Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29](Cl)=[O:30]>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:30]
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(F)cc(F)c4)C3)CC2)cn1

Procedure:
The title compound was prepared as yellow solid from coupling of 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3,5-difluorobenzoyl chloride using the procedure described in Example 18.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=2)[C:7]([C:22]#[N:23])=[C:6]([SH:24])[N:5]=1)[CH3:2].Cl[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[O:30][CH:31]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[O:30][CH:31]=[C:27]([CH2:26][S:24][C:6]3[C:7]([C:22]#[N:23])=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=4)[C:9]([C:10]#[N:11])=[C:4]([O:3][CH2:1][CH3:2])[N:5]=3)[N:28]=2)=[CH:37][CH:36]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: CCOc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
100 mg (0.293 mmol) of 2-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile together with 73 mg (0.322 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 98 mg (1.172 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 41.5 mg (26% of theory) of the target compound.
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1.[H-].[Na+].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:40][CH2:41][CH2:42][CH2:43]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CN(C=O)C>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:40][CH2:41][CH2:42][CH2:43][N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:3]4[C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=[C:2]4[N:1]=[CH:6][CH:5]=3)=[CH:12][CH:11]=2)[C:14]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:20])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccnc3nc4ccccc4n23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCCN(C(=O)OC(C)(C)C)c2ccc(-c3ccnc4nc5ccccc5n34)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
To a solution of tert-butyl (4-(benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)phenyl)carbamate (300 mg, 0.83 mmol) in DMF (9 mL) at 0° C. was added NaH (38 mg, 0.91 mmol, 60% dispersed in oil). After stirring for 5 min at 0° C. for 5 min, ice bath was removed and reaction was stirred at rt for 20 min. The reaction was cooled again at 0° C. and propane-1,3-diyl bis(4-methylbenzenesulfonate) (653 mg, 1.7 mmol) was added in 6 portions. After stirring at 0° C. for 5 min, the reaction was let stir at rt for 2 h and quenched with saturated NH4Cl solution (40 mL). The mixture was extracted with DCM (3×30 mL). The combined organic phase was washed with water (2×50 mL) and dried over MgSO4 and concentrated. The residue was first purified by silica chromatography (THF in DCM, 0% to 18%) and then reversed phase HPLC (TFA buffered water/MeCN) to afford the title compound as an orange solid (160 mg, 34%). MS (ESI) m/z [M+H]+573.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]3[S:20][C:21](=[O:23])[CH:22]=[C:16]3[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[C:26](Cl)(=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][C:17]3[S:20][C:21]([O:23][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][C:16]=3[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:2][CH2:3]1
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C1C=C2CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Reaction time: 0.5 h
Yield: 40 %

Procedure:
1.0 g (3.0 mmole) of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (prepared as described in Example 20) was dissolved in 15 ml of dimethylformamide, and then 0.18 g (4.5 mmole) of a 60% w/w dispersion of sodium hydride in mineral oil and 0.82 ml (4.5 mmole) of nonanoyl chloride were added, in that order, to the resulting mixture, whilst ice-cooling. The resulting reaction mixture was then stirred at the same temperature for 30 minutes, after which it was stirred at room temperature for a further 5 hours. 300 ml of ethyl acetate were then added to the mixture, which was then washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, using a 100:2 by volume mixture of toluene and ethyl acetate as the eluent, to give a yellow oil. The oil was crystallized from petroleum ether to obtain the title compound as white crystals, melting at 45°-48° C., in a yield of 40%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)#[N:2].[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:14])=[CH:10][CH:9]=1)[CH:17]1[CH2:18][CH2:19][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27](=[O:36])[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:35])[CH2:21][CH2:22]1)#[N:2]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: C1CNCCN1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Yield: 34.5 %

