Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CCOC(C)=O>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:21][CH2:20][CH:19]=[CH2:23])[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(CCCCC(=O)N2CCOC2=O)OCCO1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CCCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-3 (3.0 g, 11.7 mmol) and THF (125 mL) at −78° C. was added NaN(TMS)2 (15.2 mL, 15.2 mmol, 1.0 M in THF) dropwise over 20 minutes. Butenyl-4-triflate (5.0 mL, 29.2 mmol) was added dropwise; after 1 h, the reaction was warmed to 0° C. After 1 h, the reaction was diluted with EtOAc, washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 2-4 as an yellow oil.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].CO[C:11](=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[N:20]=[CH:21]N(C)C>C1COCC1>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[C:13]=1[NH:20][CH:21]=[C:6]([C:7]#[N:8])[C:11]2=[O:25]
Reactant: COC(=O)c1cccc(OC)c1N=CN(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2c(=O)c(C#N)c[nH]c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To 35.0 mL of THF was added 26.6 mL (66.4 mmol) of n-BuLi solution during 5 min at -78° C. To the stirred solution was added a solution of 3.55 mL (67.9 mmol) of CH3CN in 65 mL of THF during 10 min which time the solution became white suspension, and then continued to stir for 15 min at -78° C. To the suspension was added a solution of 5.8 g (24.5 mmol) of 2-(Dimethylamino-methyleneamino)-3-methoxy-benzoic acid methyl ester in 45 mL of THF during 30 min, and then continued to stir 30 min at -78° C. during which time the mixture gradually became clear. The solution was quenched with 8.5 mL of HOAc. The resulting thick slurry was stirred and warmed to room temperature. After most of the solvent was evaporated, the residue was diluted with cold water. The separate solid was collected by filtration and washed with water. After drying in vacuo, this afforded 3.8 g of the product as an off white solid in 77.6% of yield, m.p. 270° C. (dec.), mass spectrum (electrospray, m/e): M+H 201.1
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.Br[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(O)C.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>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Oc1cccc(-c2cccnc2)c1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A mixture of diethyl(3-pyridyl)borane (11.80 g, 80.0 mmol), 3-bromophenol (16.60 g, 96.0 mmol), Pd(PPh3)4 (0.92 g, 0.80 mmol), and Na2CO3 (17.0 g, 160.0 mmol) in toluene/water/ethanol (160/80/40 mL) was purged with nitrogen for 5 min and then heated at reflux under nitrogen for 2 h. After solvent removal, the aqueous residue was partitioned between ethyl acetate/brine (400/250 mL). The separated organic layer was washed with brine, filtered, and concentrated. The solid residue was taken up in 130 mL of 3 M HCl, stirred for 15 min, diluted with brine (150 mL), and extracted with ethyl acetate (2×250 mL). The separated aqueous layer was cooled in ice/water bath, adjusted to pH 10 with solid NaOH and Na2CO3, and extracted with ethyl acetate (2×300 mL). The organic extract was dried over sodium sulfate and concentrated to give 12.60 g (92%) of 3-pyridin-3-yl-phenol as a light yellow solid: 1H NMR (CDCl3) δ 6.99 (m, 1H), 7.08 (m, 1H), 7.22 (m, 1H), 7.36 (m, 1H), 7.43 (m, 1H), 8.00 (dd, 1H), 8.60 (d, 1H), 9.00 (s, 1H); MS m/z (relative intensity) 171 (M+, 100), 142 (17), 115 (21).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[OH-].[K+]>>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:12]=[C:3]([CH2:4][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[CH:15][CH:14]=1)[NH2:1]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(C(F)(F)F)cc1Cc1ccccc1

Procedure:
