Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(=O)O[CH2:11][CH2:10][O:9]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1(=O)OCCO1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:11][CH2:10][OH:9])[CH:3]=1
Reactant: Oc1cccnc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1cccnc1
Temperature: 86 °C
Reaction time: 13 h
Yield: 71.8 %

Procedure:
3-hydroxypyridine (20.0 kg), ethylene carbonate (19.4 kg), K2CO3 (18.9 kg), and DMF (75.5 kg) were charged to a 400 L reactor and heated to 86° C. After 13 h, an aliquot was taken. There was still some 3-hydroxypyridine left by GC so more ethylene carbonate (1.0 kg) was added. After 20 h, the reaction was deemed complete. The reaction was cooled to 20° C., H2O (85 L) was slowly added to the 400 L reactor, and stirring continued for 30 min. The title compound was extracted with 35° C. CH2Cl2 (4×170 L) sending the CH2Cl2 extractions into the 1000 L portable tank. The aqueous layer was discarded, and the 400 L reactor was cleaned. The solution of the title compound in the 1000 L portable tank was transferred to the 400 L and distilled in the 400 L reactor sending the distillate to the 400 L receiver. Toluene (200 L) was added to the 400 L reactor and distilled sending the distillate to the 400 L receiver. The resulting oil was transferred to a 20 L glass bottle to produce 21.0 kg (72%) of the title compound of 100.0% GC purity.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.O1CCCC1>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1nc(C=Cc2cccc([N+](=O)[O-])c2)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCc2cccc(N)c2)cs1

Procedure:
N-{4-[2-(3-Nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (E,Z mixture) (315 mg) in a mixed solvent of methyl alcohol (3 ml), tetrahydrofuran (6 ml), and acetic acid (1 ml) was hydrogenated over 10% Palladium on carbon (50% wet, 200 mg) under 4.3 atmospheric pressure at room temperature for 3 hours. The catalyst was removed off by filtration, and the filtrate was evaporated in vacuo. The residue was poured into water, the pH of the aqueous layer was adjusted to 9 with aqueous sodium hydrogen carbonate. The resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (9 g) using a mixed solvent of n-hexane and ethyl acetate (2:1 to 1:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give syrup. The syrup of the objective compound was changed to solid in freezer (275 mg, 96.6%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[CH:5]3[CH:14]([CH2:13][CH2:12][C:11]=2[CH:10]=1)[CH:15]1[C:2]([CH3:1])([C:18](=[O:19])[CH2:17][CH2:16]1)[CH2:3][CH2:4]3)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC12CCC3c4ccc(OCc5ccccc5)cc4CCC3C1CCC2=O
Temperature: 80 °C

Procedure:
A solution of 15 g (55 mmol) of estrone in DMF (110 mL) was cooled to 0° C. and 2.44 g (61 mmol) of NaH (60% in oil) were added slowly. The mixture was stirred at 0° C. under N2 for 1 h before addition of 13.2 mL (111 mmol) of benzyl bromine dropwise at 0° C. The reaction was then heated to 80° C. for 4 h. After cooling, the mixture was poured into water. The suspension was extracted by diethyl ether (5 times). The mixed organic layer were washed with 2N HCl (3 times) and brine, dried over Na2SO4 and concentrated in vacuo. Recrystallisation of the solid residue in ethanol gave 12.33 g (62%) of JAC01002 as beige solid. 1H NMR (400 MHz, CDCl3) δ 0.92 (s, 3H, CH3); 1.49-1.63 (m, 6H); 1.99-2.05 (m, 3H); 2.17 (dAB, J=18.9, 8.9 Hz, 1H); 2.23 (m, 1H); 2.40 (m, 1H); 2.51 (dAB, J=18.9, 8.9, 1H); 2.85 (m, 2H, CH26); 5.05 (s, 2H, OH2Ph); 6.74 (d, J=2.8 Hz, 1H, H4); 6.80 (dd, J=8.5, 2.8 Hz, 1H, H2); 7.21 (d, J=8.5 Hz, 1H, H1); 7.30-7.45 (m, 5H); Acq. Mass (FAB+) calcd 360.2089, obsd 360.21675 (M+).
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)[CH:3]=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[CH:3]=[N:13][NH:14][C:5]=1[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1
Reactant: NN
Reactant: CC(C=O)C(=O)C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1cn[nH]c1C1CCOC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2-methyl-3-oxo-3-(tetrahydrofuran-3-yl)propanal (compound 263.3, 3.00 g, 19.2 mmol) in ethanol (25 mL). Hydrazine hydrate (1.16 mL, 24 mmol) was added and the resulting solution was stirred for 3 h at 80° C. The resulting mixture was concentrated under reduced pressure to obtain the title compound as a colorless oil (3.5 g, crude).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:19]([O:21][CH2:22][C:23](Cl)=O)[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:18][C:3]1[C:2]2[N:1]=[C:20]([CH2:19][O:21][CH2:22][CH3:23])[N:12]([CH2:13][C:14]([CH3:16])([CH3:15])[OH:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Reaction time: 120 h
Yield: 71.9 %

