Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:7][N:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]2[S:18][CH:19]=[CH:20][C:9]1=2>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:7][N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]2[S:18][CH:19]=[CH:20][C:9]1=2
Reactant: CCOC(=O)c1cc2sccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2sccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 16 h

Procedure:
Sodium hydroxide (3N, 1.3 ml) was added to a stirred solution of ethyl 4-(3,4-dichlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylate (0.137 g) in THF (2.5 ml) and methanol (2.5 ml). Stirring was continued for 16 hours at ambient temperature, concentrated in vacuo and the residue dissolved in water. Dropwise addition of acetic acid led to precipitation of the product as a white solid which was filtered and dried (0.107 g, 85%), NMR d(DMSO) 5.79 (2H, s), 7.05 (1H, m), 7.28 (2H, m), 7.42 (1H, s), 7.60 (2H, m); M/z (−) 326 (M+), 324, 282, 280.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[C:4]([NH:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.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]>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][CH2:11][C:10]#[C:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)=[N:3][C:4]=1[NH:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCNc1nc(Cl)nc(C)c1C#CCCCN1C(=O)c2ccccc2C1=O
Reactant: N#Cc1ccc(N)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCNc1nc(Nc2ccc(C#N)cc2)nc(C)c1C#CCCCN1C(=O)c2ccccc2C1=O
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
To a solution of 2-(5-(2-chloro-4-methyl-6-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (T3, 65 mg) in 1,4-dioxane (3 mL), 4-aminobenzonitrile (29 mg), cesium carbonate (133 mg), tris(dibenzylideneacetone)dipalladium(0) (30 mg) and 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (38 mg) were added at room temperature, the reaction vessel was sealed, and then by using a microwave reaction system, the mixture was stirred at 160° C. for 20 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate was added to the reaction mixture. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 50% hexane in ethyl acetate) to obtain 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-methyl-6-(propylamino)pyrimidin-2-yl)amino)benzonitrile (T4, 72 mg) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:16]([C:17]#[N:18])=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1>[Ni].N.CO>[F:1][C:2]1[C:16]([CH2:17][NH2:18])=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N#Cc1cc2c(cc1F)ncn2C1CCCCO1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc2c(cc1F)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
A mixture of 5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-6-carbonitrile (1.2 g, 4.9 mmol) and Raney nickel (40 mg) in NH3/MeOH solution (7 N, 20 mL) was stirred under hydrogen at RT overnight. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford (5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-6-yl)methanamine as an oil (350 mg, 28.7%). MS (ESI): m/z=250 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=2)[N+:12]#[C-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1C(C2SC3N=CN=C(N)C=3N=2)=C(C2C=CC=CC=2)N=C1C#C[Si](C)(C)C.IC1C=C(C(N[CH:68]=[O:69])S(C2C=CC(C)=CC=2)(=O)=O)C=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([N+:12]#[C-:13])[C:14]2[CH:19]=[CH:18][C:17]([O:69][CH3:68])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [C-]#[N+]C(c1cccc(I)c1)S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Agent: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Product: [C-]#[N+]C(c1ccc(OC)cc1)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 53 but using (4-methoxyphenyl)(phenylsulfonyl)methylformamide (Tetrahedron Lett., 1996, 37 (45), 8113) in place of {(3-iodophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 52). Tan solid (26.15 g, 97%)
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.Cl>CN(C)C=O.O>[CH3:25][N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2.5 g, 0.008M) in dimethylformamide (DMF) (30 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.4 g, 0.009M). The mixture was stirred at room temperature for 0.5 hours, and then methyl iodide (1.0 g, 0.008M) was added dropwise. The reaction mixture was allowed to stir for 1 hour. The mixture was then diluted with water (50 ml), neutralized with 10% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-methyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: FC1C=CC([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2CCC2C(F)=CC=C(F)C=2F)=CC=1.FC1C=CC(N2C(C(OCC)=O)=CN=C2C#C[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]([F:57])([F:56])[F:55])=CC=1>[Pd].C(OCC)(=O)C.C(O)C>[F:55][C:54]([F:57])([F:56])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:17][CH2:16][O:15][C:13]([C:12]1[NH:8][CH:9]=[N:10][CH:11]=1)=[O:14]
Reactant: CCOC(=O)c1cnc(C#Cc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(OCCc1ccccc1C(F)(F)F)c1cnc[nH]1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenethyl)-1H-imidazole-5-carboxylate (47) was prepared in a similar manner as that described for the synthesis of compound 18 using ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) (651 mg, 1.62 mmol), Pd/C (10% Degussa type, 65 mg), and ethyl acetate/ethanol (1:2) (61 mL).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:34]B(O)O>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:34])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: CB(O)O
Product: Cc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CCC(F)(F)C3)C2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 187 step 4) and methylboronic acid. White solid (19%). MS (EI): 500.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH3:30])[C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[N:24][CH:25]=1)[O:29][CH2:2][CH2:3][CH2:4][N:5]([CH3:30])[C:6](=[O:7])[C:8]1=[C:12]3[N:13]=[C:14]([CH:15]=[CH:16][N:11]3[N:10]=[CH:9]1)[N:17]1[C@@H:18]2[CH2:19][CH2:20][CH2:21]1
Reactant: CN(CCCCl)C(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCCOc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1=O
Temperature: 90 °C
Yield: 35.7 %

