Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][O:3][C:4]([C:6]1[C:15](=O)[N:14](C2C=CC=CC=2)[C:13]2[N:12]=[C:11]([NH:23]C3C=CC=CC=3)[N:10]=[CH:9][C:8]=2[N:7]=1)=O.FC(F)(F)C(O)=[O:33]>Cl.O=[Pt]=O>[NH2:23][C:11]1[NH:10][C:9](=[O:33])[C:8]2[NH:7][CH:6]([CH2:4][O:3][CH3:2])[CH2:15][NH:14][C:13]=2[N:12]=1
Reactant: CCOC(=O)c1nc2cnc(Nc3ccccc3)nc2n(-c2ccccc2)c1=O
Reactant: O=C(O)C(F)(F)F
Agent: O=[Pt]=O
Agent: Cl
Product: COCC1CNc2nc(N)[nH]c(=O)c2N1
Yield: 85 %

Procedure:
The pteridinone (0.5 g, 2.4×10-3 mol) previously prepared, vide supra, was hydrogenated under 1 atm of H2 in 30 mL of distilled trifluoroacetic acid over 0.02 g of PtO2 for an hour. The mixture was diluted with 25 mL of 6N HCl, filtered, and evaporated. The crude product, the tetrahydro compound, was recrystallized twice from 6N HCl/acetonitrile to give 2-amino-5,6,7,8-tetrahydro-6-methoxymethyl-4(3H)-pteridinone as a light brown solid (0.6 g, 85%): UV (0.1N HCl) λmax 215.5 nm (19800), 264 nm (19900); IR(KBr) 3300, 1665, 1570, 1540, 1470, 1365, 1300, 1150, 1110, 1005, 955, and 750 cm-1 ; NMR(DMSO-d6) 3.29δ (s, OMe), 3.4 (m, CH's), 3.6 (br s, OCH2), 8.0 (NH); anal. Calcd. for C8H13N5O2.2HCl.1/2H2O: C, 32.78; H, 5.50; N, 23.89; Cl, 24.19. Found: C, 32.75; H, 5.54; N, 23.80; Cl, 24.21.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:27])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[ClH:27].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCCSc1ccncc1
Yield: 84.3 %

Procedure:
To a solution of.1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.61 ml (4.96 mmol) of pivaloyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.01 g of the desired compound (free base) (96.4%, yellow oil).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH2:8][NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:7]=1.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3[CH:29]=[CH:28][NH:27][N:26]=3)=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16]1>>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([N:27]2[CH:28]=[CH:29][C:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:24]=3)=[N:26]2)=[CH:7][C:6]=1[CH2:8][NH:9][C:10]([NH:12][CH3:13])=[O:11]
Reactant: c1cc(-c2ccc3c(c2)CCCO3)n[nH]1
Reactant: CNC(=O)NCc1cc(Br)ccc1Cl
Product: CNC(=O)NCc1cc(-n2ccc(-c3ccc4c(c3)CCCO4)n2)ccc1Cl

Procedure:
N-[(5-bromo-2-chlorophenyl)methyl]-N′-methylurea (i.e. the product of Step A) (0.61 g, 2.2 mmol) was reacted with 3-(3,4-dihydro-2H-1-benzopyran-6-yl)-1H-pyrazole (i.e. the product of Step A of Synthesis Example 1) (0.40 g, 2.0 mmol) using a procedure analogous to Step B of Synthesis Example 1 to provide the title product, a compound of the present invention, as a solid (0.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C1COCC1.CO.[Ni]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Nc1ccc(F)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc2cc(Cl)ccc2c1Nc1ccc(F)cc1

