Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.P(=O)(O)(O)O.[CH2:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>C1C=CC=CC=1>[CH3:21][C:20]1([CH3:22])[O:1][C:2]2[C:3](=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:18][CH2:19]1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CC1(C)CCc2c(ccc3[nH]c(=O)ccc23)O1

Procedure:
6-hydroxyquinoline-2-one (481 mg) and orthophosphoric acid (0.55 ml) were dissolved in 5 ml of benzene, and then a solution of 0.55 ml of isoprene in 5 ml of benzene was added thereto with stirring. The resulting mixture was heated under reflux for 30 minutes. The reaction liquid was poured into ice-cold water and extracted with ethyl acetate. The extracted liquor was washed with water, dehydrated by addition of anhydrous sodium sulfate and filtered. The solvent in the filtrate was distilled away under reduced pressure, and the resulting residue was recrystallized from ethanol to give 567 mg of pale yellow needle-like crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.[Sn](Cl)Cl>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCOc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOc1cc(Br)ccc1N
Temperature: 70 °C
Yield: 81.5 %

Procedure:
To a solution of 4-bromo-2-ethoxy-1-nitrobenzene (Preparation 100, 250 mg, 1.016 mmol) in EtOH (15 mL) was added tin (II) chloride (963 mg, 5.08 mmol). The reaction mixture was heated to 70° C. for 2 hours. The reaction mixture was diluted with ice-water (10 mL) and concentrated in vacuo. Aqueous Na2CO3 (2M, 20 mL) was added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by passage through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH to give the title compound (179 mg, 82%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][NH:8][CH2:9][C:10]#[CH:11].[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14]>C(O)C.CCOCC>[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14].[CH2:2]([N:8]([CH2:9][C:10]#[CH:11])[CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: C#CCNC
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCOCC
Product: C#CCN(C)CCCCC
Yield: 60 %

Procedure:
1-Bromopentane (12.1 g, 80 mmoles) and N-methylpropargylamine (11.1 g, 160mmoles) were refluxed in absolute ethanol (75 mL) for 72 h. to give (after addition to 80 mmoles of oxalic acid in ether) the title compound in 60% yield after recrystallization from methanol-ether, m.p.=101°-103° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:38])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:30]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution comprising 10 g (33.7 mmol) of 1,4-dibenzyl-2-hydroxymethylpiperazine (prepared in accordance with the process described by Jucker and Rissi in Helv. Chem. Acta, 1962, 45, 2383-2402) in 9.5 ml (2.8 equivalents; 94.4 mmol) of triethylamine and 95 ml of dichloromethane (CH2Cl2) is placed in a 500 ml ground-necked conical flask on which is fitted an addition funnel, and is cooled in an ice bath. After dropwise addition of 6.4 g (1.25 equivalents; 42 mmol) of phenyl chlorocarbonate dissolved in 95 ml of CH2Cl2, the mixture is stirred at 0° C. for one hour and then at room temperature for 10 hours. At the end of the reaction, the solution is washed once with saturated sodium bicarbonate (NaHCO3), solution and then with water until a neutral pH is obtained, and it is dried over magnesium sulfate (MgSO4). After filtration on paper and evaporation of the CH2Cl2, the residue is chromatographed on a column of silica gel, using dichloromethane as eluent. 8 g of 1,4-dibenzyl-2-phenoxycarbonyloxymethylpiperazine are thus obtained in the form of a viscous product. Yield: 57%. Rf=0.52 (2/98 v/v MeOH/CH2Cl2,).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[I:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.08 g), commercially available 4-iodobenzoyl chloride (2.67 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. overnight. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 722 mg of the title compound (yield: 21%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:28]=4[O:27][CH3:26])=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,4-dimethoxybenzoyl chloride as starting compounds. The crude product is purified by column chromatography (silica gel and EA/PE=2:1) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13]C(O)=O)[CH:10]([CH2:17][C:18]([OH:20])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+]>CC(OC(C)=O)=O>[O:20]=[C:18]1[CH2:13][CH:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH:10]2[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C(CC(=O)O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Temperature: 120 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
