Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].C(OCC=C)C=C>C1(C)C=C(C)C=C(C)C=1>[CH2:21]([C:6]1[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=[C:4]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:9])[CH:20]=[CH2:19]
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Reactant: C=CCBr
Agent: C=CCOCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1c(C)c(Cl)cc(C(C)C)c1O
Yield: 73.5 %

Procedure:
Treatment of 4-chloro-2-isopropyl-5-methylphenol (10.00 g, 0.054 mol) with potassium carbonate (29.94 g, 0.217 mol) and allyl bromide (7.86 g, 0.065 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 8.92 g (73%) of 2-allyl-4-chloro-6-isopropyl-3-methylphenol as a colorless oil. Rf=0.85 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C13H17ClO: C, 69.48; H, 7.62. Found: C, 69.87; H, 7.43.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][CH2:11][C:12]2[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:22])=[N:3][CH:2]=1.C1C=C[NH+]=CC=1.Br[Br-]Br.CC(O)=[O:41]>CC(O)(C)C.[Zn]>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:12]([CH2:11][O:10][C:4]1[C:5]3[CH2:9][C:8](=[O:41])[NH:7][C:6]=3[N:1]=[CH:2][N:3]=1)=[CH:21]2
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2[nH]ccc12
Reactant: CC(=O)O
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)methyl)-8-methyl-2-o-tolylquinoline (120 mg, 0.316 mmol) in AcOH (4 mL) and t-BuOH (2.43 mL) under N2 was added pyridinium bromide perbromide (303 mg, 0.947 mmol) in one portion. After stirring at room temperature for 5 h the solvents was removed, and the remaining solids suspended in H2O and extracted with ethyl acetate, after drying with brine and MgSO4 the crude dry solid was dissolved in THF (8 mL) followed by 5 mL of a saturated NH4Cl solution, this was followed in turn by Zn powder (528 mg, 26 mmol) and stirred at room temperature for 24 h. The mixture was then extracted with ethyl acetate and chromatographed {gradient elution DCM/89:9:1 (DCM/MeOH/NH4OH)}. The solid was recrystallized from DCM to provide the pure product [PI3Kδ IC50=349 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (1H, s), 8.52 (1H, s), 8.30 (1H, s), 7.89 (1H, d, J=7.8 Hz), 7.65 (1H, d, J=7.0 Hz), 7.51-7.57 (1H, m), 7.30-7.35 (3H, m), 7.22-7.29 (1H, m), 3.47 (2H, s), 2.67 (3H, s), 2.09 (3H, s) Mass Spectrum (ESI) m/e=397.1 [M+1].
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([O:12][CH2:13][C:14]#[N:15])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br>ClCCl>[Br:16][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][C:10]=1[O:12][CH2:13][C:14]#[N:15]
Reactant: BrBr
Reactant: N#CCOc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: N#CCOc1[nH]nc(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 2-(3-phenyl-1H-pyrazol-5-yloxy)acetonitrile (0.500 g, 2.51 mmol) in dichloromethane (15.0 mL), was added bromine (0.129 mL, 2.51 mmol) at 25° C. The reaction was stirred at room temperature for 1 h and quenched with 2 M Na2CO3 (aq.) to pH 12. The organics were separated. The aqueous layer was extracted with DCM (3×). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to give a red oil. This oil was purified by silica gel flash chromatography to give the title compound as a yellow solid (0.360 g). LCMS m/z=278.1, 280.