Procedure:
1.3 g (4.09 mmol) (7-chloro-3-nitro-quinolinyl)-(4-fluoro-phenyl)-amine (Example 15c) in 60 ml THF/MeOH 2:1 and 0.6 g Raney-Ni are hydrogenated at rt for 2 h. The reaction solution is filtered on Hyflo® Super Cel diatomaceous earth and is evaporated to dryness. The raw product is dissolved in 30 ml ethyl acetate, and ca. 400 ml hexane are added. The title compound precipitates and is collected by filtration. Drying follows at 65° C. over night. mp: 198-200° C.; MS: 288 (M++1); HPLC: tret=8.38 min (Grad 1).
Reaction SMILES: [CH:1]12[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)(=[O:17])=[O:16])=[CH:10][CH:9]=3)[CH:5]1[CH2:4][NH:3][CH2:2]2.[CH2:29](Br)[CH:30]=[CH2:31].C(N(CC)CC)C>CN(C)C=O>[CH2:31]([N:3]1[CH2:4][C@@H:5]2[C@@H:1]([CH2:7][C@H:6]2[C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:2]1)[CH:30]=[CH2:29]
Reactant: O=S(=O)(Nc1ccc(C2CC3CNCC32)cc1)c1ccc(OC(F)(F)F)cc1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
100 mg (0.43 mmol) of N-[4-(3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide and 40 μl (0.46 mmol) of allyl bromide were dissolved in 2 ml of N,N-dimethylformamide. 0.18 ml (1.26 mmol) of triethylamine were then added to the solution. After the mixture had been stirred at room temperature for 1 hour, a further 10 μl of allyl bromide were added to the reaction mixture, which was then stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was taken up in water and this solution was made alkaline using a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated down give 50 mg of title compound (yield 46%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)C=C.[CH3:26][C:27]1C=CC=C[C:32]=1C>>[CH2:32]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:9][CH:10]=[N:11]2)[CH:27]=[CH2:26]
Reactant: Cc1ccccc1C
Reactant: C=CCOc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine (0.92 g, 2.55 mmol) (from Example 18, Step C, supra) in o-xylene (150 mL) was heated at 150° C. for 7 hours. At the end of this period, TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solution was concentrated and filtered. The solid was collected and dried in vacuo to give the desired 5-allyl-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.65 g, 71%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:31])(=[O:30])[CH2:28][CH3:29].[K+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:31][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.4 %

Procedure:
In a mixture of 50 ml of acetone and 12 ml of water are dissolved 2.5 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 0.7 g of potassium propionate. The solution is stirred at room temperature (17°-25° C.) for 3 days and concentrated under reduced pressure. The residue is extracted with 200 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 1000 ml isopropyl ether-n-hexane (2:3), elution is carried out with 2000 ml of the same solvent system. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.87 g of the above-identified compound as white crystals.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([CH:42]=2)[C:40]#[N:41])O1>>[C:40]([C:39]1[CH:42]=[C:35]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:36]=[N:37][CH:38]=1)#[N:41]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 192.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.09 min, m/z=474.3 [M+H]+, m/z=472.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 3.42-3.52 (m, 2H) 3.52-3.62 (m, 2H) 4.68 (br. s, 1H) 7.70 (d, J=8.56 Hz, 2H) 7.88-7.98 (m, 2H) 8.14 (d, J=2.45 Hz, 1H) 8.45 (t, J=2.08 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 9.00 (dd, J=8.44, 2.08 Hz, 2H) 10.32 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([C:16]2[C:17]([CH3:21])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCCc1cccs1
Reactant: Cc1cnc(Cl)nc1Cl
Product: COC(=O)CCCc1ccc(-c2nc(Cl)ncc2C)s1
Yield: 12 %

