Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:10]([CH2:14][CH3:15])[C:11](Cl)=[O:12])[CH3:9].O>N1C=CC=CC=1>[CH2:8]([N:10]([CH2:14][CH3:15])[C:11](=[O:12])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCN(CC)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 63 %

Procedure:
A solution of 10 g of aniline in 50 ml of pyridine is cooled to 0° C. and a solution of 14.56 g of diethylcarbamoyl chloride in 10 ml of pyridine is added slowly. The mixture is stirred for 6 hours, the temperature being allowed to rise to RT, and is then poured into water. It is extracted with AcOEt, washed with water and with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 13 g of the expected product, which is used as such in the next step.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[O:18][CH:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]1)[C:20]#[CH:21].[F-].[K+].O.Cl>C(N(CC)C1C=CC=CC=1)C>[F:12][C:11]1[C:2]([F:1])=[C:3]2[C:4]([CH:21]=[CH:20][CH:19]([CH:22]3[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:27]3)[O:18]2)=[C:5]2[CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9][C:10]=12
Reactant: C#CC(Oc1cc2c(c(F)c1F)OC(CCCCC)CC2)C1CCC(CCC)CC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)c1ccccc1
Product: CCCCCC1CCc2c3c(c(F)c(F)c2O1)OC(C1CCC(CCC)CC1)C=C3

Procedure:
9.7 g (23.2 mmol) of 7,8-difluoro-2-pentyl-6-[1-(4-propylcyclohexyl)prop-2-ynyloxy]chroman are heated at 200° C. for 6 h together with 2.7 g (46.5 mmol) of potassium fluoride in 75 ml of N,N-diethylaniline. After cooling, water is added, and the mixture is acidified using 25% hydrochloric acid. The batch is extracted with MTBE, and the organic phase is washed with saturated sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, 1-chlorobutane:pentane=4:1), giving 5,6-difluoro-3-pentyl-8-(4-propylcyclohexyl)-1,2,3,8-tetrahydropyrano[3,2-f]chromene as a pale-brown oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[O:7]=[C:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1>CCOCC>[OH:7][C:8]1([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1
Reactant: Brc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2)C1
Temperature: -65 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 3-bromothiophene (10 g, 61.8 mmol) in dry ether (200 mL) at −65° C. under N2 was added n-BiLi dropwise. After stirring at −65° C. for 1 h, tert-butyl 3-oxopyrrolidine-1-carboxylate (13.7 g, 74.2 mmol) in dry ether (80 mL) was added dropwise. After addition, the reaction mixture was warmed to 0° C. and stirred for 3 h. The reacton was quenched with water and extracted with ether. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (9.8 g, 59%).
Reaction SMILES: [CH2:1](B(O)O)[CH2:2][CH2:3][CH3:4].[CH2:8]([O:15][C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=2)[O:18][C:17]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.[OH-].[Na+].Cl[Pd]Cl>[CH2:8]([O:15][C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:22][CH:23]=2)[O:18][C:17]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCB(O)O
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Yield: 23.2 %

