Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:11]1([OH:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14](=[O:17])[C:15]([CH3:16])=[C:10]1[CH3:9])[CH3:8]
Reactant: CC1=C(C)C(=O)C(C)=C(C)C1=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C(C)=C(C)C(=O)C(C)=C1C
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,3,5,6-tetramethyl-1,4-benzoquinone in 4 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After cooling, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.79 g of the desired product (yield 94%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[I-].[Li+].C1CCN2C(=NCCC2)CC1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C.O>[CH2:21]([CH:2]1[C:3](=[O:6])[CH2:4][CH2:5][C:1]1=[O:7])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(=O)C1
Agent: [I-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: O=C1CCC(=O)C1Cc1ccccc1

Procedure:
To a suspension of 1,3-cyclopentanedione (500 mg, 5.10 mmol) and anhydrous lithium iodide (750 mg, 5.61 mmol) in acetonitrile (10 ml) was added DBU. After 30 min benzyl bromide (1.74 g, 10.2 mmol) was added and the reaction heated for 24 h at reflux. The reaction was poured into water (40 ml), extracted with EtOAc (4×50 ml), dried (MgSO4), the solution concentrated in vacuo and the residue purified by chromatography (SiO2; EtOAc) to give the title compound as an off white solid (222 mg, 23%). δ H (CD3OD) 7.20 (4H, d), 7.10 (1H, m), 3.41 (2H, s), 2.52 (4H, s). m/z (ESI, 70V) 189 (MH+).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24]O)[C:7]=1[S:26]([CH3:28])=[O:27].[CH2:29](O)C>>[CH:2]([O:1][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)([CH3:29])[CH3:3]
Reactant: CCO
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CC[O-]
Agent: [Na+]
Product: CC(C)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A suspension of sodium ethoxide (0.34 g) in ethanol was added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in ethanol. 2-lodopropane (1 ml) was then added and the mixture stirred overnight at 20° C. and evaporated. The residue (in dichloromethane) was water-washed, dried (magnesium sulfate), concentrated and purified by chromatography on silica gel to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(isopropyl)oxime (0.35 g), m.p. 128-130° C. Compound 24.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:22]([O-:25])(=[O:24])C.[Na+].[CH3:27]O>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:10][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:7]1[C:2]([C:22]([O:25][CH3:27])=[O:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COC(Cc1cccnc1Br)c1ccccc1
Reactant: CC(=O)[O-]
Reactant: CO
Agent: [Na+]
Product: COC(=O)COC(Cc1cccnc1C(=O)OC)c1ccccc1
Temperature: 23 °C

