Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:5][CH:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[CH3:17][CH2:18]N(CC)CC.O=S(Cl)Cl>C(O)C>[CH2:17]([O:15][C:14]([C:2]1([NH2:1])[CH2:5][CH:4]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:3]1)=[O:16])[CH3:18]
Reactant: NC1(C(=O)O)CC(OCc2ccccc2)C1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(N)CC(OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a reactor charged with 1-amino-3-benzyloxy-cyclobutanecarboxylic acid (202.7 g, 0.94 mol) was added ethanol (7.0 l); the mixture was stirred at ambient temperature with mechanical stirring under an N2-atmosphere for 18 minutes. To the reaction mixture was added Et3N (350 ml, 2.51 mol), cooled to −1.8° C. and SOCl2 (170 ml, 2.4 mol) was added carefully keeping the reaction temperature <10° C. The reaction mixture was refluxed for 20 hours 10 minutes (reaction progress followed by TLC monitoring). Upon complete reaction the reaction mixture was cooled to 20° C. and evaporated in vacuo at 35° C. The weight of crude product including salts was 631.2 g.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:19][C:20]1[CH:21]=[C:22]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:23]([NH:26][C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][C:34]#[N:35])[N:31]=2)=[N:24][CH:25]=1.[Si]([N:47]=[N+:48]=[N-:49])(C)(C)C>C(Cl)Cl>[NH:47]1[C:34]([CH2:33][CH2:32][C:30]2[N:31]=[C:27]([NH:26][C:23]3[C:22]([O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:21][C:20]([Br:19])=[CH:25][N:24]=3)[S:28][CH:29]=2)=[N:35][N:49]=[N:48]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: Brc1cnc(Nc2nc(CCc3nnn[nH]3)cs2)c(Oc2ccccc2)c1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
To a nitrogen purged vial was added TBAF (0.249 mL, 0.249 mmol), 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanenitrile (0.200 g, 0.498 mmol) (Example 320), and TMSN3 (0.0992 mL, 0.748 mmol) were added, and the reaction was stirred at 120° C. for 24 Hr. The crude reaction mixture was dissolved in CH2Cl2 and washed with aqueous sodium bicarbonate solution. The organic layer was concentrated to a residue that was purified on silica gel by eluting with 7% MeOH/CH2Cl2 and further purified by triturating in refluxing EtOAc to give the title compound (0.128 g, 57.8% yield). 1H NMR (d6 DMSO) δ 3.03 (t, J=7.5 Hz, 2H), 3.25 (t, J=7.6 Hz, 2H), 6.70 (s, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.22 (t, J=7.3 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.2 Hz, 1H), 11.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23](=[N:29]O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[CH2:12][C:13]1[O:15][N:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2cc(C(F)(F)F)ccc2F)n1
Yield: 19.3 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2-fluoro-5-(trifluoromethyl)phenyl)acetic acid (0.420 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.116 g (20%) of ethyl 5-(2-fluoro-5-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][CH2:18][N:19](CC)CC.ClCC#N>C1COCC1>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][C:18]#[N:19])[CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCN1CCN(c2ncnc3ccccc23)CC1
Reaction time: 16 h
Yield: 73.5 %

Procedure:
To a solution of 4-(piperazin-1-yl)quinazoline (1.8 g, 8.3 mmol) in THF (50 mL) was added NEt3 (20 mL, 150 mmol) and chloroacetonitrile (12 mL, 190 mmol) and the reaction was stirred 16 h. The reaction mixture was quenched with 50% saturated aqueous NaHCO3 and extracted with EtOAc (3×200 mL). The combined organics were purified by silica gel chromatography (50% EtOAc/hexanes to 80% EtOAc/hexanes) to yield 55 (1.6 g, 6.1 mmol, 73%) as an viscous yellow oil. 1H NMR: (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.82-7.55 (m, 1H), 7.54-7.50 (m, 1H), 3.94-3.88 (m, 4H), 3.63 (s, 2H), 2.86-2.81 (m, 4H); LC/MS: (ES+) m/z (M+H)+=254; HPLC Rt=0.71 min., column O.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH:26]=[O:27])[C:18]=1[F:28])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH2:14]([O:16][C:17]1[C:18]([F:28])=[C:19]([CH:26]=[O:27])[C:20]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=2)=[CH:21][CH:22]=1)[CH3:15]