Procedure:
4-[5-(2-Chloro-5-methyl-pyrimidin-4-yl)-thiophen-2-yl]-butyric acid methyl ester was prepared analogous to Step B of Method A, starting from 4-thiophen-2-yl-butyric acid methyl ester and 2,4-dichloro-5-methyl-pyrimidine. Yield: 12%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#N)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12].C[OH:29].O>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:29])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: N#Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 M solution (1.2 ml, 1.22 mmol) of diisobutylaluminum hydride in toluene was slowly added to a solution (10 ml) of 4-(4-nitrophenyl)benzonitrile (224 mg, 1 mmol) in toluene at room temperature, and they were stirred for 1 hour. After cooling to 0° C., methanol (0.4 ml) and water (0.4 ml) were slowly added to the obtained mixture, and they were stirred. The reaction mixture was dried over sodium sulfate. After the purification by the silica gel column chromatography (ethyl acetate/hexane), 4-(4-nitrophenyl)benzaldehyde was obtained in the form of a yellow solid (yield: 127 mg, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:22]#[N:23])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: N#Cc1cccc(B(O)O)c1
Product: COc1ccc(-c2nc3cc(-c4cccc(C#N)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-cyanophenylboronic acid (126 mg, 0.86 mmol) the subtitle compound was obtained (65 mg, 31%). 1H NMR (DMSO) δ 8.75(d, 1H), 8.57(dd, 1H), 8.35(t, 1H), 8.29(d, 1H), 8.21(dt, 1H), 8.00(d, 1H), 7.97(dt, 1H), 7.93(d, 1H), 7.80(t, 1H), 7.74(d, 1H), 4.17(s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1F
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1F
Yield: 62.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-fluorophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.59 g, 31%). EI-MS m/z 292 (M+H)+
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[SH:64][C:65]1[N:70]([CH3:71])[C:69](=[O:72])[C:68]([OH:73])=[N:67][N:66]=1.O>CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:64][C:65]4[N:70]([CH3:71])[C:69](=[O:72])[C:68]([OH:73])=[N:67][N:66]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(S)nnc(O)c1=O
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)nnc(O)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
To a mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (1.5 g) and sodium iodide (769 mg) in N,N-dimethylformamide was added 3-mercapto-4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine (816 mg). After being stirred for 45 minutes at room temperature, the reaction mixture was poured into water. The resulting precipitates were collected by filtration and dissolved in ethyl acetate. The solution was washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried and evaporated under reduced pressure. The residue was triturated in diisopropyl ether and collected by filtration to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.25 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:19][CH2:20][CH:21]=[CH:22][CH2:23]OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:19][CH2:20][CH:21]=[CH:22][CH2:23][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])[CH3:17]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(=O)OCC=CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCC=CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of dibenzylamine (40 g, 0.2 mol) and 2-butene-1,4-diol diacetate (105 g, 0.61 mol) dissolved in 150 ml of tetrahydrofuran (THF) is treated with tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and the excess 2-butene-1,4-diol diacetate is removed by bulb-to-bulb distillation at 80°-90° C./1 mm. The residue is purified by eluting through a short plug of silica gel (1:1 ethyl acetate: hexanes). 1-Acetoxy-4-dibenzylamino-2-butene is obtained in a yield of 59.2 g (95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20](I)=[CH:21][C:13]1=2)=[O:11].[N:23]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([C:36]3[CH:41]=[CH:40][C:39](B4OC(C)(C)C(C)(C)O4)=[CH:38][CH:37]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14]2[N:18]=[CH:19][C:20]([C:39]3[CH:40]=[CH:41][C:36]([C:34]([N:31]4[CH2:30][CH2:29][CH:28]([N:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH2:33][CH2:32]4)=[O:35])=[CH:37][CH:38]=3)=[CH:21][C:13]1=2)=[O:11]
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: O=C(Cc1cc(F)ccc1F)N1CCNc2ncc(I)cc21
Product: O=C(c1ccc(-c2cnc3c(c2)N(C(=O)Cc2cc(F)ccc2F)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 20 %

Procedure:
2-(2,5-Difluorophenyl)-1-(7-iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)ethanone (30 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white foam (20% yield). M.p. (foam), LCMS: m/z=546.09 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42-1.72 (m, 6H), 2.22-2.42 (m, 2H), 2.54-2.64 (m, 5H), 2.85-3.11 (m, 3H), 3.56-3.62 (m, 2H), 3.88-3.92 (m, 4H), 4.55-4.66 (m, 1H), 5.23 (s, 1H), 6.91-7.07 (m, 3H), 7.41-7.49 (m, 4H), 8.16 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+]>CO.O>[C:18]([O:17][CH2:16][CH2:15][N:9]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1cnn(CCOC(C)(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OCCn1ncc(C(=O)O)c1C(F)(F)F
Yield: 75.8 %