Procedure:
A stream of CO gas was bubbled through a mixture of methyl 2-(2-(2-bromopyridin-3-yl)-1-phenylethoxy)acetate (6.5 g, 18 mmol), sodium acetate (4.6 g, 55 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.0 g, 3.7 mmol) in anhydrous methanol (650 mL) at 70° C. for 4 h. The reaction mixture was cooled to 23° C. and concentrated. The residue was dissolved ethyl acetate (200 mL) and filtered through Celite®. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in petroleum ether to give the title compound. MS: m/z=330.2 (M+1).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]([CH3:5])[CH3:4].C(Br)CC(C)C.[Mg].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@@H:22]1[C@@:42]2([CH3:43])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[CH:34]([CH:36]=[O:37])[CH3:35])[CH2:25][C@@H:24]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:23]1.[OH-].[Na+]>O1CCCC1>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@@H:22]1[C@@:42]2([CH3:43])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[C@H:34]([CH3:35])[CH:36]([OH:37])[CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:25][C@@H:24]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:23]1
Reactant: CC(C)CC[Mg]Br
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Mg]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CCBr
Solvent: C1CCOC1
Product: CC(C)CCC(O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To 20 ml of a tetrahydrofuran solution of the isoamylmagnesium bromide prepared from 2.27 g of isoamyl bromide and 0.48 g of magnesium was slowly added a solution of 5.12 g of 1α, 3β-bis(tetrahydropyran-2-yloxy)pregna-5,7-diene-20-carbaldehyde in 30 ml of tetrahydrofuran under ice-cooling. After the addition, the mixture was further stirred at 0° C. for 1 hour. To the reaction mixture thus obtained was added 2N aqueous sodium hydroxide solution, followed by extraction with diethyl ether. The extract was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 4.84 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol (yield: 83%) showing the following physical property.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][C:29](=[O:36])[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][C:29]([N:30]2[CH2:35][CH2:34][N:33]([C:4](=[O:6])[C:3]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=3[Br:1])[CH2:32][CH2:31]2)=[O:36])=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
2-Bromo-5-methoxy benzoic acid (121 mg, 0.53 mmol) was added to 4-benzyloxy-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamide (155 mg, 0.44 mmol) in DMF (5 mL). EDCI.HCl (126 mg, 0.66 mmol), HOBT (71 mg, 0.53 mmol) and DIPEA (227 μL, 1.32 mmol) were added and the resulting mixture was stirred at room temperature for 4 hours. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified twice by column chromatography using (i) silica gel of mesh size of 60-120 and 70:30 EtOAc:Hexane as the eluent (1st purification) and (ii) neutral alumina and 65:35 EtOAc:Hexane as the eluent (2nd purification) to afford 4-benzyloxy-N-{2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide in 43% yield. LC-MS purity: 99.6%. 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.5 (m, 6H), 7.2 (s, 1H), 7 (d, 2H), 6.8 (d, 2H), 5.2 (s, 2H), 4.4 (d, 2H), 4 (m, 2H), 3.8 (s, 3H), 3.7 (t, 3H), 3.6 (t, 2H), 3.5 (m, 2H), 3.3 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc(C2CCCCC2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4cyclohexylbenzoic acid (Aldrich; 1 molar eq.) in toluene was added diisobutylaluminum hydride (Aldrich; 1 M in toluene; 4 molar eq.) over a 2 hour period. After addition was complete, the reaction was heated to 60° C. for 1 hour. The reaction was cooled to 5° C. and quenched with saturated aqueous ammonium chloride. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were filtered to remove salts and concentrated.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N:10]1[CH2:11][CH2:12][CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]=12.[OH-].[NH4+]>>[N+:6]([C:21]1[CH:20]=[CH:19][C:18]2[N:14]3[CH2:13][CH2:12][CH2:11][N:10]=[C:15]3[S:16][C:17]=2[CH:22]=1)([O-:9])=[O:7]
Reactant: c1ccc2c(c1)SC1=NCCCN12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)SC1=NCCCN12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 92 parts of concentrated sulfuric acid are added portionwise 18.5 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole nitrate at 0° C. Upon completion, stirring is continued for 1 hour without cooling. The reaction mixture is poured onto 200 parts of ice-water and stirred for a while. The whole is alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 16.3 parts of 3,4-dihydro-8-nitro-2H-pyrimido[2,1-b]benzothiazole; mp. 247.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: C[C@@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(R)-methyl-piperazine (0.2 g, 0.95 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.11 mL, 0.94 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.63 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[O:17][C:18]([CH3:24])=[C:19]([C:21](Cl)=[O:22])[N:20]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:19]1[N:20]=[C:16]([CH3:15])[O:17][C:18]=1[CH3:24])=[O:22]
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c(C)o1
Yield: 66.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0459 g, 0.195 mmol), 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (0.032 g; 0.195 mmol), and triethylamine (0.0683 mL; 0.486 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.0414 g (67%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-2,5-dimethyloxazole-4-carboxamide as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](OCC)=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27].[CH2:28]([NH2:31])[CH2:29][CH3:30].[C-]#N.[Na+]>CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27]
Reactant: CCCN
Reactant: CCOC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCCNC(=O)c1cc(NCc2c(C)cccc2CC)c2nc(C)c(C)n2c1
Yield: 42.4 %