In the manner given in Preparation 11, 2-amino-5-(trifluoromethyl)benzophenone is refluxed with potassium hydroxide in diethylene glyclol to give 4-(trifluoromethyl)-α-phenyl-o-toluidine.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[C:27]=2[Cl:30])[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:32][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[C:27]=2[Cl:30])[CH2:22]1)=[O:20])[CH3:17]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccc(Cl)c(Cl)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Cl)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76529.5 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (225 mg, 1.1 mmol), 2-amino-4,5-dichloro-indan-2-carboxylic acid ethyl ester (254) (360 mg, 1.3 μmol), HATU 622 mg, 1.64 mmol) in anhydrous DMF (10 mL) is added DIPEA (360 μL, 2.20 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is suspended in H2O (50 mL) and washed with EtOAc (3×50 mL). Organics are combined and washed successively with NaHCO3 and brine, and then the organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (255) as white powder (460 mg, 90%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9](C(O)=O)=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)[C:16]([Cl:18])=[O:17]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:16]([Cl:18])=[O:17])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)oc2cc(C(=O)O)ccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid (1.0 g, [CAS Reg. No. 140934-94-7]) in CH2Cl2 (14 mL) were added two drops of DMF and oxalylchloride (0.71 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-carbonyl chloride). To a suspension of zinc powder (677 mg) in 1,2-dimethoxyethane (8 mL) was added tetrakis(triphenylphosphine)palladium(0) (60 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (8 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-chloro-benzene (1.47 g, [CAS Reg. No. 89720-77-4]) in 1,2-dimethoxyethane (10 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. Ethyl acetate (20 mL) was added to the resulting precipitate and the suspension was stirred for 1 hour at r.t. The solid was filtered off and dried in vacuo. The title compound was obtained as an off-white solid (747 mg, 38%). MS (neg. ion, m/e)=380.2 [(M−H)−].
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:14][C:15]2[NH:16][C:17]([NH2:26])=[C:18]3[C:22]([N:23]=2)=[N:21][C:20]([O:24][CH3:25])=[N:19]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32]>>[Cl:32][CH2:31][CH2:30][CH2:29][CH2:28][N:21]1[C:20]([O:24][CH3:25])=[N:19][C:18]2[C:22]1=[N:23][C:15]([O:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:16][C:17]=2[NH2:26]
Reactant: COc1nc2nc(OC3CCCCC3)[nH]c(N)c-2n1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclohexyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1>N1CCOCC1>[Cl:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Solvent: C1COCCN1
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1N1CCOCC1
Temperature: 180 °C
Yield: 90.1 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (10 mg, 25 μmol) was dissolved in morpholine (0.5 ml) and heated in a microwave oven at 180° C. for 15 min. The excess morpholine was evaporated in vacuo and the oily residue triturated with EtOAc. The crystals formed were collected by filtration and washed with a 1: I EtOAc/n-heptane mixture. This afforded the product as a white powder (5 mg, 44%).
Reaction SMILES: C[C:2]1[N:3]2[C:9]([C:10](=[O:12])[CH3:11])=[CH:8][N:7]=[C:4]2[S:5][CH:6]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C[O-].[Na+]>C1COCC1>[Br:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:11]/[C:10]([C:9]2[N:3]3[C:4]([S:5][CH:6]=[CH:2]3)=[N:7][CH:8]=2)=[O:12])=[CH:16][CH:15]=1
Reactant: CC(=O)c1cnc2scc(C)n12
Reactant: O=Cc1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Br)cc1)c1cnc2sccn12
Yield: 81 %

Procedure:
A solution of 1-(3-methylimidazo[2,1-b]thiazol-5-yl)ethanone (Formula B-1) (1.8 g) in THF (25 mL) was treated with 4-bromobenzaldehyde (3.05 mL) and sodium methoxide (0.27 g) at 25°. Within 5 minutes a heavy precipitate formed and additional THF (65 mL) was added to maintain fluididy. After 20 minutes the reaction was concentrated in vacuo and the concentrate was diluted with water and precipitated 2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazole-5-yl methanone (Formula B-9) (2.9 g) was filtered. The precipitate was recrystallized from ethanol to yield pure 2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-9) (2.8 g, 81%), m.p. 213-215°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[C:3]=1[Br:9]
