Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].N12CCCN=C1CCCCC2.N[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.CS(C)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[O:10])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: Nc1ccc(O)cc1
Reactant: NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)urea (100 g, 0.04191 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.4 ml, 0.0628 mol) and 4-amino phenol (5.48 g, 0.050 mol) were mixed with dimethyl sulfoxide (25 ml) and the reaction mass was heated to 80°-90° C. for 8-9 hours. It was then cooled to room temperature and quenched in water (150 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. The residue was then dried over sodium sulfate and evaporated under vacuum to obtain solid. The solid thus obtained was then slurried in acetonitrile (100 ml) at ambient temperature and filtered. It was washed repeatedly with acetonitrile till clear filtrate was obtained. The obtained cake was suck dried for 10 minutes and vacuum dried at 50° C. to give 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (9.8 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]4=[O:35])[CH:22]=3)[CH:13]=2)[C:9]([CH3:38])=[N:8][CH:7]=1.Br[CH2:40][CH2:41][O:42][CH2:43][CH2:44]Br>C(#N)C.C(N(CC)CC)C>[CH2:36]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[O:20][C:14]2[CH:13]=[C:12]([CH2:11][N:10]3[C:6]([CH2:5][CH2:4][N:3]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:7][N:8]=[C:9]3[CH3:38])[CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]1=[O:35])[CH3:37]
Reactant: BrCCOCCBr
Reactant: CCC1(c2cccc(Oc3cc(Cn4c(CCN)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC1(c2cccc(Oc3cc(Cn4c(CCN5CCOCC5)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-2-methyl-imidazol-1-ylmethyl]-2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile dihydrochloride (as described in Example 11) (0.25 g, 0.456 mmol) in acetonitrile (35.0 mL) and triethylamine (1.8 mL) was added 2-bromoethyl ether (0.133 mL, 1.06 mmol) and the mixture was refluxed for 48 hr. The solvents were removed in vacuo to obtain the title compound after purification by preparative HPLC.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].C[C:24]1[CH:29]=[CH:28][C:27](S(C[N+]#[C-])(=O)=O)=[CH:26]C=1.[H-].[Na+].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.CCOCC.CO.O>[OH:17][CH2:16][C:15]([CH3:18])([C:19]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([CH3:22])([C:21]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:2][OH:1]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(CO)CCCCCC(=O)CCCCCC(C)(C)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(CO)(CCCCCC(=O)CCCCCC(C)(CO)c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 56 %

Procedure:
In analogy to the procedure of 214g, to a solution of 207h (18.0 g, 63.1 mmol), tetrabutylammonium iodide (2.0 g, 5.4 mmol) and TosMIC (4.8 g, 24.6 mmol) in anhydrous DMSO (250 mL) and Et2O (80 mL) was added NaH (60% dispersion in mineral oil, 2.5 g, 62.5 mmol) while cooling with an ice bath under N2 atmosphere. After 24 h at room temperature, the mixture was hydrolyzed and worked up by extraction to give the crude intermediate (18.0 g) as a brown oil. This crude material was heated to reflux in methanol (300 mL), coned HCl (36 mL) and water (70 mL) for 3 h. Extractive workup and purification by flash chromatography (silica gel; hexanes/ethyl acetate/hexanes=10/1, 5/1, 2/1) yielded 214h (6.1 g, 56%) as a yellowish oil. 1H NMR (CDCl3): δ 7.32-7.19 (m, 10H), 3.68 (d, 2H, J=10.8), 3.50 (d, 2H, J=10.8), 2.26 (t, 4H, J=7.50H), 1.88-1.42 (m, 10H), 1.25 (s, 6H), 1.22-0.85 (m, 8H). 13C NMR (CDCl3): δ 211.68, 144.94, 128.56, 126.82, 126.23, 72.68, 43.50, 42.79, 38.42, 30.01, 23.74, 23.68, 21.62. HRMS (LSIMS, nba): Calcd for C29H43O3 (MH+): 439.3212. found: 439.3207. HPLC: 95.3% pure.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:55])=[C:33](OS(C3C(C(C)C)=CC(C(C)C)=CC=3C(C)C)(=O)=O)[N:34]=2)[C:29](=[O:56])[C:28]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:27]1.O>C(Cl)Cl.C(OCC)C>[C:2]([N:5]1[CH2:10][CH2:9][N:8]([C:33]2[N:34]=[C:35]3[C:30]([C:29](=[O:56])[C:28]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:27][N:26]3[C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[F:18])=[CH:31][C:32]=2[F:55])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OS(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Yield: 93.1 %