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 5.21 (s, 2H), 7.39-7.61 (m, 3H), 7.70-7.77 (m, 2H), 13.04 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:28](=[O:30])[CH3:29])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a flask loaded with tetrakis-(triphenylphosphine)-palladium (1.7 g, 1.48 mmol) under nitrogen was added a solution of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (5.8 g, 18.55 mmol) in DMF (150 mL). The system was purged with nitrogen three times and then tributyl-(1-ethoxy-vinyl)-stannane (6.59 mL, 19.47 mmol) was added. The temperature was increased to 100° C. and stirred overnight. After cooling, 20 mL of 3N HCl was added and the mixture was stirred for additional 2 h. Water was added and the product was then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4.8 g (79%) of the title compound as a dark yellow solid. 1H-NMR (400 MHz, MeOH-d4) ppm 8.82 (dd, 1H), 8.31 (d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.50 (q, 1H), 4.72 (s, 2H), 2.68 (S, 3H). LCMS (method A): [MH]+=321, tR=5.07 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][C:10]1[O:11][C:12]([CH3:15])=[N:13][N:14]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([C:10]1[O:11][C:12]([CH3:15])=[N:13][N:14]=1)=[O:24]
Reactant: Cc1nnc(Sc2c(C)cccc2C)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nnc(S(=O)c2c(C)cccc2C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To an ice-cooled solution of 2-(2,6-dimethylphenyl)thio-5-methyl-1,3,4-oxadiazole (0.350 g, 0.0016 mol) in CH2Cl2 (10 ml) was added dropwise m-CPBA (0.530 g, 0.002 mol, 65% pure) in CH2Cl2 (5 ml). The ice bath was removed and the reaction mixture was stirred at rt for 2 h and treated with sat. aq. Na2S2O3 (2.5 ml) solution and sat. aq. Na2CO3 (10 ml). The organic layer was separated and then the aqueous layer was extracted with CH2Cl2 (2×25 ml), dried (MgSO4) and the solvent evaporated in vacuo. Chromatography on silica gel using ethyl acetate/hexanes (1/1) as the eluant gave 2-(2,6-dimethylphenyl)sulfinyl-5-methyl-1,3,4-oxadiazole (78) (0.125 g, 23%) as a white solid; mp 79°-80° C.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:16]
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: CC[O-]
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C)c2nnc(N)n2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 2.5 g) were dissolved in ethanol (50 ml), admixed under argon with sodium ethoxide (3.86 g) and stirred at 60° C. for 1 h. Then the mixture was dried and the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 1.76 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[N:25](C(C)(C)C)[N:26]=[C:27]([CH3:29])[CH:28]=1.Cl>CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(N)cc23)n(C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(N)cc23)[nH]n1
Temperature: 80 °C
Yield: 45.8 %

Procedure:
30 mg 6-Amino-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one were dissolved in 0.5 ml methanol. 2 ml conc. HCl were added and the mixture was heated to 80° C. for 7 hrs. The mixture was evaporated under vacuum, the residue dissolved in dichloromethane and washed with sodium bicarbonate solution. Removal of the dichlormethane yielded 12 mg of the title product. 1H-NMR: (400 MHz, D6-DMSO) 11.75 (1H, br s), 8.75 (1H, br s), 8.00 (1H, d), 7.59 (2H, d), 7.46 (2H, d), 7.27 (1H, s), 7.05 (1H, d), 6.16 (br s, 2H), 2.17 (3H, s), 1.33 (9H, s); MS (ESI+)=389.22 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][S:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N+:45]=5[O-:50])(=[O:43])=[O:42])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][S:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N+:45]=5[O-:50])(=[O:42])=[O:43])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)(=O)c4cccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)(=O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (137 mg) was dissoved in ethanol (4.0 ml), sodium borohydride (36 mg) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. Sodium borohydride (36 mg) was further added to the mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 202) (85 mg).