Procedure:
Using general procedure E, 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 131) (60 mg, 0.11 mmol) and piperazine (29 mg, 0.33 mmol) afforded COMPOUND 134 as a white solid (23 mg, 34%). 1H NMR (CDCl3) δ 0.98-1.18 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.51-1.55 (m, 1H), 1.70-1.82 (m, 3H), 2.18 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.58 (t, 1H, J=11.1 Hz), 2.76-2.92 (m, 7H), 3.26-3.33 (m, 1H), 3.58-3.72 (m, 5H), 3.87 (m, 3H), 6.51 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.03-7.08 (m, 1H), 7.23-7.26 (m, 2H), 7.42-7.47 (m, 3H), 7.55 (d, 1H, J=6.6 Hz), 8.26 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.55, 29.41, 30.70, 31.42, 40.14, 43.98, 46.66, 48.43, 52.45, 56.42, 60.83, 112.64, 113.03, 119.29, 124.40, 127.70, 128.79, 129.72, 130.18, 131.01, 131.12, 134.51, 139.03, 141.94, 149.74, 170.22, 171.00. ES-MS m/z 607 (M+H). Anal. Calcd. for C37H46N6O2.CH2Cl2: C, 70.10; H, 7.36; N, 13.12. Found. C, 69.89; H, 7.48; N, 13.02.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([F:24])=[CH:26][CH:27]=1)=[O:36])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (538 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.FC(F)(F)S(O)(=O)=O.[O:18]1[CH2:23][CH2:22][CH:21]([CH2:24]O)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:24][CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: OCC1CCOCC1
Reactant: OCc1ccnc(F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc(COCC2CCOCC2)ccn1
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a mixture of (2-fluoropyridin-4-yl)methanol (300 mg), triethylamine (239 mg), and dichloromethane (24 mL) was added anhydrous trifluoromethanesulfonic acid (666 mg) under ice-cooling, followed by stirring at the same temperature for 1 hour. (Tetrahydro-2H-pyran-4-yl)methanol (1.37 g) was added to the reaction liquid at room temperature, followed by stirring at the same temperature for 8 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1) to obtain 2-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethoxy)methyl]pyridine (132 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([NH2:20])[CH2:13]2>C(N(CC)CC)C.ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([NH:20][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:13]2
Reactant: COc1cc2c(cc1OC)C(N)C2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1Cc2cc(OC)c(OC)cc21
Reaction time: 8 h
Yield: 80 %

Procedure:
1.5 mL of ethyl chloroformate are poured into a suspension of 3.4 g of the compound obtained in Step 1 in 4.5 mL of triethylamine and 50 mL of dichloromethane and left overnight, whilst stiffing at ambient temperature; washing with water and with 1N hydrochloric acid is then carried out. Drying is carried out and the solvent is evaporated off to dryness. 3.2 g of an oil corresponding to the expected product are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccccc3)c(=O)c2c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (32.5 mg, 0.16 mmol) in DMF (1.50 mL) was added potassium carbonate (66 mg, 0.48 mmol) and benzyl bromide (38.1 μL, 0.32 mmol). The reaction mixture was heated to 60° C. and stirred for 5 h. The mixture was then cooled to rt and concentrated. Water was added and the reaction mixture was extracted with DCM (5 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 2-benzyl-1-oxo-1,2-dihydroisoquinoline-7-carboxylate. LC-MS: (FA) ES+ 294.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([F:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.O.[CH3:20]O>>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([F:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: CO
Reactant: COc1c(Br)cc(C(=O)O)c(O)c1F
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Br)c(OC)c(F)c1O
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid (0.70 g) in methanol (15.0 mL) was added dropwise thionyl chloride (0.39 mL) under ice-cooling. The reaction solution was stirred at 70° C. for 15 hr under argon atmosphere, and then overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and 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 (0.52 g).
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Yield: 80.1 %

