Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C(Cl)Cl>[Si:35]([N:6]1[CH:3]([C:1]#[N:2])[C@H:4]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]1=[O:7])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1C#N
Yield: 44 %

Procedure:
To a mixture of 1.10 g of (3s, 4RS)-4-cyano-3-tritylamino-2-azetidinone, 0.50 g of triethylamine and 20 ml of methylene chloride is added 0.56 g of tert-butyldimethylsilyl chloride under ice-cooling and stirring. The mixture is stirred at room temperature (approx. 25° C.) for 30 minutes and the reaction mixture is concentrated under reduced pressure. The residue is chromatographed on a silicagel column [eluant: ethyl acetate-n-hexane (1:3)] to give 0.64 g of (3s, 4RS)-1-tert-butyldimethylsilyl-4-cyano-3-tritylamino-2-azetidinone.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([CH3:7])=[CH2:6])[CH3:3].C([Li])CCC.C(=O)=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])[CH3:17]>C1COCC1>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][C:24]([OH:27])([CH2:6][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[CH2:7])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C=C(C)CN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(CN(C)C)CC1(O)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
2-[(Dimethylamino)methyl]propene (29.75 g, 300 mmol) in anhydrous THF (300 ml) was cooled to -78° and butyl lithium (2.5M, 120 ml, 300 mmol) was added dropwise, the temperature of addition being maintained below 0°. The dry-ice bath was replaced by an ice-bath and the reaction mixture maintained at 0° for 3 hours and then cooled to -78°. 1-Ethoxycarbonyl-4-piperidinone (25.68 g, 150 mmol) in anhydrous THF (50 ml) was added dropwise and the reaction mixture maintained at -78° for 1.5 hours and then stirred at room temperature overnight. Approximately 50 g of ice was added and the reaction mixture washed with saturated NaCl several times and dried (MgSO4), yielding a tan, viscous oil (42.47 g). Purification by flash chromatography eluting with ethylacetate in hexane gave the sub-title compound (9.33 g)
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[C:18]1([CH3:36])[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:34])[F:33])[N:25]=2)[CH:19]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:17])[C:14]([NH:31][CH2:30][C:29]2[C:24]([C:20]3[CH:19]=[C:18]([CH3:36])[CH:23]=[CH:22][CH:21]=3)=[N:25][C:26]([C:32]([F:35])([F:33])[F:34])=[CH:27][CH:28]=2)=[O:16])=[CH:11][CH:12]=1)(=[O:3])=[O:4]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (60 mg, 0.233 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (62 mg, 0.233 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (67 mg, 0.349 mmol), 1-hydroxybenzotriazole (47 mg, 0.349 mmol) and triethylamine (0.08 mL, 0.582 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain 2-(4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 4) (81 mg, 69%).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8].Cl.O>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1>[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](=[O:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)ccc1Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)ccc1Br
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (4.26 mL of a 1.4M solution in tetrahydrofuran/toluene, 5.97 mmol) was added dropwise to a stirred solution of 2-bromo-5-chloro-N-methoxy-N-methylbenzamide (3-1) (0.554 g, 1.99 mmol) in tetrahydrofuran (20 mL) at approximately 0° C. After 1 h, 1N hydrochloric acid (5 mL) was added and the resulting biphasic mixture was stirred vigorously for about 10 min. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-10% ethyl acetate/hexanes as eluent) provided 3-3 (0.44 g) as a colorless oil.
Reaction SMILES: C(N[CH:5]([CH3:7])C)(C)C.C([Li])CCC.C(OC1[S:20]CCO1)C.[NH2:21][C:22]1[S:26][N:25]=[C:24]([C:27](=[N:58][O:59][CH2:60][CH3:61])[C:28]([NH:30][CH:31]2[C:56](=[O:57])[N:33]3[C:34]([C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=4)=O)=[C:35](OS(C)(=O)=O)[CH2:36][S:37][C@H:32]23)=[O:29])[N:23]=1.Cl>O1CCCC1.CCCCCC>[NH2:21][C:22]1[S:26][N:25]=[C:24]([C:27](=[N:58][O:59][CH2:60][CH3:61])[C:28]([NH:30][CH:31]2[C:56](=[O:57])[N:33]3[C:34]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=4)=[S:20])=[C:35]([CH:5]=[CH2:7])[CH2:36][S:37][C@H:32]23)=[O:29])[N:23]=1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OS(C)(=O)=O)CS[C@H]12)c1nsc(N)n1
Reactant: CC(C)NC(C)C
Reactant: CCOC1OCCS1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC)c3nsc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (0.65 ml) in tetrahydrofuran (7 ml) was added 1.55M n-butyllithium in n-hexane (2.88 ml) at -20°~-15° C. The mixture was stirred for 30 minutes at 0° C. To the solution was added a solution of 2-ethoxy-1,3-oxathiolane (642 mg) in tetrahydrofuran (2 ml) at -60° C., and the resultant mixture was stirred for 30 minutes at the same temperature. The solution was added to a solution of p-nitrobenzyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-mesyloxy-3-cephem-4-carboxylate (syn isomer) (2 g) in tetrahydrofuran (30 ml) at -62° C. After the mixture was stirred for 15 minutes at the same temperature, 1N hydrochloric acid (5 ml) was added thereto. The mixture was allowed to warm up till 0° C. and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform (1:2). The fractions containing the object compound were combined and concentrated in vacuo to give p-nitrobenzyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-vinylthio-3-cephem-4-carboxylate (syn isomer) (805 mg).
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.[Br:24][C:25]1[CH:26]=[C:27]([O:34][CH3:35])[C:28]([N+]([O-])=O)=[N:29][CH:30]=1>O>[Br:24][C:25]1[CH:30]=[N:29][C:28]([F:1])=[C:27]([O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(Br)cnc1[N+](=O)[O-]
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)cnc1F
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Tetrabutyl ammonium fluoride (1.0 M THF solution: 3.9 ml) was added to a DMF (5 ml) solution of 5-bromo-3-methoxy-2-nitropyridine (CAS No. 152684-26-9) (450 mg), and the obtained mixture was stirred at 70° C. for 72 hours. The reaction solution was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=10:1 to 2:1), so as to obtain the title compound (258 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].Cl.[CH3:15]O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH3:15])=[O:12]
Reactant: Cc1cc(C)c(CC(=O)O)cc1C
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(C)c(C)cc1C
Temperature: 25 °C