Procedure:
In 2 ml of methylene chloride was suspended 70 mg of N-acetylpiperazine monohydrochloride, and 80 mg of triethylamine was added thereto to form a solution. Subsequently, 200 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-triisopropylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate was added thereto, and the resulting mixture was subjected to reaction at room temperature for 2 hours. To the reaction mixture were added 8 ml of methylene chloride and 10 ml of water, and the organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 5 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 140 mg (yield 93.1%) of ethyl 7-(4-acetyl-1-piperazinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 217°-219° C. The physical properties of this compound were identical with those of the compound obtained in Example 39.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[NH2:54][C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[C:58]([O:65][CH2:66][CH2:67][CH2:68]O)[CH:59]=[CH:60][CH:61]=2)[N:56]=1>C1COCC1>[CH3:31][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[C:21]([O:20][CH2:68][CH2:67][CH2:66][O:65][C:58]3[CH:59]=[CH:60][CH:61]=[C:62]4[C:57]=3[N:56]=[C:55]([NH2:54])[CH:64]=[CH:63]4)[CH:22]=[CH:23][CH:24]=2)[N:29]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: Nc1ccc2cccc(OCCCO)c2n1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cccc(OCCCOc3cccc4ccc(N)nc34)c2n1
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial with a septum cap was charged with PS-PPh3 resin (Aldrich Chemical Co., Inc, 60 mg, 2.4 equiv), 8-hydroxyquinaldine (1.5 equiv) and DBAD (28 mg, 1.6 equiv) and purged by passing a stream of N2 for 45 seconds. Anhydr. THF (3 mL) was added and the contents of the vial were shaken for 5 min. Then, a solution of 3-((2-aminoquinolin-8-yl)oxy)propan-1-ol (16.7 mg/mL; 1.0 mL, 0.077 mmol) in anhydr. THF (1 mL) was added and the resulting suspension was agitated at room temperature for 8 h. Then, PS-PPh3 resin (Aldrich Chemical Co., Inc, 60 mg, 2.4 equiv) and DBAD (28 mg, 1.6 equiv) were added and the mixture was agitated at room temperature for additional 6 h. The suspension was filtered, and the resin washed with THF (3×3.0 mL). The filtrate and washings were combined and evaporated in vacuo. The residue was then treated with 6.0 mL of 4 M HCl in dioxane at room temperature for 6 h. The resulting solution was evaporated in vacuo. The residue was dissolved in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.60 (d, 1H), 7.90 (d, 1H), 7.69 (t, 1H), 7.65 (d, 1H), 7.53 (d, 1H), 7.46 (d, 1H), 7.30 (t, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 6.99 (d, 1H), 4.65 (br t, 2H), 4.48 (br t, 2H), 3.10 (s, 3H), 2.64 (m, 2H); MS (DCI/NH3) m/z 360 [M+H]+.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1N.C[O-].[Na+].C(N(C(C)C)CC)(C)C>CS(C)=O>[O:2]=[CH:3][CH2:4][C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
D-Glucosamine hydrochloride (13 mg, 0.06 mmol) was added to a solution containing sodium methoxide (3.24 mg, 0.06 mmol) in 3 mL DMSO. The reaction mixture was stirred at room temperature for 2 hrs, and purpurin-18-N-3′-(isothiocyanate)propylimide (19 mg, 0.028 mmol) and 50 μL diisopropylethylamine were added. The resulting solution was stirred under argon atmosphere for 20 hrs. After removing solvent and base by vacuum, the crude obtained was washed with both CH2Cl2 and, water and subsequently crystallized from MeOH. The desired 2-deoxyglucose conjugate (5) was obtained (8 mg). The filtrate was further concentrated and purified by silica gel plate chromatography (10% MeOH in CH2Cl2) to yield 4 mg of product. Thus, the total yield for 5 was 50% (12 mg). UV-vis in DMSO λmax: 366 nm (ε: 5.3×105), 419 (1.4×104), 550 (2.4×104), 648 (8.0×103) and 705 (5.2×104). Mass calcd for C44H53N7O9S: 878.3523 (M+Na)+; found by HRMS; 878.3542 (M+Na)+. 1H NMR (DMSO-d-6, δ ppm): 9.27, 9.16 and 8.85 (each s, 1H, for 10, 5 and 20-H), 8.01 (dd, 1H), 7.80 (br, 1H), 6.55 (br, 1H), 6.33 (d, 1H), 6.12 (d, 1H), 5.24-4.21 (9H), 3.80-3.40 (13H), 2.90 (s, 3H), 2.60 (m, 1H), 2.50-2.30 (m, 2H), 2.08 (m, 2H), 1.8 (m, 1H), 1.72 (d, 3H), 1.41 (t, 3H), −0.61 and −0.67 (each s, 1H, 2×NH).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH:5]([C:10]1[CH:11]=[C:12]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)[CH:15]=1)[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 50 °C

