Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:13]>>[C:1]1([CH2:7][C:8]([Cl:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1

Procedure:
Phenylacetic acid (PAA), 0.037 moles (5g) was heated under reflux with an excess of SOCl2 for 60 minutes at a temperature of 75-80° C. After the reaction was completed, the excess SOCl2 was eliminated by vacuum evaporation, using a water pump (40-50° C.). This process was repeated two to three times, each time adding benzene to aid in elimination of SOCl2 and yielding phenylacetyl chloride (PAC). Then, 0.018 mole of 2-hydrazino-2-imidazoline.HBr (3.5 g) was suspended in ether and shaken with 2N NaOH (2-5 equivalents) on an ice bath, until it was completely dissolved. The PAC was then added dropwise very slowly from a funnel with vigorous shaking. Excess NaOH was present to drive the reaction to completion. After the addition of PAC, the mixture was stirred at 0C for an additional 15-30 minutes. The ether layer was washed with water, then with saturated NaHCO3. It was then dried over Na2SO4, filtered and was brought to complete dryness. The solid residue from the ether layer was then crystallized from an ethanol-water mixture (70-80% ethanol). The yield, was approximately 55% without subjecting the residual amide to further separation from the aqueous layer.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O:54][C:55]([NH:57][O:58]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.CCOC(/[N:74]=N/C(OCC)=O)=O>C1COCC1>[OH:58][N:57]([CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:13]=2)=[CH:5][CH:4]=1)[CH3:1])[C:55]([NH2:74])=[O:54]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: O=C(NOC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1)N(O)C(N)=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a mixture of a-Methyl-4-[4-(4-fluorophenyl)-5-(4-pyridyl)imidazol-2-yl]benzyl alcohol (0.25 g, 0.70 mmol), P(Ph)3 (0.46 g, 1.75 mmol) and N,O-bis(benzyloxycarbonyl)hydroxylamine (0.48 g, 1.75 mmol) in THF (15 mL) was added DEAD (0.28 mL, 1.75 mmol) at rt. The reaction mixture was stirred at this temperature for 3 h and the solvent evaporated. The residue was partially purified by flash chromatography eluting with 1% MeOH/CHCl3. Methanol (25 mL) was added to this material and the mixture was cooled to -78° C. Ammonia was bubbled in at this temperature for 15 min. The reaction mixture was warmed slowly to rt, stoppered and stirred at rt for 2 days. The solvent was evaporated and the residue was purified by flash chromatography eluting with a solvent gradient of 1-10% MeOH/CHCl3. The title compound was obtained as an off-white solid (0.43 g, 14%): FABMS (m/z): 418 (M+ +H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22](O)=[O:23])[C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][CH:40]1[CH2:43][NH:42][CH2:41]1>>[CH:33]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([N:42]4[CH2:43][CH:40]([O:39][CH3:38])[CH2:41]4)=[O:23])[C:16]=3[N:15]=2)=[O:36])[CH2:28][CH2:29]1)([CH3:35])[CH3:34]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: COC1CNC1
Agent: Cl
Product: COC1CN(C(=O)c2cccc3c2nc(C(=O)NC2CCN(C(C)C)CC2)n3Cc2cc(-c3ccc(Cl)s3)on2)C1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(3-methoxy-azetidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 205 mg (0.34 mmol) 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 46.6 mg (0.37 mmol) 3-methoxy-azetidine-hydrochloride. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid. Yield: 190 mg MS (ES+): m/e=597, chloro pattern.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]#[N:26])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:5][CH:4]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]4[NH:39][N:38]=[N:37][N:26]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCOCCC#N)c23)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCOCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 137 mg (0.32 mmol) 5-(4-methoxyphenyl)-6-phenyl-N-{3-[2-cyanoethoxy]propyl}furo[2,3-d]-pyrimidine-4-amine, 552 mg (4.8 mmol) trimethylsilylazide and 119 mg (0.48 mmol) di-n-butyltin oxide in 10 ml toluene overnight at 80° C. Then cool the mixture and concentrate by evaporation. Dissolve the residue that remains in methylene chloride and wash with water and sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate in the rotary evaporator at reduced pressure. Purify the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile). 48.6 mg (32% of theor.) of the title compound is obtained as a colourless solid.
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4](C)[N:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].[CH3:16]CN(CC)CC>CCOCC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]1[O:8][C:7]2[C:2](=[N:3][CH:4]=[C:5]([CH3:16])[CH:6]=2)[CH:15]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: CCN(CC)CC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1cnc2cc([Si](C)(C)C)oc2c1
Yield: 86 %