Procedure:
To a stirring solution of n-butane boronic acid (0.133 g, 1.3 mmol, 1.4 equ) and dichloropalladium (dppf) (0.050 g, 0.06 mmol, 0.07 eq) in tetrahydrofuran (7 ml) and 3M NaOH solution (1.1 ml) was added 34 (0.500 g, 0.9 mmol) added and the reaction heated to reflux for 21 hours. The reaction was then quenched with water and diethyl ether. The organic layer was collected and the aqueous layer extracted with diethyl ether (2×). The combined organic layers were washed with IM HCl and brine then dried (MgSO4) and concentrated in vacuo to give a yellow oil. A silica plug (dichloromethane) yielded 39d (0.099 g, 23%) as an orange oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[O:35]1[C:39]2([CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[O:35]1[C:39]2([CH2:44][CH2:43][CH:42]([O:34][C:31]3[CH:32]=[CH:33][C:28]([N:4]4[C:5](=[O:27])[C:6]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]6[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=6)=[CH:15][CH:14]=5)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]4[CH2:1][CH3:2])=[CH:29][CH:30]=3)[CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.0 g), 1,4-dioxaspiro[4.5]decan-8-ol (2.82 g), diisopropyl azodicarboxylate (1.9 M in toluene, 3.2 mL), triphenylphosphine (4.67 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow amorphous solid (5.13 g, 98%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)[C:8]=1[C:23]([O:25][CH3:26])=[O:24])(=O)=O.[Li+].[Cl-].[CH2:31](N(CC)CC)[CH3:32].C([Sn](CCCC)(CCCC)C=C)CCC>O1CCOCC1.[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>[CH:31]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=2)[C:8]=1[C:23]([O:25][CH3:26])=[O:24])=[CH2:32]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cccc(-c2cccc(OS(=O)(=O)C(F)(F)F)c2C(=O)OC)c1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1COCCO1
Product: C=Cc1cccc(-c2cccc(C(=O)OC)c2)c1C(=O)OC
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 3-trifluoromethanesulfonyloxy-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.3 g, 3.1 mmol), tetrakis (triphenylphosphine) palladium (0.36 g, 0.31 mmol), LiCl (0.94 g, 22.2 mmol), triethylamine (0.6 mL, 4.3 mmol) and tri-n-butyl(vinyl)tin (1.0 mL, 3.4 mmol) in 1,4-dioxane (30 mL) was heated at reflux under N2 for 4 hours. After cooling to room temperature, the mixture was filtered through a plug of silica gel and the filtrate was concentrated. Purification by flash chromatography (1:10 EtOAc/hexanes) provided 3-ethenyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (0.91 g, 99%) as a white solid: 1H NMR (CDCl3) δ3.61 (s, 3H), 3.92 (s, 3H), 5.40 (d, J=11.1 Hz, 1H), 5.79 (d, J=17.5 Hz, 1H), 6.87 (dd, J=17.4, 11.0 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.44-7.49 (m, 2H), 7.56 (dm, J=7.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 8.03 (dm, J=7.5 Hz, 1H), 8.08 (t, 1, J=1.5 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16]([Cl:19])(=[O:18])=[O:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16]([Cl:19])(=[O:18])=[O:17])[C:9]=3[C:8]([N+:26]([O-:28])=[O:27])=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(N1CC(CCl)c2c1ccc1c(S(=O)(=O)Cl)cccc21)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1c(S(=O)(=O)Cl)cccc21)C(F)(F)F
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
The 6-sulfonyl chloride 114(750 mg, 1.9 mmol) was dissolved in conc. H2SO4 (20 mL), the solution was cooled in an ice bath, and a solution of KNO3 (195 mg, 1.95 mmol) in H2SO4 (5 mL) was added slowly. The mixture was vigorously for 30 min, quenched with cold water, and extracted with EtOAc (3×50 mL). The extracts were dried and concentrated under reduced pressure, and the resulting solid was separated by column chromatography on silica gel. Elution with EtOAc/petroleum ether (from 1:4 to 1:1) gave 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-sulfonyl chloride (115) (202 mg, 59%, based on consumption of starting material): mp (EtOAc/petroleum ether) 169° C. (dec.); 1H NMR [(CD3)2SO] δ 8.63 (s, 1H), 8.22 (dd, J=7.6, 0.9 Hz, 1H), 8.13 (dd, J=8.4 Hz, 1H), 7.71 (dd, J=7.8, 7.8 Hz, 1H), 4.66-4.56 (m, 2H), 4.49-4.43 (m, 1H), 4.17-4.02 (m, 2H); 13C NMR δ 153.4 (q, JC-F 37.4 Hz), 149.2, 145.2, 137.7, 131.4, 130.5, 129.9, 127.7, 124.9, 118.6, 115.6 (q, JC-F 288 Hz) 114.3, 52.6, 47.5, 41.4. Anal. (C15H9Cl2F3N2O5S) C, H, N. 114 (457 mg, 61%) was also recovered.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:16][C:3]1([CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1cc(C2CCNCC2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3ccncc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (0.85 g), 4-(4-piperidinyl)pyridine (0.97 g), and triethylamine (1.3 mL) was stirred under nitrogen gas at 180° C. for 15 hours. To this reaction mixture were added saturated aqueous NaHCO3 and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20.1) and crystallized from ethyl acetate/hexane to provide 0.77 g of the title compound. Yield 70%.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:39]2[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]2)=[C:22]([F:38])[C:23](F)=[C:24]([C:26](=[N:35][OH:36])[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:46][C@@H:41]1[CH2:40][N:39]([C:21]2[C:20]([CH2:19][OH:18])=[CH:25][C:24]3[C:26]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[N:35][O:36][C:23]=3[C:22]=2[F:38])[CH2:44][C@H:43]([CH3:45])[O:42]1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)C(=O)N3CCOCC3)c(F)c2F)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)N4CCOCC4)noc3c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(5-((tert-Butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-(hydroxyimino)-1-morpholinoethanone, (Intermediate 168, 133 mg, 0.20 mmol) was dissolved in DMF and stirred at 60° C. with cesium carbonate (332 mg, 1.02 mmol) for 6 hours. The reaction stirred at room temperature over 2 days. The reaction was diluted with water and extracted three times with ethyl acetate. The organic layers were combined and washed 5× with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound (34 mg, 0.086 mmol).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:14][C:15]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[O:17][N:16]=1.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[F:31][C:2]([F:1])([F:30])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[CH2:14][C:15]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[O:17][N:16]=1
Reactant: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1C(F)(F)F)CCN2Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To an ice-cold solution of 4-(trifluoromethyl)-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indole-5-carbonitrile (Example 60D) (0.025 g, 0.057 mmol) in TFA (1 mL) was added NaCNBH3 (0.050 g, 0.79 mmol) in portions. After addition, the mixture was stirred at rt for 3 h and then concentrated in vacuo. The residue was partitioned between CH2Cl2 and 0.2N NaOH. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-30% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.013 g, 52% yield): MS (ES) m/z 439 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13](C([O-])=O)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:22][CH3:23])[CH:3]=1.Cl.CO.[H-].[Na+]>>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:9])=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCN(C(=O)[O-])CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.4 %