Procedure:
To a solution of 1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (620 mg, 2.0 mmol) in methanol (2 mL) and water (2 mL) was added lithium hydroxide (67 mg, 2.8 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 1-(2-tert-butoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as a red oil (425 mg, 75%), which was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([CH3:17])[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:29]#[N:30])[C:27]#[N:28])=[CH:22][CH:21]=1)=[CH2:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:16][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH3:15])[C:9]=1[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:19]=[CH:18][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([C:27]#[N:28])[C:29]#[N:30])=[CH:22][CH:21]=2)=[CH:3][C:4]=1[CH3:17]
Reactant: C=Cc1ccc(C(C#N)C#N)cc1
Reactant: Cc1cncc(C)c1-c1c(C)cc(I)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cncc(C)c1-c1c(C)cc(C=Cc2ccc(C(C#N)C#N)cc2)cc1C
Temperature: 100 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
A flame-dried sealable Schlenk tube was charged with 11 (3.37 g, 10.0 mmol), 18 (2.52 g, 15.0 mmol), Pd(OAc)2 (224 mg, 1.00 mmol), and PPh3 (262 mg, 1.00 mmol), evacuated, and then backfilled with N2. Next, dry Et3N (5 mL) and dry DMF (10 mL) were added under an N2 flow. The Schlenk tube was sealed, and the mixture was degassed by 3 freeze-thaw cycles and backfilled with N2. The mixture was then covered with aluminum foil and stirred at 100° C. for 2 days. The reaction mixture was next cooled to room temperature, poured into water, neutralized with dilute HCl to pH=7, and extracted with CH2Cl2 (3×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel, eluting with 1:1 hexane: ethyl acetate to give 2.09 g (55.4%) of the title compound as red solid: mp 58-60° C.; 1H NMR (400 MHz, CDCl3): δ 8.405 (s, 2H), 7.640 (d, 2H, J=8.0 Hz), 7.506 (d, 2H, J=8.0 Hz), 7.337 (s, 2H), 7.160 (s, 2H), 1.936 (s, 6H), 1.929 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 148.657, 148.093, 139.804, 137.383, 135.973, 135.218, 130.978, 127.911, 127.757, 126.774, 126.410, 124.863, 111.915, 28.096, 19.988, 16.749; MS (ESI): m/z 378.5 [M++H,100];MS (high resolution, EI): m/z 377.1878 [M+]; calcd, 377.1892; Anal. Calcd. for C26H23N3·1/2 H2O: C, 80.80; H, 6.26; N, 10.87. Found; C, 80.22; H, 6.32; N, 10.28.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:17][CH:18]1[CH2:24][C:23](=[O:25])[O:22][C:20](=[O:21])[CH2:19]1.O>C1COCC1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:23](=[O:25])[CH2:24][CH:18]([CH3:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Solvent: O
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)O)ccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-amine (4.21 g, 20 mmol) in THF (40 mL) was added 3-methylglutaric anhydride (2.56 g, 20.00 mmol), and the mixture was stirred at 90° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give 5-(9-ethyl-9H-carbazol-3-ylamino)-3-methyl-5-oxopentanoic acid (6.23 g, 18.41 mmol, 92%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:17]=1
Reactant: C1CNCCN1
Reactant: O=C1Nc2cc(Cl)ccc2Cc2ccccc21
Product: Clc1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1C2

Procedure:
3-Chloro-5,11-dihydro-dibenzo[b,e]azepin-6-one (189JO59) (25 mg, 0.1 mmol) and piperazine were reacted according to GP4 to give 2.2 mg of the title compound (189JO60). MS(ESI) 312 (MH+). Purity for MH+ (UV/MS) 100/100.