Procedure:
A mixture of 2-iodo-6-methylpyridine-3-ol (20 g, 85 mmol), CuI (2.1 g, 11 mmol), trimethylsilyl acetylene (23.4 g, 238 mmol), and bis(triphenylphosphine)palladium(II)chloride (5.37 g, 7.65 mmol) in Et3N (380 mL) was heated to reflux for 20 hr. The mixture was cooled and diluted with ether and filtered through celite. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluted with 10% EtOAc in hexane) to give 15 g (86%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)N)=[O:8])=[CH:5][CH:4]=1.[C:22]([OH:29])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O>O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:11]3[C:16](=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[C:24]([CH2:23][C:22]([OH:29])=[O:28])=[C:25]2[CH3:27])=[O:8])=[CH:5][CH:4]=1
Reactant: NN(C(=O)c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: O
Product: Cc1c(CC(=O)O)c2cc3c(cc2n1C(=O)c1ccc(Cl)cc1)OCO3
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 1.9 g of N1 -(p-chlorobenzoyl)-3,4-methylenedioxyphenylhydrazine hydrochloride and 20 g of levulinic acid was heated for 1 hour at 55° - 60° C and for 3 hours at 80° - 90° C. The reaction mixture was cooled to a room temperature, and poured into 200 ml of water. The precipitates were collected by filtration and washed with water. The crystals obtained by twice recrystallizing from acetone-water (5 : 1) gave 1.19 g of 1-(p-chlorobenzoyl)-2-methyl-5,6-methylenedioxy-3-indolylacetic acid having a melting point of 217° - 218° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]5[O:36][CH2:37][O:38][C:30]=45)=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:39][CH3:40])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:35].[ClH:35].[Cl:35][C:34]1[C:29]([NH:28][C:22]2[C:21]3[C:26](=[CH:27][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:19]([O:39][CH3:40])[CH:20]=3)[N:25]=[CH:24][N:23]=2)=[C:30]2[O:38][CH2:37][O:36][C:31]2=[CH:32][CH:33]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 225.8 %

Procedure:
A mixture of 7-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propoxy]-4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxyquinazoline (0.286 g), trifluoroacetic acid (0.5 ml) and methylene chloride (6 ml) was stirred at ambient temperature for 3 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The material so obtained was triturated under a 6M solution of hydrogen chloride in diethyl ether. There was thus obtained the title compound (0.205 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.35 (m, 2H), 3.2–3.9 (m, 10H), 4.0 (s, 3H), 4.35 (m, 2H), 6.12 (s, 2H), 7.0 (s, 1H), 7.1 (s, 1H), 7.38 (s, 1H), 8.15 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 472 and 474
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>C1COCC1.C(O)C>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.5 %