Procedure:
100 g (0.56 mol) of 2,4,5-trimethylphenylacetic acid were dissolved in 230 ml of methanol, 6 ml of concentrated hydrochloric acid were added and the mixture was heated under reflux for 10 hours. It was then cooled to room temperature and the methanol was removed in vacuo. The residue was stirred into a solution of 53 g of sodium carbonate, dissolved in 260 ml of water, and the organic phase was taken up in 200 ml of toluene. The organic phase was separated off, dried and concentrated and the residue was distilled. 48.6 g of methyl 2,4,5-trimethylphenylacetate having a boiling point of 86° C. under 0.2 mbar were obtained. Dimethyl 2-(2,4,5-trimethylphenyl)-malonate
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:17]=3[S:16](=[O:26])(=[O:25])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:27][CH2:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[NH2:33][C:29]1([CH2:28][NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:32][O:31][CH2:30]1
Reactant: NCC1(N)COC1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2cc(F)ccc21
Product: NC1(CNc2cc(N3CCS(=O)(=O)c4ccc(F)cc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4,6-dichloroquinolin-2-yl)-7-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 3-2) and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 477, 1H NMR (400 MHz, CD3OD) δ ppm 8.07-7.94 (m, 2 H), 7.72 (dd, J=8.97, 2.65 Hz, 1 H), 7.53 (d, J=8.84 Hz, 1 H), 7.43 (dd, J=8.84, 2.27 Hz, 1 H), 7.15 (td, J=8.46, 2.53 Hz, 1 H), 6.23 (s, 1 H), 5.18 (brs, 2 H), 4.73-4.60 (m, 4 H), 4.51 (brs, 2 H), 3.75 (s, 2 H), 3.59 (t, J=4.67 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][C:18]#[CH:19])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].Br[CH2:21]C#CC>>[CH3:1][O:2][C:3]([C:5]1([CH2:17][C:18]#[C:19][CH3:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6]1)=[O:4]
Reactant: C#CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Reactant: CC#CCBr
Product: CC#CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-But-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 5J was prepared essentially similarly as 3-prop-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester by substituting 3-bromo-propyne with 1-bromo-but-2-yne
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].[ClH:23].C[O:25][C:26](=[O:38])[C@H:27]([NH2:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH:37][C@H:27]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([OH:25])=[O:38])=[O:16])=[C:13]([NH:12][S:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])(=[O:11])=[O:10])[CH:21]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=11.00 min. MS (ESI−): mass calcd. for C22H15Cl3F2N2O5S, 563.79; m/z found, 561/563 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.45 (s, 1H), 7.75 (d, J=1.9, 1H), 7.53-7.44 (m, 1H), 7.36 (d, J=8.2, 1H), 7.31-7.25 (m, 2H), 7.06-6.96 (m, 4H), 6.61 (d, J=6.9, 1H), 5.03 (d, J=5.6, 1H), 3.38-3.17 (m, 2H).
Reaction SMILES: CC(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:26])[C:9]2[CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[N:12]=[N:13][C:14]=2[CH:15]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C>[CH2:27]([O:26][C:8]1[CH:7]=[C:6]([CH3:5])[CH:15]=[C:14]2[C:9]=1[CH:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[N:12]=[N:13]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Temperature: 25 °C
Yield: 10 %