Procedure:
3-Amino-2-chloro-4-(2-hydroxy-2-methylpropylamino)quinoline (2.0 g, 7.5 mmol) was combined with acetonitrile (80 mL). Ethoxyacetyl chloride (0.92 g, 7.5 mmol) was added to the reaction mixture. After about 5 minutes a yellow precipitate formed. p-Toluenesulfonic acid (0.1 g) was added and the reaction mixture was heated to reflux. Refluxing was continued for about 120 hours at which time the reaction mixture was homogeneous. The reaction mixture was cooled and the acetonitrile was removed under vacuum. The resulting residue was dissolved in methylene chloride and washed with dilute ammonium hydroxide. The aqueous phase was extracted with methylene chloride (3×25 mL). The organic phases were combined, dried over magnesium sulfate and then concentrated to provide 2.6 g of crude product as a dark yellow solid. The crude product was recrystallized from t-butylmethyl ether to provide 1.8 g of a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([C:25]([F:24])([F:33])[F:34])[N:30]=3)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)ccc1Cl
Reactant: NCc1nc(C(F)(F)F)no1
Product: Cc1cc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)ncc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BN) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 493.0499 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:27][CH2:28][CH2:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1>>[F:27][CH2:28][CH2:29][NH:30][C:31]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:32]
Reactant: O=C(NCCF)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)NCCF)c3)c2cc1OC
Yield: 18.8 %

Procedure:
4-(1H-Indol-5-yloxy)-6,7-dimethoxyquinoline (75 mg, 0.3122 mmol), sodium hydride (13 mg, 0.3278 mmol) and phenyl N-(2-fluoroethyl)carbamate (45 mg, 0.3278 mmol) were used for reaction in the same manner as Example 310, followed by extraction with ethyl acetate/tetrahydrofuran, washing with saturated saline and drying over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was adsorbed onto silica gel and subjected to silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (24 mg, 0.0586 mmol, 18.78%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(SCc2ccccc2)s1
Yield: 71.6 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (2.0 g), benzyl bromide (2.6 g), and potassium hydroxide (0.8 g) were stirred in methanol (50 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.4 g of the aimed compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C1C=CN=CC=1)C.ClCCl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c(Br)c(Br)n2Cc2ccccc2)c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirring mixture of 1-benzyl-2,3-dibromo-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (492 mg, 1.08 mmol), triethylamine (300 μL, 2.16 mmol), and DMAP (13 mg, 0.11 mmol) in anhydrous dichloromethane (5 mL) was added pivaloyl chloride (160 μL, 1.30 mmol); the mixture was stirred for 1 h at room temperature before diluted with EtOAc, then washed with diluted HCl aqueous solution, saturated NaCl aqueous solution respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, the residue was purified by column to give a foamy brown solid, the desired title compound (495 mg, 85%). The title compound, ESI MS (m/z): 537 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]#[N:15])[C:7](=O)[C:6]12[O:21][CH2:20][CH2:19][CH2:18][O:17]1.N.C1COCC1>[Ni].CCO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][N:15]=[C:7]3[C:6]3([O:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C1(OCCCO1)C(=O)N2CCC#N
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Temperature: 135 °C
Yield: 27.3 %

Procedure:
A mixture of 3-(5′-methoxy-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl)propanenitrile (1.00 g, 3.47 mmol) and wet Raney Nickel (1.00 g) in 2M EtOH.NH3 (45 mL) and THF (45 mL) was hydrogenated in a Parr Hydrogenation Bottle (250 mL) at 53 lb/in H2 for 20 hr. The mixture was filtered through Celite and the filtrate was poured into a steel pressure vessel and heated at 135° C. for 66 hr. The reaction was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with a step gradient CH2Cl2/CH3OH/NH4OH (98.5/1/0.5 to 97/2/1) to give the title compound as a tan solid (0.26 g, 27% ). NMR (300 Mz, DMSO-d6): consistent. MS: (API-ES+) 275[M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18]CC3C=CC=CC=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[C:3]1=[O:26]>[Pd].C1COCC1.CO>[OH:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@@H:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:26])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H]2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(O[C@@H]2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 98 %

Procedure:
A solution of methyl 3-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-phenylmethoxy-benzoate (Intermediate 13) (1.42 g, 4.0 mmol) was added to a suspension of 10% palladium on carbon (140 mg, catalytic) in THF (40 mL) and methanol (40 mL). The mixture was stirred under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to give the product (1.04 g, 98%). 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.56-2.68 (m, 1H), 2.97 (s, 3H), 3.37-3.55 (m, 2H), 3.86 (s, 3H), 4.93 (t, 1H), 6.81 (s, 1H), 7.04 (s, 1H), 7.12 (s, 1H), 7.66 (s, 1H); m/z 266 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.N1C=CC(B(O)O)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[Cl:16][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([C:3]3[CH:2]=[CH:6][S:5][CH:4]=3)[C:8]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:9]=3[C:10]=2[CH:11]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2-c2cscc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2-c2ccsc2)C1
Temperature: 95 °C
Yield: 43.9 %