Procedure:
To a solution of 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (143 mg, 0.214 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (5 mL) at room temperature. The mixture was stirred for 7 h at room temperature. Then, the reaction mixture was concentrated, the residue was diluted with water (20 mL) and extracted with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1 N hydrochloric acid and the organic compound was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under vacuum gave 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (125 mg, 95%) as a white amorphous solid.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[C:5]([O:16][CH3:17])(=[O:15])[C:6]1[C:7](=[CH:9][C:10](=[CH:12][C:13]=1[CH3:14])[OH:11])[OH:8].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:17][O:16][C:5](=[O:15])[C:6]1[C:13]([CH3:14])=[CH:12][C:10]([O:11][CH2:2][CH2:3][CH3:4])=[CH:9][C:7]=1[OH:8]
Reactant: COC(=O)c1c(C)cc(O)cc1O
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc(C)c(C(=O)OC)c(O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1-iodopropane (1.87 g, 10.98 mmol), methyl orsellinate (2.0 g, 10.98 mmol), and sodium bicarbonate (1.84 g, 21.96 mmol) in DMF is stirred at 60° C. overnight. The mixture is cooled and partitioned between EtOAc and water. The EtOAc layer is washed with brine, dried over magnesium sulfate, and concentrated to give the crude product. Purification by silica gel chromatography using 2% EtOAc in hexane as the eluent gives 2-hydroxy-6-methyl-4-propoxy-benzoic acid methyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=O)[CH2:21][CH2:22][CH3:23])=[C:15]([OH:25])[CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2].Cl.[CH2:27]([O:30][NH2:31])[CH:28]=[CH2:29].C(=O)(O)[O-].[Na+]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:18][C:17](=[O:19])[C:16]([C:20](=[N:31][O:30][CH2:27][CH:28]=[CH2:29])[CH2:21][CH2:22][CH3:23])=[C:15]([OH:25])[CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(OC)c(NC(C)=O)c2)CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=CCON=C(CCC)C1=C(O)CC(c2ccc(OC)c(NC(C)=O)c2)CC1=O
Yield: 57.6 %

Procedure:
3 g of 5-(3-acetylamino-4-methoxyphenyl)-2-butyryl-3-hydroxycyclohex-2-en-1-one were stirred together with 0.95 g of O-allylhydroxylamine hydrochloride and 0.8 g of sodium bicarbonate in 40 ml of methanol for 16 hours. The mixture was evaporated down, mixed with methylene chloride, washed thoroughly with water, dried and evaporated down again. The residue which remained was stirred with diisopropyl ether and the product was filtered off under suction. 2.0 g (57% yield) of 5-(3-acetylamino-4-methoxyphenyl)-2-(1-allyloxyiminobutyl)-3-hydroxycyclohex-2-en-1-one of melting point 136°-137° C. were obtained (compound No. 11).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.Cl>CCOCC>[OH2:12].[ClH:1].[CH2:13]([O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Nc1ccc(OC)cc1
Product: O
Reaction time: 72 h

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate (3.1 g), 4-methoxyaniline (1.36 g) and IMS (40 ml) was boiled under reflux for 4 hours. The mixture was evaporated to dryness. The residual solid was ground in ether and then filtered. The solid was dissolved in dichloromethane and purified by column chromatography on silica using dichloromethane, then ether, then ethyl acetate, then IMS, as the mobile phase. The third fraction obtained was dissolved in IMS (30 ml) and the solution was saturated with hydrogen chloride gas. Ether was added and the mixture left to stand at approximately 4° C. for 3 days. The mixture was filtered to give ethyl 6-ethoxy-4-(4-methoxyanilino)-1,5-naphthyridine-3-carboxylate hydrochloride hydrate, m.p. 130°-133° C. Active (3/3) at 30 mg/kg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:18])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:18])=[C:11]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:12]=[CH:13]2)=[C:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(OC)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 45 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-methoxy-phenyl boronic acid (73 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (68 mg, 45%). ESI-MS m/z: 378 (M+H)+.
Reaction SMILES: BrC1N(CC=C(C)C)[C:4]([C:11](OC)=O)=[C:5]([C:7](OC)=O)N=1.[Br:20][C:21]1[NH:22][C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=1.BrCC#CC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:20][C:21]1[N:25]([CH2:11][C:4]#[C:5][CH3:7])[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:22]=1
Reactant: CCOC(=O)c1nc(Br)[nH]c1C(=O)OCC
Reactant: COC(=O)c1nc(Br)n(CC=C(C)C)c1C(=O)OC
Agent: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc(C(=O)OCC)c1C(=O)OCC

