Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:30])=[O:29])(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:40][C:37]([F:38])([F:39])[C:34]1[CH:33]=[CH:32][C:31]([S:28]([NH2:27])(=[O:29])=[O:30])=[C:36]([C:2]2[CH:22]=[CH:21][C:5]3[NH:6][C:7]([CH2:9][O:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)=[N:8][C:4]=3[CH:3]=2)[CH:35]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: NS(=O)(=O)c1ccc(C(F)(F)F)cc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.100 g, 0.269 mmol, from Example 1.1), N-tert-butyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-benzenesulfonamide (0.165 g, 0.404 mmol), sodium carbonate (0.171 g, 1.61 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.035 g, 0.0538 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product as a off-white solid. The obtained material was dissolved in TFA (2 mL) and the resulting solution was heated to 60° C. for 3 hours. The reaction mixture was concentrated in vacuo to provide a residue which was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a brown solid (0.101 g, 73%). 1H NMR (400 MHz, CD3OD) δ (ppm): 0.33 (d, 1H, J=8.0 Hz), 7.89 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.82 (d, 1H, J=0.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.69-7.65 (m, 3H), 7.50 (dd, 1H, J=8.8 Hz, J=1.6 Hz), 7.28 (d, 2H, J=8.8 Hz), 5.62 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H16F6N3O3S: 516.4 (M+H), Found 516.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([O:29][CH3:30])=[C:24]([N+:26]([O-])=O)[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:4]([CH3:33])=[N:3]1.[H][H]>C1COCC1.CO.[Pd]>[NH2:26][C:24]1[CH:25]=[C:20]([C:16]2[CH:15]=[CH:14][C:13]3[N:12]=[CH:11][C:10]4[N:9]([CH3:31])[C:8](=[O:32])[N:7]([C:5]5[C:4]([CH3:33])=[N:3][N:2]([CH3:1])[CH:6]=5)[C:19]=4[C:18]=3[CH:17]=2)[CH:21]=[N:22][C:23]=1[O:29][CH3:30]
Reactant: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N

Procedure:
A solution of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 66, 50 mg, 0.112 mmol) in 5 ml THF and 5 ml MeOH was stirred in presence of palladium 10% on charcoal under 1.1 bar of hydrogen for 5 h at rt. The reaction mixture was filtered over Celite and the catalyst was washed with MeOH/THF. The filtrate was evaporated and the crude product was purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 50:50). The fractions containing products were collected together, basified with NaHCO3, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the title compound as a light yellow solid. (HPLC: tR 2.29 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.94 (s, 1H), 8.12-8.10 (m, 1H), 8.08-8.05 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.45 (m, 1H), 7.43-7.41 (m, 1H), 7.00-6.97 (m, 11-1), 5.11 (s, br, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([C:23]2[CH:34]=[CH:33][C:26]([CH2:27]OS(C)(=O)=O)=[CH:25][CH:24]=2)=[O:22])=[CH:15][CH:14]=1)=[O:10].ClCC1C=CC(C(=O)/C=C/C2C=CC(/C=C/C(NOC3CCCCO3)=O)=CC=2)=CC=1.[N:65]1([C:71](=[O:73])[CH3:72])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>>[C:71]([N:65]1[CH2:70][CH2:69][N:68]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]3[CH:17]=[CH:18][C:13](/[CH:12]=[CH:11]/[C:9]([NH:8][OH:7])=[O:10])=[CH:14][CH:15]=3)=[CH:34][CH:33]=2)[CH2:67][CH2:66]1)(=[O:73])[CH3:72]
Reactant: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CCl)cc2)cc1)NOC1CCCCO1
Product: CC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1