Procedure:
The mixture of 4-((4,5-dichloro-2-methoxybenzyl)carbamoyl)piperidine-1-carboxylate (987 mg, 2.37 mmol) in HCl/MeOH (20 mL, 57.2 mmol) was stirred at room temperature for 1 h. Then the solvent was evaporated in vacuo and the residue was dissolved with dichloromethane (5 mL). To this mixture, NaH (85 mg, 3.55 mmol) was added. Then the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure to yield the crude product (800 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.Br.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ccccn3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (75 mg, 0.16 mmol) in dry DMF (1 mL) was added sodium hydride (15 mg, 0.38 mmol) and 2-(bromomethyl)pyridine.HBr (48 mg, 0.19 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 40% EtOAc in cyclohexane) to give the title compound (11 mg, 12%). 1H NMR (500 MHz, CDCl3): 8.49 (1H, d), 7.63 (1H, t), 7.42 (1H, s), 7.27 (1H, d), 7.19-7.13 (8H, m), 7.01-6.98 (2H, d), 5.23 (2H, s), 4.92 (2H, s), 4.91 (1H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.75-1.70 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[OH-].[K+].NN>C(O)CO>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=O)cc1OC
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: COc1ccc(C)cc1OC
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A mixture of veratraldehyde (91.5g), KOH (100 g), 95% hydrazine (75 ml) and ethylene glycol (700 ml) was heated at reflux until the KOH disappeared (30 min). The hydrazone then separated as a yellow solid and mild foaming occurred. The heating was continued at reflux causing evolution of N2 and vigorous frothing. After 3 hr., the solution was cooled, poured into 1.5 l of cold water and the resulting oil was extracted into ether. The combined extracts were washed with water, dried and evaporated to yield a yellow oil which was distilled to give 65.7 g of the product, 3,4-dimethoxy toluene as a colorless oil (bp 68°-72°at 0.05 mm).
Reaction SMILES: Cl.[CH:2]([O:5][N:6]=[C:7]([C:28]1[N:29]=[C:30]([NH:33]C=O)[S:31][CH:32]=1)[C:8]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]>O1CCCC1.CO>[CH:2]([O:5][N:6]=[C:7]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:8]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 20.3 %