Procedure:
A mixture of (R)-N-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.12 mmol) and Cs2CO3 (188 mg, 0.58 mmol) in DMF (12 mL) was heated at 90° C. for 15 minutes to reach completion. The reaction mixture was filtered, rinsed with DMF, and concentrated. The crude material was purified directly by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the title product as pale yellow powder (17 mg, 36% yield). MS (apci) m/z=397.3 (M+H).
Reaction SMILES: C(OC=C)(=[O:3])C.C(O)=C.C1(C)C=CC(S(N=C=O)(=O)=O)=CC=1.N(C1C=CC(C=C(C#N)C(O)=O)=CC=1)=[N+]=[N-].[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(OC)(=O)C.CN(C)C1C=CN=CC=1>[CH:48]1([NH:47][C:46]([NH:45][CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)=[O:3])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=COC(C)=O
Agent: C=CO
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: COC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
40g of poly (vinyl butyral) containing 74% by weight of vinyl butyral units, 2% by weight of vinyl acetate units and 24% by weight of vinyl alcohol units and having an approximate average molecular weight of 30,000, were dissolved in 500 cm3 of anhydrous methyl acetate at 40° C. To this solution, 28.5g of p-toluene sulphonyl isocyanate (TSI) dissolved in 40 cm3 of methyl acetate were added over the course of 15 minutes at 40° C. The reaction was allowed to continue for a further hour at 40° C. with stirring. 13.0g of 4-azidobenzylidene-α-cyano acetic acid were added followed by 12.46g of 1,3-dicyclo hexyl carbodiimide (DCC) dissolved in 40 cm3 of methyl acetate and finally 0.1g of 4-dimethylamino pyridine (DMAP). The reaction mixture was then refluxed for 3 hours and then cooled to ambient temperature whilst being stirred. The insoluble 1,3-dicyclo hexyl urea produced was removed by filtration and the filtrate was sprayed into 5 litres of water to isolate the product. The resulting fibrous precipitate was filtered off, washed with 3 litres of aqueous 1% w/w potassium carbonate solution to remove any free acid and then re-slurried into water 3 times. The final product was dried at 35° C. to constant weight.
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[N:18].N(OCCC(C)C)=O.[ClH:27]>O1CCCC1.[Cu](Cl)Cl>[Cl:27][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[N:18]
Reactant: N#Cc1c(N)nc2c(c1-c1ccccc1)CCC2
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nc2c(c1-c1ccccc1)CCC2

Procedure:
Under argon, 500 mg (2.12 mmol) of the compound from Example 16A, 0.57 ml (4.25 mmol) of isopentyl nitrite and 571 mg (4.25 mmol) of copper(II) chloride in 21 ml of tetrahydrofuran were heated under reflux for 6 h. After cooling, 1 N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH:23]=[C:22]([C:32]([F:35])([F:34])[F:33])[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[S:27][C:26]([C:24]2[CH:23]=[C:22]([C:32]([F:33])([F:34])[F:35])[N:21]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:25]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.6 %

Procedure:
To a cooled and stirred solution of 5-{3-[4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid tert-butylamide (0.23 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated, and purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH, dichloromethane, hexane) yielded the title compound as a light yellow solid (0.084 g, 23%). MS (ISP) 502.0 [(M+H)+]; mp 233° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl>C1COCC1.C1([Mg]Br)C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[CH:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2c(c(OC)c(F)c(F)c2[N+](=O)[O-])N(C2CC2)C1c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 169.9 %

Procedure:
To a stirred solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (3.00 g, 8.15 mmol) and cuprous iodide (467 mg, 2.45 mmol) in THF (80 mL), 2 M phenylmagnesium bromide in THF (6.10 mL, 12.2 mmol) was added under argon atmosphere at −78° C. After stirred at −78° C. for 1 h and at room temperature for 2 h, the reaction mixture was poured into ice-water (400 mL) and concentrated HCl (40 mL) was added to stirred for 30 min. The crude product was extracted with EtOAc, washed with saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 40:1→10:1) to yield ethyl 1-cyclopropyl-6,7-difluoro-1,2,3,4-tetrahydro-8-methoxy-5-nitro-4-oxo-2-phenylquinoline-3-carboxylate (3.09 g, 85%) as a yellow solid.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C:57]2([CH3:65])[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59][CH2:58]2)[N:53]=[C:52]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:51]=1>O1CCOCC1.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]>[F:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C:57]2([CH3:65])[CH2:58][O:59][C:60]([CH3:64])([CH3:63])[O:61][CH2:62]2)[N:53]=1
Reactant: CC1(Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)COC(C)(C)OC1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)COC(C)(C)OC1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.22 g), tris(dibenzylideneacetone)dipalladium (0) (97 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.52 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2,2,5-trimethyl-1,3-dioxan-5-yl)oxy]-pyrimidine (0.44 g) in dioxane (10 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8 to 3:7 gradient) as eluent to give the subtitle compound as a pale yellow oil. Yield: 0.46 g
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Br[C:20]1C=CC(C(C)(C)CO)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:20])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(C)(CO)c1ccc(Br)cc1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1