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Nc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To this solution was added N-bromosuccinimide (75 g, 426 mmol) portionwise at room temperature (water bath cooling was provided to control the exothermicity). The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC). Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].[OH-].[Na+].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH:13][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(N)ccc1C#N
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCOc1cc(NC(=O)C(C)(C)C)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 10B (1.9 g, 10.9 mmol) in anhydrous CH2Cl2 (16 mL) cooled at 0° C. was added 1 N aqueous NaOH solution (16.4 mL, 16.4 mmol), followed by pivaloyl chloride (1.9 mL, 15.3 mmol). After the addition, the reaction mixture was stirred at 0° C. for 2 h, then concentrated under reduced pressure to remove most of the CH2Cl2 solvent. The remaining residue was diluted with water, and the resulting precipitate collected by filtration, washed with water, hexane, and dried under vacuum to furnish the title compound as a light brown solid (2.6 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20](B5OC(C)(C)C(C)(C)O5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:31]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[C:33]1[N:34]=[CH:35][N:36]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[CH:37]=1.BrC1N(CC(C)(O)C)C=NC=1.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:33]5[N:34]=[CH:35][N:36]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[CH:37]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:31]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)(O)Cn1cnc(Br)c1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(O)Cn1cncc1Br
Solvent: COCCOC
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn(CC(C)(C)O)cn3)cc1OCC2
Yield: 12 %

Procedure:
2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (113 mg, 0.268 mmol), 1-(4-bromo-1H-imidazol-1-yl)-2-methylpropan-2-ol and 1-(5-bromo-1H-imidazol-1-yl)-2-methylpropan-2-ol (88.14 mg, 0.40 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II)chloride (21.90 mg, 0.027 mmol), 1,2-dimethoxyethane (3.0 mL, 29 mmol), and 1 M Cesium carbonate in water (0.54 mL, 0.5 mmol) were mixed in a microwave vial and microwaved at 140° C. for 15 minutes. Complete reaction by LCMS. Filtered through a paper filter followed by a silica plug. Concentrated in vacuo and purified by HPLC to give 202 (13.7 mg, 12% yield)
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][N:21]2[C:26]3[N:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24](=O)[O:23]C2=O)=[CH:18][CH:17]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:34][CH:33]=2)[C:26]2[C:25]([C:24]=1[OH:23])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cccnc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
Diethyl malonate (2.37 mL, 15.61 mmol) was added slowly to a suspension of NaH (60% in mineral oil, 0.62 g, 15.61 mmol) in dimethylacetamide (40 mL) and stirred at room temperature for 0.5 h under inert atmosphere. 1-(4-Methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (12) (4.47 g, 15.61 mmol) was added to the solution and heated at 110° C. for 3 h (TLC control). The solution was cooled and poured into ice water. The pH of the solution was adjusted to 3 by cold 10% HCl. The solids formed were filtered, washed by excess water, and dried in a vacuum oven. The crude product was recrystallized by ethylacetate to yield 1.2 g (21%) of 4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (13) as white solids. MP: 153° C.; 1H-NMR (DMSO-d6): δ 1.31 (t, J=7.0 Hz, 3H), 3.68 (s, 3H), 4.32 (q, J=7.0 Hz, 2H), 5.47 (s, 2H), 6.81 (d, J=7.7 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.36 (d, J=7.6 Hz, 1H), 8.42 (dd, J=1.5, 7.5 Hz, 1H), 8.73 (dd, J=1.5, 7.5 Hz, 1H), 13.00 (S, 1H); EIMS: 355 (M+1).
