Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34][O:35]C(=O)C)=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:39])[CH3:40])=[CH:4][CH:3]=1
Reactant: CC(=O)OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CN(CCC=C2c3cc(OCCO)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of 75.8 mg (0.1314 mmol) Acetic acid 2-(5-{3-[4-(4-chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-ethyl ester (example 10) in ethanol (5 ml) was added a 15% sodium hydroxide in water (2 ml) solution. The reaction was heated to reflux for 30 minutes, at which time the LC/MS showed it to be complete. After cooling to room temperature the reaction was worked up by diluting with ethyl acetate and washing with water and brine. The combined aqueous layers were back extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and the solvent was distilled under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound (42 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(N)=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]([CH3:24])[C:22]=2[CH3:23])=[O:17])=[C:11]([F:32])[CH:10]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:53]>CCOC(C)=O.O>[NH2:53][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A suspension of 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluorophenoxy)picolinamide (379 mg, 0.764 mmol) in EtOAc (4.5 mL), CH3CN (4.5 mL) and H2O (2.5 mL) was cooled and stirred at 0° C. for 30 minutes, then PhI(OAc)2 (295 mg, 0.917 mmol) was added and the mixture was stirred for another 30 minutes at 0° C., then allowed to warmed up to rt and stirred for another 10 hours. Filtered and the filter cake was washed with EtOAc (5 mL). The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (CH2Cl2/MeOH (v/v)=50/1) to give the title compound as a yellow solid (150 mg, 47.0%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3]([C:9](=[N:12][OH:13])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NO
Reactant: N#Cc1nc(Br)cnc1N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=NO)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of 3-amino-6-bromo-pyrazine-2-carbonitrile (1 g, 5.025 mmol) in MeOH (20 mL) was cooled to 0° C. and treated with hydroxylamine hydrochloride (349.2 mg, 5.025 mmol) and triethylamine (508.5 mg, 700.4 μL, 5.025 mmol) and the reaction allowed to warm to ambient temperature. After a period of 2 hours a precipitate was observed which was filtered off. The resultant filtrate was evaporated to dryness and triturated with MeOH to furnish further product as a beige solid (771 mg, 78% Yield).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[N:19][C:18]=1[NH2:25]>N1C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:7]([C:4]3[CH:3]=[CH:2][C:1]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:6][CH:5]=3)=[O:8])[C:20]([NH:24][C:7]([C:4]3[CH:3]=[CH:2][C:1]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:6][CH:5]=3)=[O:8])=[N:19][C:18]=2[NH:25][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:2][CH:3]=2)=[O:8])=[O:8])=[CH:3][CH:2]=1
Reactant: Nc1nc(N)c(N)nc1N
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Product: O=C(Nc1nc(NC(=O)c2ccc(-c3ccccc3)cc2)c(NC(=O)c2ccc(-c3ccccc3)cc2)nc1NC(=O)c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
In the same way, reaction of 4-biphenylcarbonyl chloride with tetraaminopyrazine in excess pyridine will give tetrakis(4-biphenylcarboxamido)pyrazine. Heating this compound at or near its Tp will give 2,6-bis(4-biphenylyl)-1H,5H-diimidazo[4,5-b:4',5'-e]pyrazine.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:11][CH2:10][CH2:9][CH2:8][N:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[N:17][CH:18]=1
Reactant: Fc1ccc(Br)cn1
Reactant: OCCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(OCCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Sodium hydride (0.591 g, 14.77 mmol) was added portionwise to a solution, of 3-(pyrrolidin-1-yl)propan-1-ol (1.615 g, 12.50 mmol) in THF (20 mL) at to 0° C. then stirred at ambient temperature for 30 minutes, 5-Bromo-2-fluoropyridine (2 g, 11.36 mmol) was added and the resulting mixture stirred at ambient temperature for 2 h before being quenched by the addition of a sat. aqueous solution of ammonium chloride. The moisture was extracted with EtOAc (2×100 mL), the organic layer dried, over Na2SO4, filtered and evaporated to afford pale yellow solid. The crude product was purified by FCC, elution gradient 0 to 10% MeOH in DCM, to afford the desired material (2.70 g, 83%) as a yellow solid. Mass Spectrum: m/z (ES+)[M+H]+=285.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](Br)[CH:6]=1.[CH2:16]([N:18](CC)[CH2:19]C)C.CNC>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N:18]([CH3:19])[CH3:16])[CH:6]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(Br)c1
Agent: CNC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(N(C)C)c1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
The (3-bromo-4-nitrophenyl)acetic acid methyl ester (0.320 g) obtained in Example 4 b) was dissolved in tetrahydrofuran (10 mL). To this solution were added triethylamine (0.237 g) and dimethylamine (2M tetrahydrofuran; 0.58 mL), and stirred overnight while heating. The reaction mixture was concentrated and purified by column chromatography on silica gel with ethyl acetate:hexane=1:4 to give the title compound (0.145 g) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2[NH:15][C:16]2[S:26][C:19]3[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][C:18]=3[C:17]=2[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2[NH:15][C:16]2[S:26][C:19]3[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][C:18]=3[C:17]=2[C:27]([OH:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CCN1CCc2c(sc(Nc3c(Nc4ccc(Cl)cc4)c(=O)c3=O)c2C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN1CCc2c(sc(Nc3c(Nc4ccc(Cl)cc4)c(=O)c3=O)c2C(=O)O)C1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a stirred mixture of compound O3 (293 mg, 0.600 mmol) in methylene chloride (12 mL) and toluene (3 mL) at room temperature under nitrogen was added trifluoroacetic acid (6.91 g, 60.6 mmol) dropwise over 2 min. After addition, the reaction mixture was stirred for another 2 h. The reaction mixture was diluted with toluene (20 mL) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with ammonium hydroxide/methanol/methylene chloride (1:14:85) to afford compound O4 as yellow solid (120 mg, 46%): MS (M−H) 430.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])=[O:5])[CH3:2].[CH2:30](O)[CH2:31][OH:32].O.ClCCl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:9]([C:10]2([CH3:11])[O:32][CH2:31][CH2:30][O:12]2)[C:8](=[O:13])[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1(C(=O)OCC)C(C(C)=O)C(=O)N1Cc1ccc(OC)cc1OC
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)C(C2(C)OCCO2)C(=O)N1Cc1ccc(OC)cc1OC
Yield: 84 %

