27.3 mmol) and 2-(bromomethyl)pyrimidine (1.57 g, 9.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was then dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-2-ylmethyl)sulfanyl]pyrimidin-4-ol (326 mg, 23% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 4.67 (s, 2H), 6.02 (bs, 1H), 7.42 (t, J=4.9 Hz, 1H), 8.78 (d, J=4.9 Hz, 2H); LRMS (ES+) m/z 235 (100%, M+1).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([Cl:32])[CH:25]=1.[C:33]([NH:36][C:37](=[CH2:42])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34].C(N(CC)CC)C>C(#N)C>[C:33]([NH:36]/[C:37](=[CH:42]/[C:24]1[CH:30]=[C:29]([CH3:31])[C:27]([NH2:28])=[C:26]([Cl:32])[CH:25]=1)/[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34]
Reactant: Cc1cc(Br)cc(Cl)c1N
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C(=C\c1cc(C)c(N)c(Cl)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under protective nitrogen gas 2.02 g (9.0 mmol) palladium(II)acetate and 2.82 g (9.0 mmol) tri-o-tolylphosphine were added to a mixture of 25.0 g (113 mmol) 4-bromo-2-chloro-6-methyl-aniline, 19.9 g (136 mmol) methyl 2-acetamidoacrylate, 350 ml triethylamine and 150 ml acetonitrile at ambient temperature. The reaction mixture was stirred for 18 hours at 80° C., evaporated down under reduced pressure, the residue was combined with 600 ml dichloromethane and water and filtered off from the insoluble precipitate. The organic phase was dried over sodium sulphate, evaporated down under reduced pressure and then combined with 200 ml of ethyl acetate/cyclohexane (3/1). The insoluble fraction was suction filtered and the mother liquor was purified by column chromatography through silica gel. The corresponding fractions were evaporated down under reduced pressure and combined with the insolublen fraction suction filtered previously.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2/[CH:29]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH2:23][CH2:24]1
Reactant: Cc1nc2sccn2c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2cccc(C(F)(F)F)c2)c1OCC1CC1
Yield: 41.1 %

Procedure:
The title compound was prepared by condensation of Intermediate 6 (175 mg, 0.561 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (150 mg, 0.783 mmol) in presence of sodium ethoxide (76 mg, 1.118 mmol) in ethanol (10 ml) according to the procedure of Example 24 afforded 115 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.24 (d, J=4.2 Hz, 2H), 0.48 (d, J=5.7 Hz, 2H), 0.93-0.99 (m, 1H), 3.67 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 6.85-7.01 (m, 4H), 7.53 (d, J=4.8 Hz, 1H), 7.66-7.76 (m, 4H), 8.00 (d, J=4.8 Hz, 1H), 8.16 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 499.13 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]3[N:21]=[CH:22][C:23]([CH:24]=O)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:19][CH2:20]3)[N:13]3[N:21]=[CH:22][C:23](/[CH:24]=[C:32]4/[C:30](=[O:31])[NH:29][C:27](=[O:28])[NH:26]/4)=[C:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1cnn2c(NCC3CC3)cc(Nc3ccc(F)c(Cl)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C/c2cnn3c(NCC4CC4)cc(Nc4ccc(F)c(Cl)c4)nc23)N1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To 5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (40 mg, 0.09 mmol) in 1.0 mL of ethanol was added hydantoin (9 mg, 0.09 mmol) and piperidine (8 ul). The reaction was heated at 80° C. overnight, cooled to room temperature, filtered, and washed with ethanol to yield 20 mg (31% yield) (Z)-5-((5-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethylamino) pyrazolo[1,5-a]pyrimidin-3-yl) methylene)imidazolidine-2,4-dione as a yellow powder. LCMS (M+1=442)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:25]=[CH:24][C:19]2[CH:20]([NH2:23])[CH2:21][O:22][C:18]=2[CH:17]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[F:15][C:16]1[CH:25]=[CH:24][C:19]2[CH:20]([NH:23][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:21][O:22][C:18]=2[CH:17]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: NC1COc2cc(F)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2nc(NC3COc4cc(F)ccc43)ccc2c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (1.6 g, 7.67 mmol) in N-methyl-2-pyrrolidinone (15 ml) with the above described rac-6-fluoro-2,3-dihydro-benzofuran-3-ylamine (1.3 g, 8.43 mmol) and N-ethyldiisopropylamine (1.96 ml, 11.5 mmol) was stirred at 140° C. for 2 h. Cooled to room temperature, poured onto water and extracted twice with Ethyl acetate, dried over sodium sulfate and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (1.0 g, 40%); MS (ISP) m/e=326.2 (M+H+).