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:13])=[O:12])[CH:3]=1.[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C(#N)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][S:11]([C:4]1[CH:3]=[C:2]([CH:22]=[CH2:23])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1ccccc1NS(=O)(=O)c1cc(I)c2occc2c1
Solvent: CC#N
Product: C=Cc1cc(S(=O)(=O)Nc2ccccc2C)cc2ccoc12

Procedure:
7-Iodo-N-(2-methylphenyl)-1-benzofuran-5-sulfonamide (0.41 g, 1 mmol; Intermediate 58), tributylvinyltin (0.32 mL, 1.1 mmol), bis(triphenylphosphine)palladium diacetate (10 mg) and acetonitrile (3 mL) were heated under microwave irradiation to 180° C. for 5 min. The mixture was cooled, filtered and evaporated. The resulting oil was washed with hexane (2×50 mL), dissolved in diethyl ether (50 mL), filtered and evaporated to give the crude product which was crystallized from ethanol:water (3:1). Yield 0.19 g (61%) of an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93 (s, 3H) 5.57 (dd, J=11.3, 1.0 Hz, 1H) 6.12 (dd, J=17.8, 1.0 Hz, 1H) 6.84-7.07 (m, 6H) 7.62 (d, J=1.8 Hz, 1H) 7.84 (d, J=1.8 Hz, 1H) 8.14 (d, J=2.3 Hz, 1H) 9.43 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][N:21]=[C:22](F)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:26]#[N:27])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][NH2:43])[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].FC1C=C2C(=NC=1)N=CC=C2.FC1C=CC2C(=NC=CC=2)N=1>C(Cl)Cl.CO.C1COCC1>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([NH:43][CH2:42][CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:36][CH2:37]4)[CH:23]=3)[N:18]=[CH:17][C:16]=2[C:26]#[N:27])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: Fc1ccc2cccnc2n1
Agent: Fc1cnc2ncccc2c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCNc2cc3c(Nc4ccc(Cc5ccccc5)cc4)c(C#N)cnc3cn2)CC1
Yield: 23 %

Procedure:
A microwave vial was charged with 4-(4-benzylphenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.100 g, 0.282 mmol), 1-N-BOC-4-(2-aminoethyl)piperazine and 2 mL THF, crimp-sealed, and heated in a microwave reactor at 180° C. for 35 minutes, until TLC analysis (5% MeOH in CH2Cl2) showed disappearance of the 6-fluoronaphthyridine. This process was repeated with 3 additional aliquots of the fluoronaphthyridine (0.120 g, 0.100 g, 0.100 g), and the contents of all 4 vials were then combined, partitioned between 50 mL each EtOAc and brine, and worked up as described above for the synthesis of WAY-191220. The crude product was purified by flash chromatography over silica gel (5% MeOH in CH2Cl2) and lyophilized to give pure 4-(4-benzylphenylamino)-6-(2-(1-N-BOC-piperazin-4-yl)ethylamino)-1,7-naphthyridine-3-carbonitrile (0.151 g, 23% yield): 1H NMR (400 MHz, DMSO-D6) δ 1.39 (s, 9 H) 2.34-2.44 (m, 4 H) 2.57 (t, J=6.6 Hz, 2 H) 3.21-3.42 (m, 6 H) 3.99 (s, 2 H) 6.59 (t, J=5.3 Hz, 1 H) 7.03 (s, 1 H) 7.14-7.34 (m, 9 H) 8.22 (s, 1 H) 8.81 (s, 1 H) 9.56 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:26])[CH:21](OCC)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1([CH2:31][CH2:32][N:33]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[C:36]([CH3:44])([CH3:43])[O:35][C:34]2=[O:45])[CH2:30][CH2:29]1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:26])[CH2:21][NH:27][C:28]2([CH2:31][CH2:32][N:33]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[C:36]([CH3:43])([CH3:44])[O:35][C:34]3=[O:45])[CH2:30][CH2:29]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Reactant: CC1(C)OC(=O)N(CCC2(N)CC2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(OCc4ccccc4)c4c3OCC(=O)N4)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
900 mg (2.5 mmol) of 5-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 700 mg (2.7 mmol) of 1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo [d][1,3]oxazin-2-one is dissolved in 20 mL of ethanol and stirred in each case for 30 minutes at 80° C. and 50° C. The reaction mixture is cooled, combined with 200 mg (5.3 mmol) sodium borohydride, and stirred for 2 hours at ambient temperature. Glacial acetic acid is added, the mixture is stirred for 10 minutes, and evaporated down. The residue is taken up in dichloromethane and washed successively with potassium hydrogen sulfate solution, 15% potassium carbonate solution, and sodium hydrogen carbonate solution. Then the organic phase is dried with sodium sulfate and freed from solvent. The residue is purified by column chromatography (silica gel; ethyl acetate/methanol/ammonia gradient). Recrystallization from diisopropylether. White solid. Yield: 690 mg (49%); mass spectroscopy: [M+H]+=558.