Procedure:
The product was obtained starting from a mixture of methanesulfonic acid 4-((E)-3-{4-[(E)-2-(tetrahydro-pyran-2-yloxycarbamoyl)-vinyl]-phenyl}-acryloyl)-benzyl ester and (E)-3-{4-[(E)-3-(4-chloromethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (both obtained as described in Preparation 5) and 1-piperazin-1-yl-ethanone, following the experimental procedure described for Example 28. The title compound was obtained as its hydrochloride salt.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][N:11]([CH:14]2[CH2:16][CH2:15]2)[C:10](=[O:17])[CH:9]=1.[OH:18][C:19]([CH3:53])([CH3:52])[CH2:20][C@@:21]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:26][C:25](=[O:27])[N:24]([C@H:28]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:31]=2[CH3:45])[CH3:29])[CH2:23][CH2:22]1>CN(C)C=O>[CH:14]1([N:11]2[CH:12]=[CH:13][C:8]([C:33]3[CH:34]=[CH:35][C:30]([C@@H:28]([N:24]4[CH2:23][CH2:22][C@:21]([CH2:20][C:19]([OH:18])([CH3:53])[CH3:52])([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:26][C:25]4=[O:27])[CH3:29])=[C:31]([CH3:45])[CH:32]=3)=[CH:9][C:10]2=[O:17])[CH2:16][CH2:15]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1[C@H](C)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(Br)ccn1C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccn(C3CC3)c(=O)c2)ccc1[C@H](C)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (0.41 mL) was added to a mixture of 4-bromo-1-cyclopropyl-1H-pyridin-2-one (0.11 g) and (S)-6-(2-hydroxy-2-methyl-propyl)-3-{(S)-1-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one (0.20 g) in N,N-dimethylformamide (2 mL). The resulting mixture was sparged with argon for 10 min prior to the addition of [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (33 mg). The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling the mixture to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 0.13 g (64% of theory); LC-MS (Method 5): tR=3.43 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.[CH2:18]([O:34][C:35]1[CH:54]=[CH:53][C:38]([C:39](O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:37][CH:36]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([Cl:58])(=O)C>>[CH2:18]([O:34][C:35]1[CH:54]=[CH:53][C:38]([C:39]([Cl:58])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:37][CH:36]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOc1ccc(C(O)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Product: CCCCCCCCCCCCCCCCOc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Yield: 75 %

Procedure:
In the chemical synthesis of polynucleotide fragments by the triester procedure, chromatographic methods are important for the purification of protected intermediates and for the isolation of the unprotected final product. The chromatographic behavior of the oligomers can be varied within certain limits by protecting groups, generally producing an unspecific change in the total polarity of the molecule. For example, Gortz et al. Angew. Chem. Int. Ed. Engl., 20(8): 681-683 (1981) describe introducing 4-alkoxytrityl groups for hydrophobic protection at the 5'-end of oligonucleotides. These 4-alkoxytrityl groups contain 8, 10, 12, 14, and 16 carbon atoms. Gortz et al. synthesized 4-hexadecyloxytrityl protected thymidine by first treating 4-hexadecyloxytritanol with acetyl chloride to produce 4-hexadecyloxytrityl chloride. The 4-hexadecyloxytrityl chloride was then treated with thymidine in anhydrous pyridine in the presence of 4-dimethylaminopyridine. After various purification and separation procedures, a 75% yield was obtained. This 4-hexadecyloxytrityl protected thymidine was then condensed onto the 5'--O--position of the terminal nucleotide of a support bound oligonucleotide.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[C:15]([S:19]([NH2:21])=[O:20])([CH3:18])([CH3:17])[CH3:16]>[O-]CC.[Ti+5].[O-]CC.[O-]CC.[O-]CC.[O-]CC.C1COCC1>[CH3:16][C:15]([S:19](/[N:21]=[CH:11]/[C:10]1[CH:13]=[CH:14][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1)=[O:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)S(N)=O
Reactant: CCCS(=O)(=O)c1ccc(C=O)cc1
Agent: [Ti+5]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1ccc(/C=N/S(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Propylsulphonyl)benzaldehyde (1.81 g, 8.53 mmol, prepared as described in Example 47a, tert-butyl sulphinamide (1.55 g, 12.8 mmol), titanium(V) ethoxide (3.58 mL, 17.1 mmol) and THF (50 mL) were heated at reflux for 3 h then stirred at room temperature overnight. The reaction mixture was quenched with water (200 mL) before addition of ethyl acetate (200 mL). Celite was added and the mixture stirred for 15 min before being filtered. The phases were separated and the organic extract dried (MgSO4) and concentrated. The yield of the title compound was assumed to be quantitative and the material was used without further purification. m/z (ES+) 316 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11](O)=[O:12])=[CH:4][C:3]=1[Cl:14].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([Cl:17])=[O:12])=[CH:4][C:3]=1[Cl:14]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)cc(C(=O)Cl)c2c1CCO2
Yield: 100 %

