Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:13]([C:14](=[O:22])[C:15](=[O:21])[C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][NH:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>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.[Cu]I>[CH3:20][C:16]([CH3:19])([CH2:17][CH3:18])[C:15](=[O:21])[C:14]([CH:13]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Reactant: Ic1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1C(=O)CCCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 1-(2-hex-5-ynoylperhydropyridazinyl)-3,3-dimethylpentane-1,2-dione (0.384 g, 1.25 mmol) in 10 ml CH2Cl2under nitrogen was added 3-iodopyridine (0.283 g, 1.38 mmol), (Ph3P)2PdCl2 (0.044 g, 0.06 mmol), CuI (0.0024 g, 0.013 mmol) and triethylamine(0.3 ml, 2 mmol). The reaction mixture was stirred 30 minutes at room temperature and then refluxed overnight. The mixture was concentrated and purified by silica gel column, eluting with 30% ethyl acetate in hexane, to yield product as light yellow oil (0.31 g, 65%). 1H NMR (CDCl3, 400 MHz): δ 0.84 (t, 3H, J=7.4); 1.21 (s, 6H); 1.70 (m, 6H); 1.96(m, 2H), 2.52 (m, 3H); 2.90 (m, 2H); 3.60 (m, 1H); 4.42(m, 2H); 7.20 (m, 1H); 7.66 (m, 1H); 8.49 (m, 1H); 8.62 (m, 1H).
Reaction SMILES: I[CH2:2][C@H:3]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[C:8]1([CH2:7][O:6][C@@H:5]2[C@@H:14]([CH2:16][OH:17])[O:15][C@@H:3]([CH3:2])[CH2:4]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC[C@H]1O[C@H](CI)C[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1C[C@H](OCc2ccccc2)[C@@H](CO)O1
Yield: 75.7 %

Procedure:
A mixture of 6.0 g of product from Example 334, Isomer A, 34 ml of ethyl alcohol, 17.2 ml of 1N sodium hydroxide and 7.8 g of 10% palladium on carbon is hydrogenated in a Parr apparatus at 45 psi of hydrogen for 15 hours. The reaction mixture is filtered, diluted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated in vacuo to give 2.9 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.C1C=CC(N[S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])=CC=1>O>[F:49][C:48]([F:51])([F:50])[S:45]([O:26][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1)(=[O:47])=[O:46]
Reactant: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A vial charged with (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.200 g, 0.572 mmol) and potassium carbonate (0.087 g, 0.630 mmol) was treated with 2 mL DMF and was allowed to stir for 15 minutes. The reaction mixture was cooled to 0° C. and n-phenyltriflamide (0.245 g, 0.630 mmol) was added. After stirring for one hour the reaction mixture was poured into water and extracted with EtOAc. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.183 g, 0.380 mmol, 66.4% yield)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:3]=1.[OH-].[NH4+:27]>C(O)CO.O1CCOCC1.[Cl-].[Na+].O.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[N:12][C:8]([C:4]2[CH:3]=[C:2]([NH2:27])[CH:7]=[CH:6][N:5]=2)=[N:9]1
Reactant: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1cscn1
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: OCCO
Product: Nc1ccnc(-c2nc(-c3cscn3)n(Cc3ccccc3F)n2)c1
Temperature: 100 °C
Yield: 59.6 %

Procedure:
To a stirring suspension of 4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole (I-51, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane (approx. 4:1) in a sealed tube was added ammonium hydroxide. The resultant reaction mixture was heated at 100° C. for 12 h and then cooled to room temperature, treated with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified using SiO2 chromatography (methylene chloride/acetonitrile/methanol) to afford 2-(1-(2-fluorobenzyl)-5-(thiazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-amine as a solid in 59.6% yield.
Reaction SMILES: [OH-:1].[Na+].Br[CH:4]([CH3:23])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:6]>O.CN(C=O)C>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH:4]([CH3:23])[OH:1]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)Br)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)O)cc2)CC1
Reaction time: 0.67 h