To a suspension of 2,2′-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (3.40 g, 11.8 mmol) in Ac2O (21 mL) was added NaOAc (0.78 g, 9.5 mmol) and the reaction mixture was stirred at 120° C. for 3 h. After that, the resulting mixture was cooled down to rt then filtered and washed with EtOAc (20 mL×2). The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc/PE (v/v)=1/4) to give the title compound as orange yellow oil (1.38 g, 55.0%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11](=[O:29])[NH:12][CH2:13][C:14]1[C:18](=[N:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C:17]([NH2:28])=[N:16][N:15]=1)=[O:4].[OH-].[K+]>C(O)C>[NH2:28][C:17]1[C:18](=[N:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C:14]([CH2:13][NH:12][C:11]([CH2:10][N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[C:3]([OH:4])=[O:2])=[O:29])=[N:15][N:16]=1
Reactant: COC(=O)C1CCCN1CC(=O)NCC1=NN=C(N)C1=NNc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC1=NN=C(CNC(=O)CN2CCCC2C(=O)O)C1=NNc1cccc(F)c1
Temperature: 76 °C
Yield: 89.9 %

Procedure:
1-[({5-Amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}carbamoyl)-methyl]pyrrolidine-2-carboxylic acid methyl ester (80 mg, 0.20 mmole) was dissolved in 1.5 mL of 95% ethanol with KOH (19.7 mg (85%), 0.29 mmole). The solution was heated at 76° C. for 1 hour. The reaction was quenched by the addition of 1 mL of water and then acidified to pH 3 with 1.5 M HCl. The solution was evaporated to dryness together with 2-PrOH and silica gel. The resulting powder was then placed onto a silica gel column. The crude material was purified by column chromatography (CH2Cl2:MeOH:H2O:HOAc=240:60:4.7:2.2) to yield 70 mg of the title compound as a yellow powder. MS (m/z, ES−): 388 (M−1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 8.77 (br s, 1H), 7.35-7.60 (m, 3H), 7.09 (m, 1H), 6.99 (br s, 2H), 4.50 (m, 2H), 3.31 (m, 1H), 3.01 (m, 2H), 2.29 (m, 1H), 2.05 (m, 1H), 1.93 (m, 1H), 1.72 (m, 1H), 1.50-1.61 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.29 min, m/z=431 (M+1); 1H NMR (CDCl3) 8.71 (d, 1H, J=6 Hz), 7.78 (d, 1H, J=6 Hz), 7.7 (s, 1H), 7.49 (t, 2H, J=7, 7 Hz), 7.27-7.24 (m, 2H), 7.17 (m, 2H), 7.09-7.02 (aq, 2H, J=9, 17 Hz), 5.73 (q, 1H, J=7, 14 Hz), 4.27 (t, 1H, J=6, 6 Hz), 3.60 (t, 1H, J=6, 6 Hz), 3.09-3.03 (m, 1H), 2.95 (s, 3H), 2.41-2.25 (m, 3H), 2.06-1.90 (m, 2H) 1.73-1.64 (m, 1H), 1.58 (d, 3H, J=7 Hz), 1.40-1.33 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@@H](O)[C@H](C)CNC(=O)C3C=CC=CC=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3]C1.O.NN.[OH-].[Na+].CC[O-].[Na+]>>[C:9]1([O:8][C:7]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](CNC(=O)c1ccccc1)[C@H](O)c1cccc(OCC2CCCCC2)c1
Agent: CC[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 60 °C

Procedure:
A mixture of N-((2R,3S)-3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)benzamide (0.179 g, 0.47 mmol), hydrazine monohydrate (0.2 mL), aqueous solution of NaOH (50% w/w, 0.5 mL) and NaOEt (30% in MeOH, 1 mL) was heated at 60° C. under argon for 6 days. The reaction mixture was concentrated under reduced pressure, brine added and the product was extracted into MTBE. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (5% 7N NH/MeOH in CH2Cl2) to give Example 76 as a colorless oil. Yield (0.049 g, 38%). 1H NMR (400 MHz, DMSO-d6) δ 7.15 (t, J=8.0 Hz, 1H), 6.78-6.81 (m, 2H), 6.88-6.72 (m, 1H), 4.60 (d, J=4.1 Hz, 1H), 3.71 (d, J=6.5 Hz, 2H), 2.56 (dd, J=6.3 Hz, 12.5 Hz, 1H), 2.40 (dd, J=6.1 Hz, 12.5 Hz, 1H), 1.50-1.84 (m, 7H), 1.08-1.27 (m, 4H), 0.96-1.07 (m, 2H), 0.66 (d, J=6.9 Hz, 3H); ESI MS 278.5 [M+H]+. Chiral HPLC: 92.6%, tR=10.0 min.