Procedure:
To a solution of a mixture of 4-methyl-2-{4′-trifluoromethyl-5-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester (69 mg, 0.12 mmol) in MeOH (2 mL) was added 3N NaOH (0.100 mL) and heated to 50° C. for 14 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 4-methyl-2-{4′-trifluoromethyl-5-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid. 1H-NMR (DMSO-d6): δ 0.88 (d, 6H), 1.44 (m, 1H), 1.60 (m, 1H), 1.69-1.99 (m, 5H), 2.92 (m, 4H), 3.68 (m, 2H), 4.02 (d, 2H), 7.10 (s, 1H), 7.13 (s, 1H), 7.29 (s, 1H), 7.51 (m, 4H), 7.85 (dd, 4H); Calcd for C31H31F6NO2 (M+H) 564.57, Found 564.3
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])=[N:13]1)=[O:11])([CH3:8])[CH3:7]>C(O)(=O)C>[CH:6]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[C:15]([Cl:4])[C:14]([O:18][C:19]2[C:20]([Cl:30])=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[CH:23][C:24]=2[Cl:25])=[N:13]1)=[O:11])([CH3:8])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NC(C)C
Solvent: CC(=O)O
Product: Cc1c(Cl)c(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-isopropyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.40 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/20), to give a white solid of N-isopropyl-4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.19 g, yield: 44.1%) [mp: 109-111° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (d, J=7.5 Hz, 6H), 2.61 (s, 3H), 3.85-4.10 (m, 1H), 6.25-6.50 (m, 1H), 7.67 (s, 2H).] and a white solid of N-isopropyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-trichloromethylpyrazole-1-carboxamide (0.04 g, yield: 8.0%) [mp: 105-106° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (d, J=6.5 Hz, 6H), 3.85-4.15 (m, 1H), 6.25-6.55 (m, 1H), 7.69 (s, 2H), 8.24 (s, 1H)].
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([S:34]([CH3:37])(=[O:36])=[O:35])[C:12]1[C:13]([O:32][CH3:33])=[CH:14][C:15]2[C:19]([CH:20]=1)=[N:18][N:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:16]=2[C:28]([NH:30][CH3:31])=[O:29])(C(C)(C)C)(C)C.[F-].[NH4+].O>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[C:16]([C:28]([NH:30][CH3:31])=[O:29])=[C:15]3[C:19]([CH:20]=[C:12]([N:11]([CH2:10][CH2:9][OH:8])[S:34]([CH3:37])(=[O:35])=[O:36])[C:13]([O:32][CH3:33])=[CH:14]3)=[N:18]2)=[CH:22][CH:23]=1
Reactant: CNC(=O)c1c2cc(OC)c(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1c2cc(OC)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 60 °C
Yield: 33.1 %

Procedure:
To a stirred solution of Compound (11) (250 mg, 0.45 mmol) in MeOH (20 mL) was added ammonium fluoride (166 mg, 4.5 mmol) and water (5 mL). The reaction mixture was heated to 60° C. for 5 h (monitored by TLC and LCMS). MeOH was removed in vacuo and the residue was diluted with water. The resulting precipitate was filtered, washed with ethanol and dried in vacuo at 40° C. to give Compound (12) (65 mg, 33%). ESI-MS m/z calculated for [M+Na]+: 459.11; found: 459.11; 1H NMR (400 MHz, d6-DMSO) δ 8.65 (s, 1H), 7.77 (s, 1H), 7.65-7.52 (m, 2H), 7.46-7.32 (m, 2H), 7.15 (s, 1H), 4.80-4.70 (m, 1H), 3.92 (s, 3H), 3.78-3.39 (m, 4H), 3.08 (s, 3H), 2.88-2.77 (m, 3H).
Reaction SMILES: [Cl:1]C(Cl)(Cl)C=O.C(#N)C=C.[Cl:11][CH:12]([CH2:15][C:16]([Cl:20])(Cl)[CH:17]=O)[C:13]#[N:14]>O>[Cl:1][C:17]1[C:16]([Cl:20])=[CH:15][C:12]([Cl:11])=[CH:13][N:14]=1
Reactant: N#CC(Cl)CC(Cl)(Cl)C=O
Reactant: O=CC(Cl)(Cl)Cl
Solvent: O
Solvent: C=CC#N
Product: Clc1cnc(Cl)c(Cl)c1