Procedure:
According to the procedure for the preparation of 73C, 74A (1.93 g, 8.42 mmol) afforded 3.04 g of 74B as a colorless oil. MS (ESI) m/z 211.1 (M-OTBS)+.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9]>>[F:2][C:3]1[CH:4]=[C:5]([S:10]([NH2:1])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Product: Cc1ccc(S(N)(=O)=O)cc1F

Procedure:
To ˜20 mL of liquid ammonia at −78° C. was added 2.1 g (10 mmol) of 3-fluoro-4-methyl benzenesulfonyl chloride. The excess ammonia was then naturally evaporated to dryness overnight at room temperature. The crude sulfonamide was partitioned methylene chloride (100 mL) and water (100 mL). The aqueous phase was further extracted with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate. Evaporation of the solvents afforded 1.9 g of 3-fluoro-4-methylbenzenesulfonamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[Li+].[CH3:26]C([N-]C(C)C)C.IC.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C@@:5]1([CH3:26])[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
To a solution of (2S,3R)-3-(tert-Butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (51A) (195 mg, 0.54 mmol) in THF (6 mL) at −78° C. was added a 1.8 M solution of LDA (0.66 mL, 1.19 mmol). After stirring for 1.5 h at −78° C. and 0.5 h at −30° C., the reaction was cooled again to −78° C. and iodomethane (0.2 mL, 3.21 mmol) was added. The mixture was stirred at −78° C. for 1 h and at −20° C. for 4 h. After warming to rt, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, dried (Na2SO4), filtered then concentrated under reduced pressure. The resulting residue was purified via preparative HPLC (Luna C-18, 21.1×100 mm, eluting with 75-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 12 min; Flow rate at 20 mL/min. UV detection at 220 nm) to provide the title compound (36 mg). LC/MS m/z 374 [M+H]+.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O)C.[CH2:12]([OH:14])[CH3:13].[OH-].[K+].[ClH:17]>CCOCC>[ClH:17].[Cl:17][C:8]1[CH:9]=[CH:10][C:12]([O:14][CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:13][CH:7]=1
Reactant: CCO
Reactant: CCOC(=O)N1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Clc1ccc(OC2CCNCC2)cc1

Procedure:
12.1 ml. of ethylchloroformate are added to a solution of 19.4 g of 1-benzyl-4-(p-chlorophenoxy)piperidine in 220 ml. of benzene and the solution is refluxed for 18 hours. The benzene and benzylchloride is removed under reduced pressure to give the N-ethoxycarbonylpiperidine as an uncrystallizable yellow oil. The N-ethoxycarbonylpiperidine is dissolved in 210 ml. of ethanol and 130 ml. of 45% aqueous potassium hydroxide are added. The solution is refluxed for 12 hours under nitrogen, cooled, most of the ethanol is removed under reduced pressure and the resultant oily dispersion is extracted with ether. The ether phase is extracted with 3 N hydrochloric acid, the acid extract is basified with 6N sodium hydroxide, and the basic solution is extracted with benzene. The benzene is dried and removed under reduced pressure to give a colorless oil. The oil is dissolved in 200 ml. of ether, the solution is cooled and stirred and 200 ml. of a saturated ethereal-HCl solution is slowly added. The salt forms and is collected. The salt is recrystallized from absolute ethanol to give 4-(p-chlorophenoxy)piperidine hydrochloride.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:13])[CH:7]=1>O1CCCC1>[OH:13][CH:12]([C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)[CH:1]([CH3:3])[CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C(O)c1cccnc1
Yield: 22 %

Procedure:
According to Reference Example 8-1, by use of isopropylmagnesium bromide (a 0.76 mol/L solution in tetrahydrofuran, 4.18 mL, 3.18 mmol), 3-pyridinecarboxaldehyde (200 μL, 2.12 mmol) and tetrahydrofuran (2.0 mL), the mixture was stirred and reacted at 0° C. for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 3-(1-hydroxy-2-methylpropyl)pyridine (Compound CE) (69.0 mg, yield: 22%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3c(c21)CCCC3
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccc(F)cc3Sc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.