Procedure:
Ethyl 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (0.12 g, 0.33 mmol), propylamine (1.0 g, 17 mmol) and a catalytic amount of sodium cyanide were refluxed in methanol (20 ml) for 24 h. An additional amount of propylamine (1.0 g, 17 mmol) was added and the reaction mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using diethyl ether as eluent. Crystallization from diethyl ether gave 0.053 g (42%) of the title compound. 1H-NMR (300 MHz, CDCl3): δ 1.0 (t, 3H), 1.2 (t, 3H), 1.65-1.75 (m, 2H), 2.3 (s, 3H), 2.35 (s, 3H), 2.38 (s, 3H), 2.7 (q, 2H), 3.4-3.5 (m, 2H), 4.35 (d, 2H), 4.9 (bs, 1H), 6.2 (bs, 1H), 6.35 (s, 1H), 7.0-7.2 (m, 4H), 7.85 (s, 1H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:35])[NH2:34])/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:61][C@@H:62]1[C:80](=[O:81])[N:64]2[C:65]([C:77]([OH:79])=[O:78])=[C:66]([CH2:69][S:70][C:71]3[N:75]([NH2:76])[N:74]=[N:73][N:72]=3)[CH2:67][S:68][C@H:63]12.C(N(CC)CC)C.NC1SC=C(/C(=N/OCCCC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(N)N=NN=4)CS[C@H]23)=O)N=1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:35])[NH2:34])/[C:27]([NH:61][C@@H:62]2[C:80](=[O:81])[N:64]3[C:65]([C:77]([OH:79])=[O:78])=[C:66]([CH2:69][S:70][C:71]4[N:75]([NH2:76])[N:74]=[N:73][N:72]=4)[CH2:67][S:68][C@H:63]23)=[O:29])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(N)n1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 69.3 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-carbamoylmethoxyiminoacetic acid (3.02 g, 6.2 mmol), 1-hydroxybenzotriazole (0.900 g, 6.7 mmol) and N,N'-dicyclohexylcarbodiimide (1.38 g, 6.7 mmol) in dimethylacetamide (17 ml) was stirred at 0°-5° C. for an hour. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.38 g, 7.2 mmol) and triethylamine (1.60 g, 15.8 mmol) in dimethylacetamide (12 ml) and water (2 ml) at the same temperature and allowed to react for 2 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale yellow powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-carbamoylmethoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.43 g, 69.3%), mp~115° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([OH:30])[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]OC)=[CH:36][CH:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: COCc1ccc(F)cc1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Reaction time: 16 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (250 mg; 0.55 mmol), 1-fluoro-4-methoxymethyl-benzene (103.8 mg; 0.82 mmol), tributylphosphine (0.33 mg; 1.65 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.414 g; 1.65 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h and purified by prep. HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 564.1 (M+H); Rt: 1.99 min.
Reaction SMILES: N1C=CC(N)=NC1=O.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:34][CH2:35][C:36]1[N:37]=[C:38]2[CH:43]=[CH:42][N:41](C3C=CC(F)=CC=3)[C:40](=[O:51])[N:39]2[CH:52]=1>>[Cl:34][CH2:35][C:36]1[N:37]=[C:38]2[CH:43]=[CH:42][N:41]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=3)[C:40](=[O:51])[N:39]2[CH:52]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: Nc1cc[nH]c(=O)n1
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Product: O=c1n(-c2cccc(F)c2)ccc2nc(CCl)cn12

Procedure:
2-chloromethyl-6-(3-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from cytosine and 3-fluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+]([O-])=O)=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])(=[O:27])C.[K+]>CS(C)=O.O>[F:21][C:20]([F:23])([F:22])[C:19]([N:9]1[CH2:10][CH:11]2[CH2:18][CH:7]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:14]([OH:27])=[CH:13][C:12]=32)[CH2:8]1)=[O:24]
Reactant: CC(=O)[O-]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c(O)cc12)C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (900 mg, 2.61 mmol) and potassium acetate (KOAc) (2.6 g, 26.1 mmol) were dissolved in DMSO (10 mL) and warmed with stirring to 100° C. for 16 hours. The mixture was cooled and diluted with H2O (50 mL) then extracted with 80% ethyl acetate/hexanes (6×25 mL). The organic layer was washed with H2O (3×20 mL), dried (Na2SO4), filtered and concentrated and purified by chromatography to give an oil (575 mg, 70%). (TLC 50% ethyl acetate/hexanes (NH3) Rf 0.56)
Reaction SMILES: [CH3:1][C:2](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](O)=[O:27].C(N(CC)CC)C.Cl>C(OCC)(=O)C.CCOCC>[CH3:35][O:34][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[C:31]=1[O:32][CH3:33])[C:26]([N:4]([CH2:3][C:2]([CH3:1])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])=[O:27]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(=Cc1ccccc1)CNCCCN1CCCC1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(CCCN2CCCC2C)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 17.1 %

Procedure:
Experimental condition analogous to Example 3 were used with (2-Methyl-3-phenyl-allyl)-[3-(2-methyl-pyrrolidin-1-yl)-propyl]-amine (prepared from 2-methyl-pyrrolidine describe on scheme 10) 0.14 g (0.5 mmol), 3,4,5-trimethoxybenzoic acid 0.130 g (0.65 mmol), triethylamine 0.1 ml, and propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate) solution (50% in ethyl acetate) 0.7 g in 10 ml ethyl acetate. The free amine was transformed to the HCl salt in ether, giving 40 mg of a brown semi-solid. Yield: 15%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25]#N)=[CH:22][N:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.C(O)C.[OH-:41].[Na+].Cl.[OH2:44]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25]([OH:44])=[O:41])=[CH:22][N:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: [OH-]
Reactant: O
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC#N)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 91 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}acetonitrile (0.86 g) and ethanol (30 mL) was added 2N aqueous sodium hydroxide solution (30 mL), and the mixture was heated under reflux for 6 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water; and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}acetic acid as yellow crystals (0.80 g, yield 91%). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 179-180° C.