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH:65]([S:85][CH2:86][C:87]2[N:88]=[N:89][NH:90][CH:91]=2)C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH2:65][S:85][CH2:86][C:87]4[N:88]=[N:89][NH:90][CH:91]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(SCc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCSCc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-trityl-1,2,3-triazol-4-ylmethylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.13 g: 0.884 mMol.) in a mixture of anisole (3 ml) and nitromethane (12 ml) at -40° C. is added a solution of aluminum chloride (0.94 g: 7.07 mMol.) in anisole (3 mi), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is mixed with 1N-hydrochloric acid (7.5 ml) and diluted with water. The aqueous solution is washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove the remaining organic solvents, subjected to chromatography over styrene-divinylbenzene copolymer column (methanol : water=4:1). The resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,3-triazol-4-ylmethylthiomethylthio)-3-cephem-4-carboxylic acid (318 mg) as pale yellow white powder. Yield: 68%.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[S:7][C:6]([CH3:9])=[N:5][C:4]=1[CH2:3][Cl:2]
Reactant: BrBr
Reactant: Cc1nc(CCl)cs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(CCl)c(Br)s1
Reaction time: 2.5 h
Yield: 61.1 %

Procedure:
To 11 g of 4-chloromethyl-2-methylthiazole, hydrochloride (0.06 mol), dissolved in 150 ml of glacial acetic acid are added while stirring, 11.5 g of anhydrous sodium acetate (0.14 mol) and at 45°-50°, 9.6 g of bromine (0.12 mol) in 50 ml of glacial acetic acid. Stirring is continued for an additional 2.5 hours at 60°-80° C. Then the solution is evaporated in vacuo to dryness and the residual product is extracted with ether. Evaporation of the solvent gives 8.3 g oil which is then dissolved in hexane. Charcoal treatment, evaporation of the solvent, dissolving of the oil again in 100 ml of ether and addition of ethereal hydrochloric acid, yield the hydrochloride. Yield: 6.5 g (41%), m.p. 154°-156° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[CH2:31]([C:33]1[S:34][CH:35]=[C:36](/[CH:38]=[CH:39]/[C:40]2[C:41]([OH:52])=[N:42][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])[CH:44]=2)[N:37]=1)[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:31]([C:33]1[S:34][CH:35]=[C:36](/[CH:38]=[CH:39]/[C:40]2[C:41]([O:52][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:42][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])[CH:44]=2)[N:37]=1)[CH3:32]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3C)nc2O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5C)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (552 mg), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-(2-methylphenyl)-1H-pyrazol-3-ol (400 mg), anhydrous potassium carbonate (177 mg) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:4-1:3-1:2, v/v). The obtained eluate was subjected to reversed phase HPLC and eluted with acetonitrile-water (10:90-100:0, v/v). The obtained fraction was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ethyl acetate-hexane to give ethyl [4-(4-{[4-({[4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-(2-methylphenyl)-1H-pyrazol-3-yl]oxy}methyl)-2-methoxyphenoxy]methyl}-5-methyl-1,3-oxazol-2-yl)phenyl]acetate as pale-yellow amorphous form (173 mg, yield 19%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21]O>>[CH3:21][O:19][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Yield: 96 %

Procedure:
In FIG. 6A, the results of using Zn3La1 in esterifying pure oleic acid with methanol using the step-rise heating method (i.e., a heating rate of 2° C./minute, and holding the reaction mixture at the target temperature for 1 minute) is provided. When the temperature is higher than 140° C., Zn3La1 shows activity in regards to the esterification of FAA. At 200° C., a 96% yield of oleic acid methyl ester can be obtained in 10 minutes (see FIG. 6B).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:39])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]3[O:33][CH2:32]3)[CH:24]=2)[CH:20]=1)=[O:13]>>[CH3:39][N:8]([CH3:7])[C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:35])=[C:19]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH:31]([OH:33])[CH2:32][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:24]=2)[CH:20]=1)=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Reactant: C1COCCN1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN2CCOCC2)c1
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 29, morpholine was reacted with N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)-benzamide to give the title compound in 64% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.44 (m, 4H), 2.94 (s, 6H), 3.15 (m, 1H), 3.55 (t, 4H), 3.96 (m, 2H), 4.06 (m, 1H), 4.89 (m, 1H), 6.9 (m, 1H), 7.14 (m, 1H), 7.21 (m, 3H), 7.32 (t, 1H), 7.42 (t, 1H), 7.56 (m, 3H), 7.79 (d, 1H), 9.88 (br s, 1H), 10.08 (br s, 1H); Mass Spectrum: M+H+ 533.