Reaction SMILES: [F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)=[O:4].O.[OH-].[Na+]>CO>[F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:26])([CH3:27])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)c1ccc(NC(=O)C(F)(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
4-[2,2-Difluoro-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid methyl ester 17 (500 mg, 1.20 mmol) was dissolved in methanol (33.5 mL). Water (3.35 mL) and NaOH (270 mg, 4.81 mmol) were successively added at RT. The mixture was stirred at 70° C. for 1 h. The mixture was evaporated in vacuo and dissolved in water (100 ml) and extracted with diethyl ether (2×50 mL). The aqueous layer was acidified by HCl (1M) to about pH=1 and extracted with diethyl ether (2×100 mL), the organic layer was dried over MgSO4, filtered and evaporated. 4-(2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoic acid 18 was obtained (169 mg, 35% yield) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.C([Li])(CC)C.CN(C)[CH:21]=[O:22]>C1COCC1>[CH2:12]([C:4]1[C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=[C:2]([CH:21]=[O:22])[CH:3]=1)[CH3:13]
Reactant: CCc1cc(Br)cc2c(C)coc12
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCc1cc(C=O)cc2c(C)coc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
5-Bromo-7-ethyl-3-methylbenzofuran 31 (21.25 g, 89 mmoles) was dissolved in dry THF (470 ml) and cooled to −78° C. under a nitrogen atmosphere. Sec-butyl lithium (69.8 ml of a 1.4 M solution, 98 mmoles) was added drop wise to the cooled reaction. The reaction mixture turned a reddish color. Dimethylformamide (51.6 ml, 666 mmoles) was added to the reaction at −78° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into 800 ml of ice/ethyl acetate and the organic layer separated. The aqueous layer was washed with ethyl acetate and the combined organic layer washed with water. The solution was dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (750 g silica, 8% ethyl acetate in hexanes) to yield 7.02 g of 7-ethyl-3-methylbenzofuran-5-carbaldehyde 32.
Reaction SMILES: [Na+].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][S:17]([O-:20])(=O)=[O:18])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>C1COCC1.C(OCC)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][S:17]([Cl:29])(=[O:20])=[O:18])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(Cl)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
Under inert gas, 5.70 g of (4-benzyloxyphenyl)methanesulfonic acid sodium salt and 1.48 ml of N,N-dimethylformamide were initially charged in 110 ml of THF, then, at a temperature of −20° C., 4.17 ml of oxalyl chloride were added dropwise and the reaction solution was allowed to come to 0° C. within 15 minutes. The reaction solution was diluted with 100 ml of diethyl ether and washed with water, dilute aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue (4.89 g) was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](I)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.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]>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:13]=1
Reactant: Clc1ccnc(I)c1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccccc1-c1cc(Cl)ccn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A mixture of 2-fluorophenylboronic acid (141 mg, 1 mmol, 1.2 eq) in EtOH (1 mL) is added to a mixture of 4-chloro-2-iodo-pyridine [Choppin, S.; Gros, P.; Fort, Y., European Journal of Organic Chemistry (2001), (3), 603-606] (200 mg, 0.84 mmol), PdCl2(dppf) (18 mg, 0.025 mmol, 0.03 equiv) and Na2CO3 (2 M solution in H2O, 1.68 mL, 3.36 mmol, 4 equiv) in toluene (2 mL) at 105° C., under an argon atmosphere. The reaction mixture is stirred at 105° C. for 1 h, allowed to cool to rt, quenched by addition of a saturated solution of NaHCO3 and extracted with EtOAc. The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 1:0→97:3) to afford 127 mg of the title compound as a white solid: ESI-MS: 208.1 [M+H]+; tR=4.66 min (System 1); TLC: Rf=0.27 (Hex/EtOAc, 9:1).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CCOC(C)=O>[CH:1]1([N:6]2[C:10]3=[N:11][C:23]([C:22]4[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[C:20]([O:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH:21]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COc1ccc(C=O)cc1OCCN1CCOCC1