Procedure:
25.5 g (0.063 moles) of diethyl-3-acetyl-1-(2,4-dimethoxybenzyl)4-oxo-2,2-azetidine-dicarboxylate prepared according to Example (1e), 6.8 ml (0.126 moles, 7.8 g) of ethylene glycol and 15.8 ml (0.126 moles, 17.9 g) of borotrifluoride diethyl etherate in 100 ml of dry dioxane are allowed to stand at room temperature for 3 days, whereupon 150 ml of water and 150 ml of dichloromethane are added to the reaction mixture. Thereafter the organic phase is separated and shaken with 50 ml of a 5% aqueous sodium hydrogen-carbonate solution and 50 ml of water. The organic phase is separated again, dried with magnesium sulfate, filtered and the filtrate is evaporated. 23.6 g (84% of diethyl-1-(2.4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2,2-azetidine-dicarboxylate are obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][CH2:10]P(OCC)(=O)OCC.[CH3:25][CH:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH:27]=O.O>O1CCCC1.CCOCC>[CH3:25][CH:26]([CH:27]=[CH:10][CH:9]=[C:8]([CH3:7])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(CC=C(C)CCC=C(C)C)OCC
Reactant: CCOC(OCC)C(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)C(C)C=CC=C(C)CCC=C(C)C
Temperature: -27.5 °C
Yield: 66.3 %