Procedure:
Conc. hydrochloric acid (1 ml) was added to a solution of 7-[2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)(1.3 g) in a mixture of tetrahydrofuran (10 ml) and methanol (10 ml). The mixture was stirred for 3.5 hours at ambient temperature and then concentrated to dryness. Water was added to the residue and to the mixture was added sodium bicarbonate to give a solution. The solution was adjusted to pH 3.0 with conc. hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)(0.25 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][C:31]1=[O:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:33]4[CH2:34][CH2:35][NH:30][C:31](=[O:36])[CH2:32]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C1CNCCN1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: O=C1CN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CCN1
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and piperazinone to give the title compound in 28% yield; NMR Spectrum: 2.70 (t, 2H), 2.89 (t, 2H), 3.09 (s, 2H), 3.14-3.17 (m, 2H), 4.45 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.73 (br s, 1H), 7.87 (t, 1H), 7.92 (s, 1H), 8.29 (s, 1H), 8.48 (br s, 1H), 8.59 (s, 1H); Mass Spectrum: 495 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>COCCO>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:16]=[C:15]2[CH2:14][CH2:13][CH2:12][OH:11]
Reactant: C1=COCCC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: COCCO
Product: OCCCc1c[nH]c2ccc(Br)cc12
Yield: 68.8 %

Procedure:
A modification of a procedure reported by Grandberg (Chem. Abstr. 1973, 79,918895) was used. Thus, to a suspension of 4-bromophenylhydrazine hydrochloride (56.0 g, 0.25 mol) in 200 mL of 2-methoxyethanol was added 3,4-dihydro-2H-pyran (25.5 mL, 0.28 mol) over ca. 5 min and the resulting mixture was heated to reflux under Ar for 3.5 h. The cooled reaction mixture was evaporated and the residual oil was poured into 500 mL of cold water. The aqueous mixture was extracted with ether (2×250 mL) and the ethereal extract was washed with H2O (250 mL), 1N HCl (2×250 mL) and brine (250 mL). The organic phase was then dried (Na2SO4) and evaporated to give a dark orange-brown oil. This oil was purified on a 10×15 cm SiO2 pad (elution with CH2Cl2 then CH2Cl2 -ethyl acetate, 1:1) to give the title compound (43.7 g, 69%) as a viscous orange-brown oil: IR (neat) 3570, 3430, 3300 (br), 1460 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ0.11 (br s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.30-7.18 (m, 2H), 6.97 (s, 1H), 3.72 (t, J=6.4 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.03-1.89 (m, 2H), 1.68 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](N)=[N:5][CH:6]=[CH:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH2:4][N:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Brc1ccccc1
Reactant: COc1cccnc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1C
Product: COC1=CC=CN(c2ccccc2)C1

Procedure:
A 1 L 3-neck flask is charged with 3-methoxypyridine-2-amine (17.65 g, 143 mmol), bromobenzene (15 g, 96 mmol), Pd2DBA3 (1.75 g, 1.91 mmol), Sodium tert-butoxide (18.36 g, 101 mmol), S-Phos (1.56 g, 3.82 mmole) and 400 mL of xylene. The reaction mixture is refluxed for 4 h. The product is isolated by column chromatography (5% EtoAc in Hexs) to yield the desired product.