Procedure:
A mixture of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (4.3 g) in thionyl chloride (100 ml) and CHCl3 (200 ml) was stirred and refluxed for 2 hours. The mixture was cooled and the solvent was evaporated. Toluene was added and evaporated again, yielding 4.8 g of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarbonyl chloride (100% crude residue) (intermediate 7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:56][N:57]1[CH2:61][CH2:60][CH2:59][C@H:58]1[CH:62]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:62]/[C@@H:58]4[CH2:59][CH2:60][CH2:61][N:57]4[CH3:56])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOP(=O)(CC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1)OCC
Reactant: CN1CCC[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1/C=C/C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 4f (277 mg, 0.50 mmol) was dissolved in 2.5 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (750 μL, 0.75 mmol). After stirring for 45 minutes, the reaction mixture was added with (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (113 mg, 2 mmol), and stirred for 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 4 (85 mg, yield 33.0%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:24]([Cl:25])=[C:23]([OH:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:15])[CH:14]=[CH:19][C:18]3[CH:21]=[CH:22][C:23]([OH:26])=[C:24]([Cl:25])[C:17]=3[Cl:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CC(=O)c1ccc(-c2ccc(Br)cc2)s1
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(Br)cc2)s1

Procedure:
1-(5-(4-Bromophenyl)thien-2-yl)-3-(2,3-dichloro-4-hydroxyphenyl)prop-2-en-1-one is prepared from 1-(5-(4-bromophenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].S1C=CN=C1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2ccccc2)cs1
Agent: c1cscn1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccccc2)cs1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (ice/water) solution of 8.9 g. of 2-methylthio-4-phenyl-thiazole pre-dissolved in 90 ml. of methylene chloride is added in portions over 5 minutes, 8.7 g. of m-chloro-peroxybenzoic acid. Examination by TLC after 90 minutes indicates the presence of essentially all of the sulfinyl compound (reaction complete) with a faint trace of sulfone and an even fainter trace of remaining thiazole starting material. The precipitated m-chloro-benzoic acid is filtered off and the methylene chloride solution is washed successively with a 10% solution of sodium sulfite and with saturated sodium bicarbonate solution, dried, evaporated in vacuo to dryness and the residue further dried overnight in vacuo, to yield 2-methylsulfinyl-4-phenyl-thiazole, m.p. 104°-105° C.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8]1)[CH3:5]>O1CCCC1.O>[ClH:1].[CH3:5][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([OH:17])[CH2:15][CH2:14][C:9](=[O:10])[CH2:8]1)[CH3:3]
Reactant: CN(C)CC1CC2(CCC1(O)c1ccccc1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1CC(=O)CCC1(O)c1ccccc1
Reaction time: 16 h
Yield: 65 %

