Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:16][Si:17]([CH3:43])([CH3:42])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[C:26]2[N:27]=[CH:28][N:29]=[C:30]([C:31]3[CH:32]=[N:33][N:34]([CH:36]([CH2:40][CH3:41])[CH2:37][CH:38]=O)[CH:35]=3)[C:25]=2[CH:24]=[CH:23]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:40]([CH:36]([N:34]1[CH:35]=[C:31]([C:30]2[C:25]3[CH:24]=[CH:23][N:22]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:16])([CH3:42])[CH3:43])[C:26]=3[N:27]=[CH:28][N:29]=2)[CH:32]=[N:33]1)[CH2:37][CH:38]=[CH2:1])[CH3:41]
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: C=CCC(CC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.6 %

Procedure:
To an ice cooled solution of methyl triphenylphosphonium bromide (100 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added 0.5 M potassium bis(trimethylsilyl)amide in toluene (0.8 mL). The mixture was stirred for 1 h at 0° C. ice bath, and was then cooled to −78° C. and treated with 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (80 mg, 0.0002 mol) (from Example 498). The reaction was stirred at −78° C. and gradually was warmed to room temperature overnight. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[1-(1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine 150 mg as a crude product. LC/MS=398 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][N:17]4[C:21]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:22][N:23]=[C:16]34)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[N:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:17]3[CH2:18][CH2:19][CH2:20][N:15]([CH:13]([C:10]4[N:11]=[N:12][N:8]([C:4]5[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=5)[C:30]#[N:31])[N:9]=4)[CH3:14])[C:16]3=[N:23][N:22]=2)=[CH:29][CH:28]=1
Reactant: CN(C)C=O
Reactant: CC(c1nnn(-c2cccc(I)c2)n1)N1CCCn2c(-c3ccncc3)nnc21
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1nnn(-c2cccc(C#N)c2)n1)N1CCCn2c(-c3ccncc3)nnc21

Procedure:
The title compound is prepared from 8-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:24][CH3:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:7][NH:8]2.Cl>C1COCC1.O>[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:24][CH3:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:7][NH:8]2
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cnc1OC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Sodium hydroxide (30 mg) was added to a solution of ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D50) (157 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E25) (110 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.62 (2H, t), 3.06 (2H, t), 3.95 (3H, s), 5.42 (1H, m), 6.99 (1H, dd), 7.26 (1H, d), 7.92 (2H, m), 8.67 (1H, d), 11.07 (1H, s), 12.14 (1H, br s). δF (DMSO-d6, 376 MHz): −118.8. MS (ES): C22H21FN4O5 requires 440; found 441.2 (M+H+).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C@@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH2:8][NH:9][CH3:10]>>[OH:3][CH2:2][C:1]([N:9]([CH3:10])[CH2:8][C@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH3:6])=[O:5]
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: O=C(O)CO
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN(C)C(=O)CO)c34)cc2C)cn1
Yield: 86 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[(1R)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine to give the title compound in 86% yield; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 3.59 (dd, 1H), 4.16-4.07 (m, 3H), 5.08 (m, 1H), 6.92 (d, 1H), 7.02 (d, 1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.50 (m, 2H), 7.65 (m, 2H), 8.28 (s, 1H), 8.61 (s, 1H), 9.87 (s 1H); Mass spectrum: MH+ 488.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[Na+]>[Pd].O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][S:25](=[O:26])([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[O:27])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccc(N)cc2)cc1
Reaction time: 22 h

Procedure:
A solution of p-hexadecylamino-N-(p-nitrophenylsulfonyl)benzamide in 150 ml. of tetrahydrofuran is hydrogenated in the presence of 0.9 g. of 10% palladium on carbon catalyst at approximately 50 lbs. for 22 hours. The mixture is filtered through a bed of diatomaceous earth and the filtrate is evaporated to an incompletely reduced, off-white solid as indicated by thin layer chromatography on silica gel using chloroform:ethyl acetate:acetic acid 95:4:1 as solvent. The product is hydrogenated again in 80 ml. of dimethylformamide plus 1.0 g. of 10% palladium on carbon catalyst for 18 hours at 50 lbs. pressure. The mixture is filtered through a bed of diatomaceous earth and the filtrate is diluted with 500 ml. of eater to give a suspension which is coagulated by the addition of 50 g. of sodium chloride. The mixture is filtered, the product is washed thoroughly with water and dried in a dessicator to give 8.35 g. of product which is a single spot of TLC. The product is crystallized twice from ethyl acetate and dried in an Abderhalden pistol at 65° C. to provide 6.45 g. of pale tan crystals, melting point 193°-196° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.F[C:10]1[CH:11]=[CH:12][C:13]([CH3:33])=[C:14]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[CH2:19]2)=[O:17])[CH:15]=1>CCCCCC>[CH3:33][C:13]1[CH:12]=[CH:11][C:10]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)=[CH:15][C:14]=1[C:16]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]2[N:29]=[CH:30][CH:31]=[CH:32][C:20]=2[CH2:19]1)=[O:17]
Reactant: Cc1cc[nH]n1
Reactant: Cc1ccc(F)cc1C(=O)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C)c(C(=O)N3Cc4cccnc4Nc4ccccc43)c2)n1
Yield: 71.7 %