Procedure:
A mixture of 1321 g of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene, 695 g of acetic anhydride, and 32.6 ml of pyridine was heated at 95°-100° for 1 hour. The low boiling by-products were removed under vacuum, and the residue was then distilled, yielding 1276 g of 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene; bp, 87°/5.5 mm.
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].C[Mg]Br.C([O:14][C:15]([C:17]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([OH:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=O)C.[Cl-].[NH4+]>CCOCC.O>[OH:24][C:17]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([C:15](=[O:14])[C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CCOC(=O)C(O)(Cn1cncn1)c1ccc(F)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: O=C(C(O)(Cn1cncn1)c1ccc(F)cc1)C(F)(F)C(F)(F)F
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Gaseous pentafluoroethyl iodide (5 g., 0.02M) was passed into a flask containing dry ether (40 ml.) at -70° and fitted with a dry-ice condenser. A 3 molar solution of methylmagnesium bromide (5.8 ml., 0.017M) was then added over 5 minutes keeping the temperature between -70° and -65°. The mixture was then stirred at -70° for 1/2 hour. 1-Ethoxycarbonyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol (1.3 g., 0.0047M) in dry ether (10 ml.) was then added over 10 minutes keeping the temperature at -65° or below. The mixture was then stirred at -70° for 1 hour and was then allowed to warm to -25° over 11/2 hours. A solution of ammonium chloride (5 g.) in water (30 ml.) was then added. The ether layer was separated and the aqueous layer was extracted further with ether (2×40 ml.). The ether layers were combined, dried (MgSO4) and evaporated to give the crude title compound as an oil. The oil was purified by chromatography on silica (230-400 mesh) eluting with ethyl acetate:60°-80° petrol (4:1, by volume) to give the title compound, 1.2 g (55% yield). The compound was recrystallised from cyclohexane, m.p. (after said recrystallisation) 128°-132°.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromothiophene (233.0 g, 1.43 mol), 4-fluorophenyl boronic acid (200.0 g, 1.43 mol), bis(triphenylphosphine)palladium(II) dichloride (10.0 g, 14.2 mmol) and aqueous Na2CO3 (454.5 g, 4.3 mol in 1.5 L of H2O) in 1,2-dimethoxyethane (2 L) was stirred at 75-80° C. (internal temperature) for 2 hours. The resulting mixture was cooled to room temperature and then stirred overnight. The solid was separated and discarded. The liquid was washed with water (2×500 mL). The combined aqueous layer was extracted with diethylether (2×500 mL). The combined organic layers were then dried over NaCl, concentrated and purified by flask distillation to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([NH:12][C:13]([C:15]2[C:16](=[O:33])[C:17]([O:31][CH3:32])=[C:18]([C:27]([O:29][CH3:30])=[O:28])[N:19]([CH2:21][CH:22]([O:25]C)[O:23]C)[CH:20]=2)=[O:14])[CH2:11][CH2:10]1.CS(O)(=O)=O>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([NH:12][C:13]([C:15]2[C:16](=[O:33])[C:17]([O:31][CH3:32])=[C:18]([C:27]([O:29][CH3:30])=[O:28])[N:19]([CH2:21][CH:22]([OH:23])[OH:25])[CH:20]=2)=[O:14])[CH2:10][CH2:11]1
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)NC2(c3ccc(F)cc3F)CC2)cn1CC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1c(OC)c(=O)c(C(=O)NC2(c3ccc(F)cc3F)CC2)cn1CC(O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (27-1B, 0.150 g, 0.32 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70° C. After 16 hours, the mixture was cooled to afford a crude solution of methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 27-C. LCMS-ESI+ (m/z): [M+H]+ calculated for C18H19F2N2O7: 439; found: 439.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(O)C>[CH2:2]([O:1][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)[CH3:3]
Reactant: CC[O-]
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1sc(OCC)nc1C(F)(F)F
Temperature: 80 °C
Yield: 78 %

Procedure:
To a cold (0° C.) solution of sodium ethoxide, prepared from 0.46 g (0.02 mole) of sodium and 40 ml. of dried ethanol, was added 5.2 g (0.02 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate. A precipitate formed immediately. The reaction mixture was heated to 80° C. and then poured into ice water. The precipitate was collected to give 4.2 g (78%) of the desired product as a white solid, m.p. 30.5°-31.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])(O)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1.S(Br)([Br:26])=O.Cl>C(#N)C.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Br:26])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1
Reactant: O=S(Br)Br
Reactant: OC(Cn1cncn1)(c1ccc(Cl)cn1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ccc(C(Br)(Cn2cncn2)c2ccc(Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(5-Chloropyrid-2-yl)-1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol (0.55 g, 1.49 mmoles) was stirred in acetonitrile (20 ml) and thionyl bromide (0.4 g, 1.92 mmoles) was added. After 1 hr. at room temperature, a small amount of starting material remained (as shown by t.l.c.) and thus a further 0.1 g of thionyl bromide was added and the solution was stirred overnight at room temperature. The acetonitrile was then removed by evaporation under reduced pressure and the residue was basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3×40 ml). The combined organic extracts were dried over magnesium sulfate and evaporated and the residue was flash chromatographed on silica (230-400 mesh), eluting with ethyl acetate:hexane (1:3, v:v) to give an oil which was dissolved in dry ether and treated with ethereal hydrogen chloride. The white solid which precipitated (0.23 g) was recrystallized from isopropanol/diisopropyl ether to give the title compound as white crystals, 0.112 g (16%), m.p. 130° -150° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 61.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide as starting materials to give (S)—N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (44 mg, 61.3%) as a yellow solid.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:16])([F:15])[CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:25](#[N:29])[CH2:26][C:27]#[N:28].O>CS(C)=O>[F:15][C:8]([F:16])([CH:9]([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:7][CH:26]([C:25]#[N:29])[C:27]#[N:28]
Reactant: N#CCC#N
Reactant: O=S(=O)(OCC(F)(F)C(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(C#N)CC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
8.0 g of 2,2,3,4,4,4-hexafluorobutyl trifluoromethanesulfonate was dissolved in 15 ml of dimethyl sulfoxide, and 6.9 g of potassium carbonate was added. 5.0 g of malononitrile dissolved in 15 ml of dimethyl sulfoxide was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.0 g of 2-(2,2,3,4,4,4-hexafluorobutyl)malononitrile.