Solvent: CCOC(C)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OC)c(OCCN4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.25 g, 5.63 mmol), 4-methoxy-3-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.64 g), and xylenes (12 ml) was heated at 160° C. overnight. Additional aldehyde (0.5 g) was added and the mixture was refluxed until complete, then cooled to room temperature. The solvent was stripped, the residue was slurried with EtOAc and the product was collected by filtration and combined with the product from a similar experimental run. The combined product was recrystallized from CH3CN to afford 1-cyclopentyl-3-ethyl-6-[4-methoxy-3-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 205-206° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[N:6]2[CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31].C(N(CC)CC)C>C(O)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:5]1[N:6]([CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:35]1[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: CCN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(C3CN(C(=O)OC(C)(C)C)C3)c2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CN(C(=O)OC(C)(C)C)C2)CC1
Yield: 48.8 %

Procedure:
Heat a solution of tert-butyl 3-(6-chloro-8-(2-chlorophenyl)-2-methyl-9H-purin-9-yl)azetidine-1-carboxylate (0.012 mol, 5.5 g), N-ethyl piperazine (0.013 mol, 1.59 g, 1.1 equiv.), and triethylamine (0.013 mol, 1.41 g, 1.1 equiv.) in ethanol (25.0 mL) at 90° C. for 16 hours. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane. Wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give the residue. Purify the residue by silica gel chromatography eluting with dichloromethane:methanol 98:2 to give tert-butyl 3-(8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purin-9-yl)azetidine-1-carboxylate (3.0 g). MS (m/z): 512.31 (M+1).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:39])[C:37]=1[F:38])[CH2:33]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:33][C:32]3[CH:31]=[C:30]([F:29])[C:37]([F:38])=[C:36]([F:39])[CH:35]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Fc1cc(CBr)cc(F)c1F
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cc(F)c(F)c(F)c2)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27 step D from methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4,5-trifluorobenzyl bromide, and was isolated as beige solid after reverse phase chromatography (81%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.43 (s, 3H), 3.65 (s, 3H), 5.46 (s, 1H), 5.75 (s, 2H), 6.08 (d, J=2.7 Hz, 1H), 6.87 (t, J=7.1 Hz, 2H), 7.01 (d, J=2.7 Hz, 1H), 7.28 (d, 2H), 7.31-7.39 (m, 1H), 7.48-7.57 (m, 1H). LCMS (m/z) ES+=513 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:34]1[N:38]=[CH:37][S:36][N:35]=1)[C:19]([NH:21][CH:22]1[C:32](=[O:33])[N:24]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:34]1[N:38]=[CH:37][S:36][N:35]=1)[C:19]([NH:21][CH:22]1[C:32](=[O:33])[N:24]2[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1ncsn1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1ncsn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Trifluoroacetic acid (3.6 ml) was added to a suspension of 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.2 g) in anisole (1.2 ml), and the mixture was stirred for 2 hours at ambient temperature. The resultant solution was added dropwise to diisopropyl ether (100 ml) and the precipitates were collected by filtration. The precipitates were added to a mixture of water (50 ml) and ethyl acetate (50 ml) and adjusted to pH 6.5 with 5% aqueous sodium bicarbonate. The separated aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to give 7-[2-carboxymethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (0.5 g).