Procedure:
Prepared analogously to 1b from 3.50 g (12.02 mmol) diethyl 2-bromo-imidazole-4,5-dicarboxylate with 1.09 ml (12.1 mmol) 1-bromo-2-butyne and 2.07 g (15.00 mmol) potassium carbonate in 15 ml of dimethylformamide.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][NH:23][C:22]=2[N:21]=1)(=[O:7])[O:5][CH3:6]
Reactant: COC(=O)CCCCc1ccc2c(n1)NCCC2
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCCC2)OC
Reaction time: 0.75 h

Procedure:
A solution of dimethyl methylphosphonate (13.20 g, 106.5 mmol) in anhydrous THF (165 mL) was cooled to −78° and treated dropwise with 2.5 M n-BuLi (42.3 mL). After stirring at −78° for 45 min, a solution of ester 1-5 (6.6 g, 26.6 mmol) in THF (35 mL) was added dropwise and the resulting solution stirred for 30 min at −78°, quenched with sat. NH4Cl (100 mL), then extracted with ethyl acetate (3×150 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to afford a yellow oil. Chromatography on silica gel (5% MeOH/CH2C12) afforded 1-6 as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)=[CH:3][CH:2]=1.[OH-].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CC(C)=O.C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1ccc(-c2nc(Nc3ccncc3)c3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ccncc2)c2nc(-c3ccccc3)nc3ccccc23)cc1
Temperature: 25 °C

Procedure:
4-(4-pyridylamino)-2-phenyl quinazoline, 1 equivalent, was dissolved in reagent grade acetone, to this was added 5 equivalents of potassium hydroxide and 1.5 equivalents of 4-methoxybenzyl chloride. The mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature the reaction mixture was concentrated and the residue taken up in ethyl acetate and washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate and concentrated to give an oil. This crude material was dissolved in ethyl acetate and chromatographed as in Example 1. EIMS confirmed the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH3:30])[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[I-].[Na+].[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.Cl>CC(C)=O.C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH3:30])[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][N+:42]4[CH:41]=[CH:40][C:39]([C:35]5[O:34][CH:38]=[CH:37][N:36]=5)=[CH:44][CH:43]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: c1cc(-c2ncco2)ccn1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(-c4ncco4)cc3)CS[C@H]12)c1csc(N)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.75 g of sodium 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (hereinafter referred to Compound 1), 2.25 g of sodium iodide and 0.51 g of 4-(oxazol-2-yl)-pyridine were added to a mixture of 0.4 ml of 4 N hydrochloric acid and 1.2 ml of acetonitrile, followed by stirring at 80° C. for 1 hour. After allowing the mixture to cool, the reaction mixture was poured into acetone, and the precipitate formed was separated by filtration and washed with acetone. The resulting crude powder was dissolved in water, and the solution was subjected to column chromatography of Diaion HP-20 (trade name of Mitsubishi Chemical Industries, Ltd.). The column was developed with a mixture of water-tetrahydrofuran (93:7 by volume). The eluate was further subjected to reversed phase high performance liquid chromatography (column packing: Develosil, trade name of Nomura Chemical Co., Ltd.) and developed with a mixture of water-acetonitrile (89:11 by volume) to obtain the titled compound. Melting point: 160°-170° C. (decomposition).
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C([Mg]Cl)(C)C.[O:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:23]1=2.Cl>C1COCC1.CC(OC)(C)C.O>[O:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6])[CH:30]=[CH:31][C:23]1=2
Reactant: Br[Mg]c1ccc2c(c1)OCCO2
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCCO2
Temperature: -17.5 °C
Reaction time: 17 h

Procedure:
A suspension of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) was placed under a protective atmosphere of Argon and cooled down to −15 to −20° C., isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol) was added keeping the temperature below −10° C. The slurry started to dissolve, temperature was allowed to reach 0° C., a freshly prepared solution of (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature was allowed to reach r.t., the reaction mixture was stirred for 17 h. 1N HCl (300 mL) was cooled on icebath to +10° C., the reaction mixture was poured into the acidic water solution, TBME=tert-butyl methyl ether (300 mL) was added and the mixture was transferred to a separation funnel. The waterphase was backextracted with TBME (200 mL). The ether phases were washed with water, brine and dried (Na2SO4).