Procedure:
Sodium hydride (60% suspension in oil, 0.25 g, 6.25 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (10 mL). Neat 3-methylpyrazole (0.28 mL, 3.5 mmol) was added in one portion at ambient temperature. Stirring was continued until the gas evolution subsided. The (5-fluoro-2-(methyl)-phenyl)-(6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step B (0.75 g, 1.94 mmol) was added in one portion to the clear solution. The mixture was heated to reflux for 26 hours, cooled and partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with hexane-ethyl acetate (gradient from 8:2 to 7:3) provided the title product (0.55 g) as a pale yellow foam which was crystallized by sonication from hexane-ethanol, m.p. 209-210° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Cl[CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.O>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]2)[CH:12]=1
Reactant: CC1(C)OCC(CCl)O1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCC(Cn2cc(Br)cn2)O1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
Cs2CO3 (5.3 g, 16.3 mmol) was added to a solution of 4-bromo-1H-pyrazole (2 g, 13.6 mmol) in DMF (10 mL), followed by 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (2.46 g, 16.3 mmol) and the resulting mixture heated to an internal temperature of 65° C. After stirring for 14 h, water and EtOAc was added and the layers separated. The organic layer was washed a second time with water, dried with over anhydorus magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was absorbed on silica gel and purified by column chromatography on silica (0 to 100% EtOAc/Hex) to afford 4-bromo-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazole as a light yellow oil, MS ESI calcd. for C9H14BrN2O2 [M+H]+ 261. found 261.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2C=C(S([O-])(=O)=O)C=C[C:29]=2C)=[CH:24][CH:23]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([C:3]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)([CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: COc1ccc(-c2cc(S(=O)(=O)[O-])ccc2C)cc1
Reactant: N#CC(Cc1cccnc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(CCC(C#N)(Cc2cccnc2)c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
1-Cyano-1-(4-chlorophenyl)-2-(3-pyridyl)ethane (4.0 gms, 0.0165 m) was placed in a 100 ml three neck flask, under a nitrogen atmosphere, equipped with a magnetic stirrer, thermometer, gas inlet tube and a cooling bath. To the flask was added 50 ml DMF-toluene (1:2), and the resulting solution was cooled to 5° C. Sodium hydride (0.4 gm, 0.018m of 60% NaH) was added and the mixture was stirred for 30 minutes. Then 4-methoxyphenyl-p-toluene-sulfonate (5.0 gm, 0.0165 m) was added and the mixture was stirred for 1 hour at 5° C., followed by stirring at room temperature for another 2 hours. The reaction mixture was quenched with water (10 ml), then placed in a separatory funnel using methylene chloride (200 ml) as a rinse. The organic layer of methylene chloride was washed with water (5×100 ml) and brine (100 ml), then dried. Solvent removal followed by column chromatographic purification afforded 3.6 gms of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16](OC)=[O:17])[C:12]1[N:8]([CH:9]=[C:10]([C:20]3[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][N:21]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH2:16][OH:17])[C:12]1[N:8]([CH:9]=[C:10]([C:20]3[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:22][N:21]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: COC(=O)c1cc2c(cc1C)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1CO)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of methyl 12-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-13-carboxylate (100 mg, 0.272 mmol) in THF (10 mL) was added LiAlH4 (52 mg, 1.37 mmol). The mixture was heated to reflux for 2 h. After cooling to room temperature, the reaction was quenched with a piece of ice cube. The solid was filtered, washed with EtOAc (3×5 mL). The combined filtrate was concentrated to give {12-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca 1(14),2,4,10,12-pentaen-13-yl}methanol (92 mg, 100% yield), which was directly used in the next step without further purification. LCMS (ESI) m/z: 340.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH2:20][CH2:21][C:22](O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:9]=[C:22]([CH2:21][CH2:20][C:19]#[C:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: O=C(O)CCC#Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: Fc1ccc(-c2noc(CCC#Cc3ccccn3)n2)cc1
Temperature: 100 °C
Yield: 25.1 %

Procedure:
A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5 mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=[C:33]=[N:34][CH2:35][CH3:36].O.ON1C2C=CC=CC=2N=N1.N1CC1>CN(C)C=O.C(Cl)(Cl)Cl.O>[N:34]1([C:23]([C:20]2[CH:21]=[CH:22][N:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[CH:19]=2)=[O:24])[CH2:33][CH2:36][CH2:35]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1
Agent: C1CN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
A suspension of 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylic acid (0.1 g) synthesized in Example 2, 1-{3-(dimethylamino)propyl}-3-ethylcarbodiimide hydrochloride (0.085 g), 1-hydroxybenzotriazole hydrate (0.067 g) and aziridine (0.034 g) in N,N-dimethylformamide (0.1 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extraction was conducted with chloroform. The organic layer was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (NH form silica gel; eluent: n-hexane/ethyl acetate=88/12-0/100) to give the titled compound as a colorless solid (0.056 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CN)cc1
Reactant: Brc1cncnc1
Product: COc1ccc(CNc2cncnc2)cc1
Yield: 85 %