Procedure:
To an acetone solution (5 mL) of 7-methyl-3-(3-trifluoromethylphenyl)cinnolin-5-ol (69 mg, 0.2 mmol) obtained in Example 70 were added benzyl bromide (0.024 mL) and potassium carbonate (28 mg, 0.2 mmol), followed by stirring at room temperature over night and refluxing under heating for 3 hours. The reaction liquid was further added with benzyl bromide (0.024 mL) and potassium carbonate (28 mg, 0.2 mmol), followed by stirring at room temperature over night, concentration of the reaction liquid under reduced pressure, adding distilled water (1 mL), extraction with ethyl acetate and purification of residue obtained after concentration of an organic layer under reduced pressure, with HPLC column chromatography (hexane/ethyl acetate=3/1) to obtain an objective compound (8 mg, 10%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]2[N:41]=[CH:42][S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][C:40]2[N:41]=[CH:42][S:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2cscn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2cscn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.32 g), sodium hydrogen carbonate (1.87 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(1,3-thiazol-4-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.01 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.36 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.34 g, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
1-(4-hydroxy-3-nitro-phenyl)-ethanone was treated with benzyl bromide in the presence of K2CO3 in DMF, and processed as reported in the synthesis of example 20a to obtain the crude product which was purified using flash chromatography (silica gel, 5% CH3CN in chloroform). Yield, 94%; mp, 132° C.; MS (CI): 300 (M++29), 272 (M++1), 91; analysis: C15H13NO4 requires, C, 66.42; H, 4.83; N, 5.16; found; C, 66.58; H, 4.52; N, 5.30%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([F:10])[CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][CH2:20][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:10]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCBr)c(F)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 51.2 %