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1>O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([O-:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.[Na+:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
4N Aqueous solution of sodium hydroxide was carefully added dropwise to a stirred suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 52 g.) in water (100 ml.) below 5° C. to make a solution of pH 7.0 to 7.5. After filtration and washing, the combined filtrate and the washings (200 ml.) was added dropwise to ethanol (2 l.) under stirring over 30 minutes, and stirred at room temperature for 15 minutes and then at 5° to 10° C. for an hour. The precipitates were collected by filtration, washed with ethanol (200 ml.) and dried in vacuo at 30° C. to give amorphous sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 46.3 g.).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2=[N:7][CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]2[CH:4]=1)[CH3:2].[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([F:30])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([C:3]1[NH:12][C:6]2=[N:7][CH:8]=[C:9]([NH:11][C:16](=[O:17])[C:15]3[C:19]([F:30])=[CH:20][CH:21]=[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:14]=3[F:13])[CH:10]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: CCc1cc2cc(N)cnc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(CC)cc3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
2-Ethyl-1H-pyrrolo[2,3-b]pyridin-5-amine (0.100 g, 0.62 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.182 g, 0.65 mmol), EDCI (0.125 g, 0.65 mmol) and HOBt (0.084 g, 0.65 mmol) were dissolved in DMF (1.5 mL) and stirred at room temperature overnight. The solution was then directly purified by reverse phase HPLC to afford N-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.061 g, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ 11.46 (s, 1H), 10.75 (s, 1H), 9.79 (br s, 1H), 8.26-8.25 (m, 1H), 8.19-8.18 (m, 1H), 7.56-7.50 (m, 1H), 7.24 (t, 1H), 6.18-6.17 (m, 1H), 3.13-3.09 (m, 2H), 2.74 (q, 2H), 1.77 (sx, 2H), 1.28 (t, 3H), 0.99 (t, 3H); m/z (ES-MS) 423.2 (100.0%) [M+1].
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].[O:34](C(C)=O)[C:35]([CH3:37])=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:3][C:2]([CH:4]1[CH:8]2[CH:9]3[C:22]([CH3:25])([CH2:23][CH2:24][C:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C:21]1([CH3:26])[CH:12]([C:13]2([CH3:30])[CH:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[CH:16]([O:29][C:35]([CH3:37])=[O:34])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C1CCC2(C(=O)O)CCC3(C)C(CCC4C5(C)CCC(OC(C)=O)C(C)(C)C5CCC43C)C12

Procedure:
Betulinic acid, 100 mg (0.22 mmoles) was added to a solution containing 4 mg of 4-dimethylaminopyridine (DMAP) and 0.5 ml of (CH3CO)2O in 5 ml of CH2Cl2. After 2 hrs CH2Cl2 was removed in vacuo, and the remaining residue stirred with 25 ml of water. During the stirring enough of K2CO3 was added to decompose an excess of acetic anhydride, after which the reaction mixture was extracted with 25 ml of CH2Cl2. The extract was evaporated to dryness and the resulting solid crystallized from MeOH to give 104 mg of acetylbetulinic acid as white crystals, m.p. 285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:17]=3)[CH2:12][N:11]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:41]1[N:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:41]4[N:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=4)=[CH:16][CH:17]=3)[CH2:12][N:11]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:29])=[O:30])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC3c2ccc(Cl)c(Cl)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cnc(-c2ccc3c(c2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC3c2ccc(Cl)c(Cl)c2)cn1
Temperature: 90 °C
Yield: 14.1 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (300 mg, 0.51 mmol), 5-bromopyrazin-2-amine (174 mg, 1.0 mmol) and cesium carbonate (490 mg, 1.5 mmol) in water (1.5 mL) and N,N-dimethylformamide (5 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 90° C. for 3 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was partially purified by column chromatography (9:1 hexanes/ethyl acetate to ethyl acetate) to give 5-(4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine (40 mg, 14%) as a yellow oil: ESI MS m/z 556 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([OH:7])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[N:25]2[CH2:24][C:23]2[CH:26]=[CH:27][C:20]([CH3:19])=[CH:21][CH:22]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Yield: 74 %

Procedure:
The named compound was synthesised from 2-(4-chlorobenzoyl)-benzoic acid (2.0 g, 7.6 mmol) and 4-methyl benzylamine (1.07 mL, 8.4 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 10-80% EtOAc/hexane) and obtained as a white solid (2.045 g, 72%).