Procedure:
Sodium hydroxide (370 mg, 9.25 mmol) in water (2 mL) was added to a stirred solution of methyl trans-4-[4-(2-bromopropanoyl)phenyl]cyclohexanecarboxylate (prepared as described in Patent Application WO2004/047755) (3.264 g, 9.25 mmol) in DMF (10 mL). The mixture was stirred for 40 minutes then extracted with ether (5×20 mL). The extracts were combined, dried and concentrated. The crude product was purified by flash column chromatography eluting with 20-40% EtOAc/hexanes to give the title compound (1.76 g, 66%) as a solid; 1H NMR δ 7.94 (2H, d), 7.39 (2H, d), 5.29 (1H, d), 5.08-4.98 (1H, m), 3.62 (3H, s), 2.68-2.54 (1H, m), 2.48-2.35 (1H, m), 2.08-1.94 (2H, m), 1.90-1.79 (2H, m), 1.60-1.40 (4H, m), 1.28 (3H, s); MS 313 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH2:12])=[C:7]2[C:3]=1[C:4]([CH2:14][CH:15]([N+:21]([O-])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][NH:6]2.Cl.[OH-].[Na+]>C(O)(C)C.C1COCC1.CCOC(C)=O.[Zn]>[NH2:21][CH:15]([CH2:14][C:4]1[C:3]2[C:7](=[C:8]([C:11](=[O:13])[NH2:12])[CH:9]=[CH:10][C:2]=2[Br:1])[NH:6][CH:5]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(Cc1c[nH]c2c(C(N)=O)ccc(Br)c12)[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C(N)Cc1c[nH]c2c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
A solution of ethyl 3-(4-bromo-7-carbamoyl-1H-indol-3-yl)-2-nitropropanoate (4.6 g, 11.97 mmol) in isopropanol (200 mL) and THF (100 mL) was cooled in an ice bath and treated portionwise with zinc dust (8.85 g, 135 mmol), followed by 1 M aqueous HCl (150 mL) in portions. The mixture was stirred at room temperature for 3 h, then treated with NaOH pellets and 1 M aqueous NaOH to pH 9-10. The mixture was diluted with THF and EtOAc, stirred for 15 min and filtered through a CELITE® pad. The solids were rinsed with EtOAc, THF, and NaHCO3 (aq). The filtrates were concentrated to remove most of the organic solvents, and the aqueous residue was extracted with EtOAc. The combined extracts were washed with brine, dried and concentrated to provide the desired product as an off-white solid (3.65 g, 86% yield). LCMS (M+H)+ m/z 353.8, 355.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)(Cl)Cl>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)nc1)OCc1ccccc1
Yield: 53.3 %

Procedure:
5-Amino-2-chloropyridine(643 mg)in 3 mL of chloroform containing 505 mg of triethylamine was stirred with 853 mg of benzyl chloroformate for 4 hours at 60 degrees C. The mixture was then diluted with 20 mL of chloroform and washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give 700 mg of 5-benzyloxycarbonylamino-2-chloropyridine. 5-Benzyloxy carbonylamino-2-chloropyridine (272 mg) and 163 mg of 2,4-dichlorophenol were stirred overnight at room temperature in 1 mL of dimethylformamide containing 138 mg of potassium carbonate. The reaction mixture was evaporated to dryness under high vacuum and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. Hydrogenolysis in methanol over palladium on carbon gave 5-amino-2-(2,4-dichlorophenoxy) pyridine. The 5-amino-2-(2,4-dichlorophenoxy)pyridine was treated with 4-(trifluoromethylmercapto)phenylisocyanate under conditions similar to those in Example 1 to give N-[2-(2,4-dichlorophenoxy)pyrid-5-yl]-N'-[4-trifluoromethyl mercapto)phenyl]urea.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(OC([N:29]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH2:39]([N:29]1[C:10]2[C@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1cc(Cl)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2cc(Cl)ccc2Cl)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3.2 %

Procedure:
Triethylamine (380 μL, 2.7 mmol) was added dropwise to a solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 318 mg, 1.5 mmol) in 1,2-dichloroethane (4 mL) over 1 min. Then a solution of N-benzyl-N′-(2,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (265 mg, 0.72 mmol) in 1,2-dichloroethane (8 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 100° C. for 45 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. An additional portion of HCl in dioxane (4 M; 2 mL, 8 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 2 h. The reaction mixture was allowed to cool to room temperature and dichloromethane (100 mL) was added. The mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified on an ISCO system using a 12 g column, eluting with 33-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with diethyl ether and petroleum ether, and then dried under high vacuum at 90° C. to give (4R,7S)-1-benzyl-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (10 mg, 3%) as a pale yellow solid. ES(+)-MS (M+H) 427.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].ClCCl>CS(C)=O>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCN(C(=O)OC(C)(C)C)CC5)nccc34)no2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCNCC5)nccc34)no2)cc1Cl
Yield: 64.5 %

Procedure:
1,1-Dimethylethyl 4-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]-1-piperazinecarboxylate (D15; 24 mg, 0.044 mmol), trifluoroacetic acid (1 ml, 13.0 mmol) and dichloromethane (1 ml) were stirred at room temperature for 1 h. The samples were dissolved in DMSO (1 ml) and purified by Mass Directed Preparative HPLC (supelcosil ABZ+Plus alkylamide phase column), eluting with solvents A/B (A: water+0.1% formic acid, B: MeCN:Water 95:5+0.05% formic acid). The solvent was evaporated in vacuo to give the title compound as a white solid (16 mg).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:21])[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.Cl.Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1OC1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=CN=1>>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([CH3:21])=[C:10]2[N:9]([CH:13]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:4][C:3]1[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:2]=1[F:1]
Reactant: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(N)cc3F)c12

Procedure:
3-(4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-N,N-dimethylpropan-1-amine (170 mg, 0.44 mmol) was converted to the title compound in a manner similar to the preparation of Compound B of Example 28. The resultant yellow solid was used in the next step without further purification. MS(ESI+) m/z 360.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:25][CH3:26])=[O:6].[S:30](Cl)(Cl)=[O:31]>C(Cl)(Cl)(Cl)Cl>[S:30](=[N:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]=1[CH2:25][CH3:26])=[O:6])=[O:31]
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N=S=O)c1
Temperature: 50 °C