Procedure:
To a 500 mL three-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 2.4 g potassium tert-butoxide (0.11 mol) in 60 mL of anhydrous tetrahydrofuran was added. Then 29.2 g of diethyl 3,7-dimethyl-2,6-octadienyl-phosphonate (3B) (0.10 mol) was added dropwise over 30 min under mechanical stirring by use of an external cold bath to maintain the internal temperature of approximately −30 to −25° C., and the reaction mixture was subsequently stirred in the cold for 60 min to ensure the formation of carbanion thoroughly. Then 16 g of 2-methyl-3,3-diethoxy-1-propanal (4B) (0.10 mol)) was added dropwise at −30˜−25° C. over 1 h and the reaction mixture was subsequently stirred for 30 min at this temperature until the reaction completed according to GC. Followed by the addition of 50 mL water and 100 mL ether and stirring for 10 min, after stratification, the organic layer was washed with 5% aqueous sodium chloride (3×25 mL), then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents in vacuo, the residue subsequently was fractional distillated to afford 19.7 g of (5-E and 5-Z)-2,6,10-trimethyl-1,1-diethoxy-3,5,9-undecatriene (2D) of 99-103° C./1 mmHg, as a colorless liquid with GC content of 94.2% (total content of cis and trans) and the yield of 66.3%. There are 2 peaks according to GC and GC-MS. ascertained is the same with that of Example IV
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([C:18](O)=[O:19])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][NH2:29].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([C:18]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:33])=[C:25]([F:24])[CH:26]=2)=[O:19])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: CC(C)c1c(C(=O)O)c2cnc(Cl)cc2n1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (Compound 15, 138 mg, 0.42 mmol) and 3,4-difluorobenzylamine (0.15 ml, 1.26 mmol) in DMF (4.0 ml) was added EDC (121 mg, 0.63 mmol) and DMAP (77 mg, 0.63 mmol). The mixture was stirred at room temperature for 16 h and was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([OH:25])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27][NH:28][CH3:29].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([N:28]([CH3:29])[CH3:27])=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COCCn1c(C)nc2cc(C(=O)O)cc(OCc3ccccc3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1c(C)nc2cc(C(=O)N(C)C)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A mixture of 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylic acid (520 mg, 1.53 mmol, Step 5 of Example 1), dimethylamine hydrochloride (374 mg, 4.58 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (498 mg, 2.60 mmol), 1-hydroxybenzotriazole hydrate (413 mg, 3.06 mmol), and triethylamine (0.64 mL, 4.58 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 day. The mixture was poured onto water, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford the title compound as a white solid (524 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH2:23][CH2:24][N:25]=3)[C:9]([NH:13][C:14]([C:16]3[S:20][C:19]([CH3:21])=[N:18][C:17]=3[CH3:22])=[O:15])=[N:10][C:11]=2[CH:12]=1.ClC[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:21][C:19]1[S:20][C:16]([C:14]([NH:13][C:9]2[N:8]3[CH2:23][CH2:24][N:25]=[C:7]3[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH2:1][C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=4)=[CH:12][C:11]=3[N:10]=2)=[O:15])=[C:17]([CH3:22])[N:18]=1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: COc1ccc2c(c1)N=C(NC(=O)c1sc(C)nc1C)N1CCN=C21
Product: Cc1nc(C)c(C(=O)NC2=Nc3cc(OCc4ccc(S(C)(=O)=O)cc4)ccc3C3=NCCN23)s1

Procedure:
The procedure used for the preparation of Example 24, Step 2 was used to prepare the title compound from N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide (Step 1) and 1-(chloromethyl)-4-(methylsulfonyl)benzene (15 mg, 51%). TLC: Rf 0.93 in 10% MeOH/CH2Cl2, HPLC MS RT=2.27 min, MH+=510.1; 1H NMR (DMSO-d6) δ: 2.80 (3H, s), 2.86 (3H, s), 3.39 (3H, s), 4.30-4.35 (2H, m), 4.50-4.54 (2H, m), 5.56 (2H, s), 7.39 (1H, d), 7.87 (2H, d), 7.95 (1H, s), 8.11 (2H, d), 8.50 (1H, d).
Reaction SMILES: C([O:8][C:9]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:11]([CH3:19])[N:10]=1)C1C=CC=CC=1.O1CCCC1>[C].[Pd].C(O)C>[OH:8][C:9]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:11]([CH3:19])[N:10]=1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)Cc1cn(C)nc1O
Reaction time: 5 h
Yield: 79.4 %

Procedure:
A mixture of methyl 3-benzyloxy-1-methyl-1H-pyrazol-4-ylacetate (12.2 g), 5% palladium-carbon (25.0 g), tetrahydrofuran (100 ml) and ethanol (100 ml) was stirred under hydrogen atmosphere for 5 hrs. Palladium-carbon was filtered off and the filtrate was concentrated to give methyl 3-hydroxy-1-methyl-1H-pyrazol-4-ylacetate (6.33 g, yield 79%) as colorless crystals. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 118–119° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[CH3:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[CH3:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.66 h
Yield: 86.5 %