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:14])[CH3:13])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: c1coc(Cn2cccc2)c1
Product: CC(=O)c1cccn1Cc1ccco1

Procedure:
a. 1-furfuryl-2-acetyl-pyrrole was prepared starting from 1-furfuryl-pyrrole described by Reichstein in Helv. 15, 1450 (1932) as well as Gianturco et al. in Tetrahedron 207, 1763 (1964). Acetylation by reaction of the Grignard intermediate with acetyl chloride [cf. Chem. Ber. 47, 1416 (1914)] led to the desired ketone. (A small amount of the 3-isomer was also obtained, separable by fractional distillation). The product boils at 100°-102° C./0.03 mm Hg. and crystallizes on standing. Recrystallization from a mixture of methylene dichloride and petroleum ether gave a white crystalline product with a m.p. of 42°-43° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:15]1[CH2:14][CH2:13][CH:12]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[O:11])[CH2:17][CH2:16]1)[CH3:24]
Reactant: O=C(c1ccc2c(c1)CCO2)C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Temperature: 85 °C
Yield: 41.5 %

Procedure:
To a solution of (2,3-dihydro-benzofuran-5-yl)-piperidin-4-yl-methanone (0.30 g, 1.30 mmol) in acetonitrile (10 mL) was added ethyl 2-bromoacetate (0.26 g, 1.6 mmol) and triethylamine (0.66 g, 6.5 mmol). The mixture was heated at 85° C. overnight, the solvent was evaporated under reduced pressure and purified via flash column chromatography (ethyl acetate:heptane) to provide desired product as a white solid (0.18 g, 0.54 mmol). MS (ESI) m/z 317.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.22 min.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4](C(=O)C)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].N1CCOCC1.[S].Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[C:3]([OH:13])=[C:4]([CH2:23][C:22]([OH:25])=[O:24])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CC(=O)O
Reactant: CC(=O)c1cc(F)c(F)c(F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [S]
Solvent: C1COCCN1
Solvent: O
Product: O=C(O)Cc1cc(F)c(F)c(F)c1O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(3,4,5-trifluoro-2-hydroxyphenyl)ethanone (7.5 g), p-toluenesulfonic acid monohydrate (0.375 g), morpholine (10 mL) and sulfur (2.0 g) was stirred at 120° C. for 5 hr, and allowed to cool to room temperature, and hydrochloric acid (20 mL) and acetic acid (20 mL) were added to the reaction mixture. The reaction mixture was stirred at 100° C. for 3 hr, allowed to cool to room temperature, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.0 g).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[CH:21]=[O:22]>O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][N:11]=1)[CH:21]=[O:22]
Reactant: OCc1ccc(F)cn1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To an N,N-dimethylformamide (20.0 mL) solution of (5-fluoro-pyridin-2-yl)-methanol (760 mg, 5.98 mmol) described in Manufacturing Example 41-1-1 was added sodium hydride (239 mg, 5.98 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 10 minutes at room temperature. 3,4-Difluorobenzaldehyde (935 mg, 6.58 mmol) was then added at room temperature, and stirred for 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane=1:3) to obtain the title compound (629 mg, 42.2%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:4][CH:3]1[CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34].ClC(Cl)(Cl)C[O:45][C:46](=O)[NH:47][C:48]1[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:52]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:53]([C:51]1[CH:52]=[C:48]([NH:47][C:46]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]([CH2:30][O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:4]5)=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:45])[N:49]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)[N:50]=1)([CH3:56])([CH3:54])[CH3:55]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCC1CN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCN1C)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
A mixture of Intermediate 56e (87.0 mg, 0.15 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 66.8 mg, 0.17 mmol), DIPEA (39.2 μL, 0.23 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo and the residue purified by FCC, using 0-10% MeOH in DCM, to provide the title compound as a pale yellow foam (64 mg, 51%). LCMS (Method 3): Rt 3.63 min, m/z 834 [M+].