Procedure:
A suspension of 3-amino-N-[2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.100 g, 0.237 mmol) (Example 4.1) in carbon tetrachloride (1 ml) was heated to 50° C. until it became a clear solution. A solution of thionyl chloride in carbon tetrachloride (1.68 M) (0.725 ml, 1.218 mmol) was added and the mixture was heated to 80° C. for one hour. The reaction mixture was evaporated under reduced pressure and the residue was triturated with cyclohexane. The suspension was filtered and the solid dried under high vacuum. The desired compound was obtained as white crystals. M.p. 100-108° C. 1H-NMR as described for Example 2.2. Mass spectrometric analysis: conditions as described for Example 2.1. Calculated exact mass: 468; [M-H]− observed: 467.06.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:9]([C:19]([CH3:21])=[O:20])=[C:8]([O:22]C)[CH:7]=1)(=[O:4])=[O:3].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:22][C:8]1[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:9]=1[C:19]([CH3:21])=[O:20]
Reactant: COc1cc(NS(C)(=O)=O)c(Oc2ccccc2)cc1C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
10.0 g of methyl 4-methylsulfonylamino-2-methoxy-5-phenoxyphenyl ketone was dissolved in 100 ml of methylene chloride. 3.98 g of aluminum chloride was added thereto in portions in 30 minutes with ice-cooling. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was introduced into 100 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from isopropyl alcohol to obtain 8.8 g (yield: 91.9%) of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone having a melting point of 151-153° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(S(C)(=O)=O)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 36.6 %

Procedure:
Using a procedure analogous to Example 26, the product from Example 14 (120 mg, 0.150 mmol) was treated with methanesulfonyl chloride (24.0 mg, 1.4 eq) to provide the title barbituric acid (42.0 mg, 37%). MS found: (M+H)+=538.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:23]1([NH2:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:29][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NN1CCOCC1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-morpholinamine (CAN 4319-49-7) as starting materials; LC-MS (UV peak area/ESI) 100%, 415.0911 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[CH3:20][O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:8](=[O:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Triethylamine (25.26 ml) and cinnamoyl chloride (16.60 g) were successively added to a methylene chloride solution (300 ml) of L-proline methylester hydrochloride (15.0 g) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. After stirring at room temperature for 1.5 hours, the mixture was poured into ice water and successively washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate, and saturated salt water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 23.09 g of N-cinnamoyl-L-proline methyl ester.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:15]([CH:18]=[CH:19][C:20]4[S:24][CH:23]=[N:22][C:21]=4[CH3:25])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CO>[NH2:10][CH:11]1[C:42](=[O:43])[N:13]2[C:14]([C:26]([O:28][CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:27])=[C:15]([CH:18]=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH3:25])[CH2:16][S:17][C@H:12]12
Reactant: Cc1ncsc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: Cc1ncsc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Temperature: -20 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
In 40 ml of methylene chloride was dissolved the diphenylmethyl 7-phenylacetamido-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylate (3.04 g, 5 mmoles) obtained as above. The resultant solution was cooled down to -20° C. After adding pyridine (1.62 ml) and phosphorus pentachloride (2.08 g), the resultant mixture was stirred at 5° C. for 3 hours and then cooled again to -20° C. After a prompt addition of 4 ml of methanol, the resultant mixture was stirred at 20° C. for 2 hours. The reaction mixture was then cooled to -10° C., followed by addition of 20 ml of chilled water. The mixture obtained was agitated vigorously. An aqueous solution of sodium bicarbonate was added to the mixture to adjust its pH to 2.0. The organic layer was then separated, followed by its washing with an aqueous solution of sodium bicarbonate and then with saline. The organic solution was then dried magnesium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate (10 ml) was added to the residue and the resultant mixture was allowed to stand overnight in an ice box. Deposited crystals were collected by filtration, washed with ethyl acetate and then dried under reduced pressure, to give 1.34 g of diphenylmethyl 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4carboxylate as yellow powder (yield: 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[NH2:28][CH:25]1[CH2:26][CH2:27][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:41]5[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12](=[O:15])[CH2:13][CH3:14])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 8.5 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (81 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (8 mg, 9% over two steps) as an orange-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.27-8.19 (m, 2H), 8.07-7.99 (m, 2H), 7.85-7.70 (m, 1H), 7.29 (s, 2H), 6.96 (d, J=9.2 Hz, 1H), 4.15-4.05 (m, 1H), 4.07-3.99 (m, 1H), 3.89-3.80 (m, 1H), 3.79-165 (m, 2H), 3.27-3.18 (m, 2H), 2.63-2.52 (m, 1H), 2.34-2.23 (m, 1H), 1.31-1.22 (m, 3H); ESI MS m/z 522 [C27H25Cl2N5O2+H]+; HPLC 95.7% (AUC), tR=10.98 min.