Procedure:
A mixture of 4-cyano-2-fluorophenol (8.5 g, 0.0620 mol; see Preparation D(iv) above), anhydrous K2CO3 (17.14 g, 0.124 mol) and 1,3-dibromopropane (37.7 mL, 0.372 mol) in dry DMF (80 mL) was stirred at 60° C. for 3 days under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 4% ethyl acetate in petroleum ether, as eluent, to yield 8.2 g of the sub-title compound as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C(OC([N:43]1[CH2:46][CH:45]([N:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][C:48]2=[O:54])[CH2:44]1)=O)(C)(C)C>>[NH:43]1[CH2:44][CH:45]([N:47]2[CH:52]=[CH:51][C:50]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:49][C:48]2=[O:54])[CH2:46]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(C)OC(=O)N1CC(n2ccc(Br)cc2=O)C1
Product: C[C@@H](c1ccc(-c2ccn(C3CNC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 3-(4-bromo-2-oxo-2H-pyridin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described in Example 26, followed by removal of the tert-butoxycarbonyl group using F3CCO2H in CH2Cl2. LC (method 4): tR=0.82 min; Mass spectrum (ESI+): m/z=502 [M+H]+; 1H NMR (CDCl3) δ 1.05 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.10-2.22 (m, 4H), 2.34 (m, 1H), 2.72 (m, 1H), 3.71 (m, 2H), 4.13 (m, 2H), 5.52 (m, 1H), 5.64 (m, 1H), 6.40 (m, 1H), 6.61 (m, 1H), 6.97 (d, 2H), 7.25 (m, 7H), 7.71 (d, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH2:6][C@H:5]2[CH2:26][C@@H:3]1[C:4]2([CH3:28])[CH3:27].C(N(CC)CC)C.[C:36]1([CH2:42][CH2:43][C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:36]1([CH2:42][CH2:43][C:44]([N:8]([CH:9]2[CH2:10][CH2:11][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH2:13][CH2:14]2)[C@H:7]2[CH2:6][C@H:5]3[CH2:26][C@H:3]([C:4]3([CH3:28])[CH3:27])[C@@H:2]2[CH3:1])=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1ccc(C2CCC(N[C@H]3C[C@H]4C[C@@H]([C@@H]3C)C4(C)C)CC2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C2CCC(N(C(=O)CCc3ccccc3)[C@H]3C[C@H]4C[C@@H]([C@@H]3C)C4(C)C)CC2)cc1
Reaction time: 24 h

Procedure:
To a solution of EXAMPLE 45C (192 mg, 0.5 mmol), triethylamine (0.077 mL, 0.55 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) in tetrahydrofuran (5 mL) was added 3-phenylpropanoyl chloride (0.082 mL, 0.55 mmol), and the reaction was stirred for 24 hours. The residue was chromatographed on silica gel using 20-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: S[C:2](=[CH:7][SH:8])[C:3]([O:5][CH3:6])=[O:4].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](C=O)[CH:10]=1.C1(C)C=C[C:20]([S:23](O)(=O)=O)=CC=1>>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([SH:23]2[CH2:20][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:7][S:8]2)[CH:10]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)C(S)=CS
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)C1CS[SH](c2cccnc2)C1

Procedure:
According to the foregoing reaction Scheme 2, 2,3-dibromopropionic acid (8) is treated with sodium bisulfide (NaSH) followed by esterification with HCl in methanol to give methyl 2,3-dimercaptopropenoate (9). This dithiol (9) is condensed with 3-pyridine carboxaldehyde in the presence of an acid catalyst, preferably p-toluenesulfonic acid, to afford methyl 2-(3-pyridinyl)-4-dithiolanecarboxylate (10). The dithiolane ester is hydrolyzed to the corresponding acid (11) by treatment with aqueous base, preferably lithium hydroxide. This acid is coupled to an amine (3) using a coupling agent such as dicyclohexylcarbodiimide or BOPCl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride) to yield the amide 12. ##STR8##
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.Cl[C:17]1[C:26](C)=[C:25](Cl)[C:24]2[C:19](=CC=C(Cl)C=2F)[N:18]=1.C([Sn](CCCC)(CCCC)C1C=CC=CN=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=[C:2]([C:17]2[CH:26]=[CH:25][CH:24]=[CH:19][N:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ccc(Cl)c(F)c2c1Cl
Reactant: Cc1c(Cl)nc2cc(F)c(Cl)cc2c1Cl
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)c(Cl)cc2c1Cl

Procedure:
The stille coupled products were prepared according to Procedure E using a mixture of 2,4,6-trichloro-7-fluoro-3-methylquinoline and 2,4,6-trichloro-5-fluoro-3-methylquinoline (0.50 g, 1.90 mmol), 2-(tributylstannyl)pyridine (0.77 mL, 2.08 mmol), palladium tetrakistriphenylphosphine (0.22 g, 0.19 mmol) in toluene (1.90 mL) to give 4,6-dichloro-7-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline as a white solid. Further elution gave 4,6-dichloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=307.0 (M+1). Further elution gave 4-chloro-7-fluoro-3-methyl-2,6-di(pyridin-2-yl)-quinoline.