Procedure:
215 ml of hydrochloric acid (32%, excess) were added rapidly at 0° C. to a solution of 7-dimethylaminomethyl-8-phenyl-1,4-dioxa-spiro[4.5]decan-8-ol hydrochloride (85 g, 259 mmol) in tetrahydrofuran/water mixture, and stirring was then carried out for 16 hours at RT. The resulting colorless solid was filtered out with suction and dried. 47.5 g (65%) of the product were obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.O>[CH2:16]([O:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 2,5-dibromopyridin-3-ol (200 mg, 0.791 mmol) in dry N,N-dimethylformamide (8 mL) was added potassium carbonate (164 mg, 1.19 mmol) and benzyl bromide (0.11 mL, 0.949 mmol). The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1→3/2) to give the title compound as a white crystal (211 mg, yield 78%).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[C:3]#[CH:4].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:5][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:1])[CH:3]=[CH2:4]
Reactant: C#CC(C)(C)NC(=O)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
Five percent Pd/BaSO4 (100 mg) was added to a solution of N-(1,1-dimethyl-2-propynyl)-2,4-difluorobenzamide obtained in Example 36 (1.0 g, 4.5 mmol) and quinoline (100 mg) in methanol (20 ml), and stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and washed, with 1N hydrochloric acid (×3), saturated aqueous NaHCO3 and brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the title compound (0.95 g; 94%).
Reaction SMILES: C(C[O:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([C:19]([O:21][CH3:22])=[O:20])=[C:7]([C:23]([F:26])([F:25])[F:24])[N:6]=1)#N.BrCC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([C:19]([O:21][CH3:22])=[O:20])=[C:7]([C:23]([F:25])([F:24])[F:26])[N:6]=1
Reactant: COC(=O)c1c(OCC#N)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This example illustrates the preparation of Compound 80, namely, dimethyl 2-(cyanomethoxy)-4-(2-methylpropyl)-6-(trifluoromethyl)-3, 5-pyridine-dicarboxylate. A solution of 6.38 g (0.019 mol) of dimethyl 2-hydroxy-4-(2-methylpropyl)-6-(trifluoromethyl)- 3, 5-pyridinedicarboxylate (Compound 1) in 50 mL of dimethylformamide was prepared and to it was added 7.2 g (0.06 mol) of bromoacetonitrile and 8.3 g (0.06 mol) of anhydrous potassium carbonate. The mixture was stirred at room temperature overnight then suction filtered. The filtrate was diluted with 400 mL of water and extracted with four 50 mL portions of methylene chloride. The combined extracts were dried with magnesium sulfate and the solvent was removed by rotary evaporation giving 7.09 g (98.9% yield) of a dark amber oil. Silica gel chromatography with 10% ethyl acetate, 90% cyclohexane gave 3.51 g (49%) of Compound 80 as a clear colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[CH3:19][S-:20].[Na+].C(OCC)C>CN(C)C=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:20][CH3:19])=[N:3][CH:4]=1)=[O:18]
Reactant: C[S-]
Reactant: O=C(Cc1ccc(F)cc1F)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A solution of the product of part (ii) (23.9 g, 89 mmol) in N,N-dimethylformamide (DMF) (105 ml) was treated with sodium methanethiolate (6.6 g, 94 mmol) and the resulting suspension was stirred for 2 hours at room temperature. The mixture was poured into diethyl ether (1000 ml) and the suspension was washed with water (2×500 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was triturated with diethyl ether to afford the title compound as a yellow solid, (3.3 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11](Cl)[C:10]2[CH:18]=[CH:19][S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1([C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1N2CCN(CC2)C1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:22][CH2:23]2)[C:10]2[CH:18]=[CH:19][S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Cl)c2ccsc2n(Cc2ccccc2)c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccsc2n(Cc2ccccc2)c1=O
Yield: 28.7 %

Procedure:
A solution of 7-benzyl-4-chloro-6,7-dihydro-6-oxo-thieno[2,3-b]pyridine-5-carbonitrile (64) (0.750 g, 0.0025 mol), piperazin-1-yl-thiophen-2-yl-methanone (0.69 g, 0.0035 mol), and DABCO (0.56 g, 0.005 mol) in anhydrous DMF was heated at 110° C. for 12 h. The solution was cooled and poured into a 5% ammonium chloride aqueous solution and the precipitated solid was collected by vacuum filtration. The solid was purified by reverse phase chromatography (MeCN/water) to yield 0.330 g (29%) of 7-benzyl-6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile. MP 257° C.; 1H-NMR (DMSO-d6) δ 3.83 (m, 8H), 5.28 (s, 2H), 7.16 (m, 1H), 7.33 (m, 7H), 7.51 (d, J=3.2 Hz, 1H), 7.81 (d, J=4.8 Hz, 1H) ppm; EIMS m/z 461 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3](O)[CH2:2]2.N12CCC(CC1)CC2O.[CH2:19]1[S:23](=[O:25])(=[O:24])[O:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[N+:1]12([CH2:21][CH2:20][CH2:19][S:23]([O-:25])(=[O:24])=[O:22])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: O=S1(=O)CCCO1
Agent: OC1CC2CCN1CC2
Solvent: ClC(Cl)Cl
Product: O=S(=O)([O-])CCC[N+]12CCC(CC1)CC2
Temperature: 0 °C
Yield: 97.8 %

Procedure:
1.91 grams of 3-quinuclidinol was added to a 100 mL round bottom flask containing a stir bar. 50 mL of chloroform was added to the flask and mixture stirred to dissolve the quinuclidinol. The solution was cooled to near 0° C. in an ice bath. 1.83 grams of propane sultone was dissolved in 8 mL of chloroform in a test tube and then added dropwise to the solution of 3-quinuclidinol with stirring. During the addition of the propane sultone a white solid began to precipitate from solution. Following the addition the ice bath was removed and the solution allowed to warm to room temperature. The mixture was allowed to stir overnight then diluted with 50 ml of acetone and the solid collected on a fine porosity fritted glass funnel. The white precipitate was washed with 30 mL of acetone and the solid dried in a drying chamber containing Drierite® to obtain 3.42 g of a white solid. The structure was confirmed by positive mode electrospray mass spectrometry (M+Na)=286.2 and 1H NMR.