Procedure:
Using the general procedure, 5-bromopyrimidine (159 mg, 1.0 mmol) was coupled with 4-methoxybenzylamine (196 μL, 1.5 mmol) at 90° C. for 22 h. Purification of the crude product by column chromatography on silica gel using dichloromethane (saturated with ammonia)/ethyl acetate (1:1) as eluent afforded the desired product as a white solid (183 mg, 85% yield). Rf=0.2 (dichloromethane (saturated with ammonia)/ethyl acetate=1:1).
Reaction SMILES: [C:1]([C:4](C(O)=O)([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7])([OH:3])=[O:2].Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[C:1]([CH:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7])([OH:3])=[O:2]
Reactant: O=C(O)CC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)O
Agent: [Cu]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccc2ncccc2c1
Product: O=C(O)CC(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 145 °C

Procedure:
3,3-Dicarboxy-4-(indol-3-yl)butanoic acid (10.0 g) was dissolved in freshly distilled quinoline (50 ml) under dry nitrogen and copper powder (1.0 g, 40-80 mesh) was added. The reaction mixture was treated with ultrasound for 0.5 hours and heated to 125° C. for 0.75 hours and 145° C. for 1 hour. The reaction was cooled and poured onto ice, acidified with 5N hydrochloric acid and saturated with sodium sulphate. The mixture was extracted with ethyl acetate (4×100 ml). The combined organic extract was extracted with 5% sodium bicarbonate solution and the combined aqueous extract was poured onto ice, acidified with 5N hydrochloric acid, saturated with sodium sulphate and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and evaporated. The resulting oil was taken up into 1,2 dichloroethane and heated and scratched to induce crystallisation. Filtration gave the title compound as white crystals, mp 144°-145° C.; found: C, 62.93; H, 5.48; N 5.62; C13H13NO4 requires C, 63.15; H, 5.30; N, 5.67%
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)N1CCN(c2ccccc2)CC1
Yield: 51 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 1-phenylpiperazine to give Compound 21 (0.21 g, 51%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([CH3:33])[S:31][CH:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([CH3:33])[S:31][CH:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2csc(C)n2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4csc(C)n4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-methylthiazol-4-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(2-methylthiazol-4-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a off white solid (0.039 g, 10% yield). MS: m/z 528.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][CH:19]([CH2:24][CH3:25])[C:20](OC)=[O:21])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][OH:21])=[CH:16][CH:15]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCC(Cc1ccc(OCCc2ccc(S(C)(=O)=O)cc2)cc1)C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CCC(CO)Cc1ccc(OCCc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: -78 °C
Yield: 64.9 %

Procedure:
Methyl 2-(4-{2-[4-(methylsulfonyl)phenyl]ethoxy}benzyl)butanoate (0:40 g; 1.02 mmole) was dissolved in dry methylene chloride (10 ml) and cooled to −78° C. 1 M DIBAH (3.00 ml; 3.00 mmole) was slowly added and the reaction was stirred over night and allowed to reach r.t. The reaction was cooled to −10° C. and quenched with hydrochloric acid (2 M, 5 ml) and extracted with methylene chloride. The organic phase was dried with magnesium sulfate. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 nmm) using acetronitrile (50%) in ammonium acetate buffer (pH 7) as mobil phase gave 0.24 g (63% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH2:12].[Cl:14][C:15]1[S:19][C:18]([CH2:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:21](=[O:22])[CH2:20][C:18]1[S:19][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Reactant: O=C(Cl)Cc1ccc(Cl)s1
Product: COC(=O)c1cc(I)c(Cl)cc1NC(=O)Cc1ccc(Cl)s1
Yield: 74.1 %

Procedure:
Prepared essentially as described in EXAMPLE 1, Step A from 5.0 g 2-amino-4-chloro-5-iodobenzoic acid methyl ester and 2.8 g (5-chlorothiophen-2-yl)acetyl chloride (also prepared essentially as described in EXAMPLE 1) to give the title compound (5.0 g).
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[S:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:11])=CC=1)([O-])=O>C(O)(=O)C.[Zn]>[CH2:33]([S:32][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:17]2[C:12]=1[C:10]([OH:11])=[O:9])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCc3ccccc3)CS[C@H]12
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3ccccc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
425 mg of activated zinc powder are added to a solution of 425 mg (0.72 mmol) of 3-benzylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 40 ml of glacial acetic acid and the mixture is stirred vigorously for 2 hours at room temperature and under nitrogen. The solvent is removed in vacuo and the residue is stirred with ethyl acetate and filtered. The solution is extracted with aqueous sodium bicarbonate solution and water. The combined aqueous phases are washed with ethyl acetate, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel with toluene containing 10% of acetone and gives 3-benzylthio-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid; [α]D20° =+19±1° (c=0.8; chloroform); IR spectrum (methylene chloride): characteristic bands at 5.61 and 5.90μ.