Procedure:
Diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(3,4-dioxo-2-methyl-1-cyclobutenyl)-3-cephem-4-carboxylate (550 mg) was added to stirred and cooled (ice/H2O bath) trifluoroacetic acid (5 mL) containing anisole (1 mL). The cooling bath was removed, and stirring was continued for 0.66 hr at ambient temperatures. The solution was added to stirred diisopropyl ether to precipitate the trifluoroacetic acid salt of the title compound (353 mg, 70% yield) as a yellow powder.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:18].[OH-].[Na+].CO>C(Cl)Cl>[OH:18][C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccc(OCCF)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Oc1cccc(OCCF)c1
Yield: 76.2 %

Procedure:
In a manner similar to that described by Godfrey et al., (J. Chem. Soc. Perkin I, 1353-1354 (1974), the reaction of 7.0 grams (0.042 mole) of 3-(2-fluoroethoxy)benzaldehyde with 3-chloroperoxybenzoic acid (14.0 grams of 75% technical, 0.061 mole) in 100 ml of dry methylene chloride followed by treatment with an aqueous, 15% sodium hydroxide solution and methanol yielded 5.0 grams of 2-fluoroethyl 3-hydroxyphenyl ether as an oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])#[N:2].[C:16]([Cl:21])(=O)[C:17](Cl)=[O:18].[Cl:22]C1C=CC=CC=1Cl>>[Cl:21][C:16]1[C:17](=[O:18])[N:4]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[CH3:15])[C:8]([O:10][CH3:11])=[O:9])[CH:3]=[C:1]([Cl:22])[N:2]=1
Reactant: Clc1ccccc1Cl
Reactant: COC(=O)c1ccc(C)c(NCC#N)c1
Reactant: O=C(Cl)C(=O)Cl
Product: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(Cl)c2=O)c1
Temperature: 100 °C

Procedure:
To 3-[(cyanomethyl)amino]-4-methyl-benzoic acid, methyl ester (Example 1a, 1.2 g) was added 1,2-dichlorobenzene (20 mL) and oxalyl chloride (3 mL). The reaction was heated at 100° C. for four h before the volatiles were removed under reduced pressure. The residue was purified (SiO2 chromatography eluting with dichloromethane) to afford the subtitle compound (800 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17](OB(O)O)=[CH:16][CH:15]=1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>COCCOC>[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc(OB(O)O)cc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOc1ccc(-c2ccc(F)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Under an argon atmosphere, tetrakistriphenylphosphine palladium (69 mg) was added to 5 ml of 1,2-dimethoxyethane. A mixture resulting from dissolving 5-bromo-2-fluorobenzaldehyde (406 mg) in 5 ml of 1,2-dimethoxyethane was added. A mixture resulting from dissolving 4-ethoxyphenylboric acid (398 mg) in 1.5 ml of 1,2-dimethoxyethane was added. Two milliliter of 2M sodium carbonate solution was added. Stirring was conducted for one hour and ten minutes under reflux. After cooling to room temperature, 20 ml of toluene was added and was washed with 10 ml of water twice, 10 ml of a 2N sodium hydroxide solution twice and 10 ml of water twice. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was purified by silica gel chromatography (hexane/ethyl acetate=4/1). The resulting effective fractions were concentrated to yield 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde (369 mg, Yield 76%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:39][CH:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:41](Cl)=[O:42]>C1C=CC=CC=1>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([O:26][CH2:27][CH2:28][O:29][C:41](=[O:42])[CH:40]([CH3:39])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:24][CH2:25]3)[C:5]=2[CH:4]=1
Reactant: CCCCCC(C)C(=O)Cl
Reactant: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCC(C)C(=O)OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
13.55 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine (prepared by Example XLIII), 5.4 ml of triethylamine and 100 ml of anhydrous benzene were added to a flask and a solution of 5.7 g of 2-methyl-heptanoic acid chloride in 50 ml of anhydrous benzene was added thereto. The mixture was agitated at room temperature for 24 hours and then the precipitate formed was removed by filtration. The benzene filtrate was washed with an aqueous solution of sodium bicarbonate, then with water. After drying and concentration of the benzene solution, the resulting oil was purified by chromatography on silica gel. After elution with ethanol and evaporation of the solvent, 5.2 g of 2-trifluoromethyl-10-[3-(4-β-{2-methylheptanoyloxy}ethoxypiperidino)-propyl]-phenothiazine as a clear oil were obtained.