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5].C(N(CC)CC)C.[CH3:22][SH:23]>CCOCC>[CH3:22][S:23][CH:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:5]
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Reactant: CS
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CSC(C)CC(=O)C1=C(C)C=CCC1(C)C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a 50 ml, three-necked, round-bottom flask equipped with a magnetic stirring assembly, a tube submerged for the introduction of gas, an immersion thermometer and a dry ice isopropanol condenser, the outlet of which leads through a 50% alkali trap to the hood sink, is placed 8.3 grams of beta-damascenone and approximately 1 gram of triethylamine. Gaseous methyl mercaptan is introduced into the stirred reaction mixture which is maintained at 10° C. Addition is continued for approximately one hour and then stopped. The stirred reaction mix is allowed to attain room temperature, and the reaction mix is stirred overnight at room temperature. The next morning the light yellow reaction mix is transferred to 50 ml of ether in a separatory funnel and washed twice with dilute sulfuric acid, twice with saturated sodium bicarbonate solution, and then with saturated saline solution until the wash is neutral. The dried ether layer is stripped of solvent on a `rotovap` and GLC of the residue on an 1/8'×10" stainless steel, 5% carbowax 20 M column isothermally at 190° C. shows one major late eluting peak which is trapped for infra-red and nuclear magnetic resonance/mass spectral analyses. Infra-red analysis suggests that the cyclohexadienyl ring structure is intact and in conjugation with the side chain ketone which is, however, now out of cross conjugation. Therefore, reaction appears to have occurred at the side chain olefinic site. Mass spectral analysis shows a molecular weight of 238, and the proper fragmentation for the proposed structure. The mass spectral analysis also is a satisfactory match with the scan for peak "A" as set forth in Example I. This peak has an IE on SE-30 of 13.00. A trap of the synthetic material is run for IE and the IE on SE-30 is 13.08.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[K+]>O1CCCC1.O>[C:15]1([C:14]2[NH:21][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=3)[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1Cl
Reaction time: 2 h

Procedure:
A solution of 68.0 g (0.254 mol) of the above-mentioned crude 2-bromo-3′,4′-dichloroacetophenone in 110 ml of tetrahydrofuran was added dropwise over 30 minutes, under reflux with heating, into a suspension of 39.8 g (0.254 mol) of benzamidine hydrochloride, 102.1 g (1.02 mol) of potassium bicarbonate in 400 ml of tetrahydrofuran and 100 ml of water. After the addition was complete, further refluxing with heating was carried out for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, to give a residual solid. This solid was successively washed with water and toluene, to give 45.5 g (62.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile, to give a purified white powder.
Reaction SMILES: [C:1](#[N:3])C.[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>CCOCC>[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](=[O:9])[C:1]#[N:3]
Reactant: CC#N
Reactant: O=C(Cl)c1ccccc1CCl
Solvent: CCOCC
Product: N#CC(=O)c1ccccc1CCl
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A mixture of 98% cuprous cyanide (2.01 g), acetonitrile (40 ml) and 2-chloromethylbenzoyl chloride (3.79 g) was heated under reflux with stirring for 4 hours. After the mixture was cooled by allowing it to stand, the mixture was diluted with ether, the precipitated insoluble materials were filtered off, and then the filtrate was washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated brine. The ether layer thus obtained was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain the crude product (3.49 g). The crude product was crystallized from ether-haxane to give the title compound (2.85 g, yield: 79.5%, white crystals).