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), 4-pyridinylboronic acid (48.5 mg, 0.394 mmol) and K3PO4 (139.39 mg, 0.657 mmol) in DMF-water (2:0.2 mL) was added dichlorobis(triphenylphosphine) palladium (II) (9.23 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 8-chloro-2-methyl-5-thiophen-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 7.7 (dd, 1H), 7.58 (m, 2H), 7.2 (m, 3H), 4.76 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH3:14][N+:15]([CH3:17])=[CH2:16].[I-:18]>C(O)(=O)C>[IH:18].[CH3:13][O:12][C:10]([C:5]1[C:4]2[C:3]([CH2:14][N:15]([CH3:17])[CH3:16])=[CH:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: [I-]
Reactant: C=[N+](C)C
Reactant: COC(=O)c1cccc2[nH]ccc12
Solvent: CC(=O)O
Product: COC(=O)c1cccc2[nH]cc(CN(C)C)c12
Product: I
Temperature: 65 °C

Procedure:
Methyl indole-4-carboxylate (7.0 g, 40 mmol) and Eschenmoser's salt (N,N-dimethylmethyleneammonium iodide; 7.8 g, 42 mmol) are combined in 130 ml of acetic acid. After heating at 65° C. for 2 hours, the reaction mixture is concentrated in vacuo. The resulting solid is triturated with ethyl acetate, filtered and dried in vacuo to give 3-dimethylaminomethyl-1H-indole-4-carboxylic acid methyl ester hydroiodide in quantitative yield.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(N(CC)CC)C.CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: N#CCCl
Reactant: CCOCCn1c(CC2CCNCC2)nc2cccnc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(CC2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 4.53 parts of chloroacetonitrile, 17.3 parts of 3-(2-ethoxyethyl)-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine, 6 parts of N,N-diethylethanamine and 94 parts of N,N-dimethylformamide was stirred for 3 hours at room temperature. The reaction mixture was poured into water and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated, yielding 23.75 parts (100%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineacetonitrile as a residue (compound 104).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][C:21]#[CH:22].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH2:22]([C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[C:21]#[CH:20]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: C#CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 0.83 g of 1-bromo-2-propyne were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate 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 0.65 g of 2-(2-propynyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (76)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:59]=[CH:58][C:55](CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][C:55]2[CH:58]=[CH:59][C:52]([F:51])=[CH:53][CH:54]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(F)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 67.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluorobenzyl alcohol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Cl:9]C1C=C(C)C=CC=1.ClC1C=CC(C)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:7]1[C:2]([Cl:1])=[C:3]([CH3:8])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(Cl)c1
Reactant: Cc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: Cc1ccc(Cl)cc1
Product: Cc1cccc(Cl)c1Cl
Yield: 4.5 %

Procedure:
The chlorination of toluene in the presence of catalysts is known to produce the ring-chlorinated isomeric o-, m- and p-monochlorotoluenes in a ratio which varies according to the type of catalyst used and the reaction conditions chosen. Thus, for example, the chlorination of toluene at 50° C. in the presence of FeCl3 as catalyst up to a density of 1.043 g/cm3 (20° C.) leads to a product comprising 19% by weight of toluene, 49% by weight of o-chlorotoluene, 2% by weight of m-chlorotoluene and 25.5% by weight of p-chlorotoluene. Apart from these, 4.5% of dichlorotoluene are additionally formed (Ullmanns Encyl. der techn. Chemie [Ullmann's Encyclopedia of Industrial Chemistry] (1975), Volume 9, page 512). The use of TiCl4, SnCl4, WCl6 or ZrCl4 as catalysts at a chlorination temperature of 10°-30° C. increases the o-chlorotoluene content to 75% by weight (U.S. Pat. No. 3,000,975), while the use of disulfide dichloride and the metal chlorides mentioned or of sulfur and SbCl3 shifts the isomeric ratio in favor of p-chlorotoluene (U.S. Pat. No. 1,946,040). There is no successful instance of obtaining a single isomer by a suitable choice of catalyst or reaction conditions. All these processes therefore require a subsequent separation of the reaction mixture into the pure isomers, which separation is customarily carried out in two stages where, in a first working-up stage, which is expensive in outlay and energy, o-chlorotoluene (boiling point 158.5° C.) is separated as top product by distillation, for example in a bubble cap column having over 200 theoretical plates, from a bottom comprising m- and p-chlorotoluene. Due to the small difference in the boiling points of these isomers (161.2° C. and 161.5° C. respectively), it is no longer possible to separate their mixture by distillation. Pure p-chlorotoluene (melting point 7.6° C.) must therefore be separated in a second step by crystallization from the m-isomer, which has a lower melting point (melting point -48.7° C.).