Procedure:
A process for producing 2,3,5-trichloropyridine, which process comprises causing trichloroacetaldehyde to undergo an addition reaction, in the presence of a catalyst, with acrylonitrile, and cyclising the formed 2,4,4-trichloro-4-formylbutyronitrile of the formula I ##STR2## with the splitting-off of water, to give 2,3,5-trichloropyridine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([OH:20])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([Cl:18])[C:9]=2[Cl:19])=[CH:5][CH:4]=[N:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([Cl:18])[C:9]=2[Cl:19])=[O:20])=[CH:5][CH:4]=[N:3]1
Reactant: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
20 g of manganese dioxide are added to a solution of 7.08 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol in methylene chloride and the mixture is stirred at room temperature for 3 days. The reaction mixture is filtered and washed with chloroform. The filtrate and the washings are combined and evaporated to remove solvent. The residue is crystallized from n-hexane to give 6.35 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dimethoxyphenyl)-methanone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccc(F)cc3)CC1)O2

Procedure:
Compound 125 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-fluorobenzene and conditions outlined in procedure V. M.p.=104-106° C.; 400 MHz 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 3.55 (s, 2H), 2.9 (s, 2H), 2.75 (d, 2H), 2.45 (t, 2H), 2.1 (d, 2H), 1.85 (t, 2H); LCMS: 410 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]=[N+]=[N-])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl azide (step 8, 2.35 g, 7.3 mmol) in methanol (50 nmL) was added 10% Pd—C (200 mg). The resulting mixture was stirred for 4 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol/triethylamine (100:5:1) to afford 2.01 g (94%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.39 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.05 (2H, t, J=7.3 Hz), 2.88–2.78 (4H, m), 2.65 (3H, s), 2.51 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2ccc(F)cc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2ccc(F)cc2N1
Yield: 93.7 %

Procedure:
The product is prepared by following the procedure described in reference example 2c (step 1c) using 1.4 g of 6-fluoro-2-methylindole, 51 ml of acetic acid and 1.9 g of sodium cyanoborohydride. After silica column purification, eluent: 90/10 heptane/ethyl acetate, 1.33 g of 6-fluoro-2-methyl-2,3-dihydro-1H-indole are obtained, which is used as it is in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20](O)=[O:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])=[O:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: CNCCOC
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Product: COCCN(C)C(=O)c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1

Procedure:
This material is prepared by a method analogous to that described for Example 21, starting from 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylic acid and 2-methoxyethyl-N-methyl amine.
Reaction SMILES: Br[CH:2]=[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH2:4]1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:23]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])=[CH:4][CH:5]=1)([O:13][CH3:14])=[O:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1ccccc1C1=CCC(=CBr)C=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Yield: 7.4 %

Procedure:
Methyl 2-[4-(bromomethylene)phenyl]benzoate (1.22 g, 0.04 mole), phthalimide (0.59 g, 0.04 mole), and potassium carbonate (0.55 g, 0.04 mole) are combined in 120 mL acetonitrile. The mixture is heated at reflux for 24 hours. At that time the mixture is filtered through celite and rotovapped to a residue. The residue is crystallized from ethyl acetate to afford 1.1 g (71% ) of the title compound as a tan solid mp 148°-150° C. 1H NMR (CDCl3) 7.9-7.1 (12H, m); 4.92 (2H, s); 3.63 (3H, s). Mass Spec. (DCI) m/z 372 (M+H). Analysis -calc'd for C23H17NO4.1/2 H2O: C, 72.62; H, 4.77: N, 3.68; found: C, 72.88; H, 4.55; N, 3.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])/[C:10](/[CH3:19])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])/[C:10](/[CH3:19])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)[CH:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: C/C(=C\c1cccc(O)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C/C(=C\c1cccc(Oc2ccnc(C#N)c2)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 68.6 %

Procedure:
(E)-N-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-hydroxyphenyl)-2-methylacrylamide (1.0 g, 2.81 mmol), 4-chloropicolinonitrile (428 mg, 3.09 mmol) and cesium carbonate (2.75 g, 8.43 mmol) were combined and stirred in DMF. The reaction mixture was heated at 100° C. overnight and then cooled to rt. The mixture was filtered to remove cesium carbonate, the collected precipitate was washed with EtOAc, and the combined filtrate was concentrated. Purification by column chromatography (SiO2, 0-80% EtOAc in hexanes) provided the title compound (883 mg). LCMS, FA: Rt=2.15 min, [MH+ 458.0].