Reactant: CCCc1ccc(Br)c(C=O)c1F
Reactant: CCOc1ccc(B(O)O)c(C=O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCc1ccc(-c2ccc(OCC)c(F)c2C=O)c(C=O)c1F
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, a mixture of compound (51) (4.9 g, 19.99 mmol), compound (55) (4.9 g, 23.12 mmol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.199 mmol), sodium carbonate (4.9 g, 46.23 mmol) and TBAB (0.96 g, 2.978 mmol) was refluxed in a toluene (30 mL)-ethanol (20 mL)-water (50 mL) solvent for 5 hours. The reaction mixture was extracted with 30 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-ethoxy-3,3′-difluoro-4′-propyl-[1,1′-biphenyl]-2,2′-dicarboaldehyde (56) (5.35 g, yield 80.5%) was obtained.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)(C)C.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([CH:45]([NH:51][C@H:52](C(O)=O)[CH2:53][CH:54]([CH3:56])[CH3:55])[C:46]([N:48]([CH3:50])[CH3:49])=[O:47])=[CH:44][C:39]=2[CH:38]=[CH:37]1>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([CH:45]([N:51]3[C@H:52]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:6](=[O:7])[NH:8][C@H:9]([CH:13]4[CH2:14][C:15]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:21]4)[C:10]3=[O:12])[C:46]([N:48]([CH3:49])[CH3:50])=[O:47])=[CH:44][C:39]=2[CH:38]=[CH:37]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1Cc2ccccc2C1
Reactant: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc2occc2c1)C(=O)O
Agent: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)N(C)C)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (419 mg) in dry tetrahydrofuran (5 ml) at −20° C. under a nitrogen atmosphere was added N-methylmorpholine (158 μl) and a solution of isopropylchloroformate in toluene (1.0M, 1.44 ml). After 10 minutes, a solution of N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478 mg) in dimethylformamide (5 ml) was added and the reaction was allowed to warm to room temperature. After 20 hours, the solvent was removed in vacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4 ml). After 4 hours methanol (13 ml) was added and the reaction was left to stand for a further 18 hours. The solvent was then removed in vacuo and the residue was separated between dichloromethane and saturated sodium bicarbonate solution. The organic phase was evaporated in vacuo and the residue was applied to an SPE (10 g, silica). The product was eluted using an ethyl acetate:methanol gradient (3:1 to 1:3) to afford (2R)-2-(benzofuran-5-yl-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (51 mg).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[I-].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Zn+]>O1CCCC1>[CH3:4][O:3][C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH2:9][CH2:10]1)=[O:2]
Reactant: Fc1ccccc1[Zn+]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: [I-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
In an oven dried 1 neck round bottom flask with reflux condenser and stirbar, trans-4-carbomethoxycyclohexane-1-carboxylic acid (840 mg; 4.5 mmol) was heated to reflux in the presence of 15 mL thionyl chloride. After 3 hours reflux, mixture cooled to 40° C. under nitrogen flow, and excess thionyl chloride was removed at reduced pressure. Residue was taken up in 5 mL of dry tetrahydrofuran and added to a 0° C. mixture of 2-fluorophenylzinc iodide (9.0 mL; 4.5 mmol), tetrakis(triphenylphospine)palladium (0) (272 mg; 0.2 mmol) in 10 mL anhydrous tetrahydrofuran. Mixture was allowed to warm to room temperature over 16 hours. Reaction was quenched with 6 mL 1N HCl and ethyl acetate was taken in. Organics separated and aqueous re-extracted with 20 mL ethyl acetate. Combined organics were washed with sat. NaHCO3, water, brine and dried over MgSO4. Material was purified via flash silica plug (10:1) using 15% ethyl acetate in hexanes isocratic to give 800 mg of title compound. (67% yield)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][CH:3]=1.[ClH:15].[N:16](OCCC(C)C)=[O:17]>O1CCCC1>[ClH:15].[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[N:16]=[O:17]
Reactant: CC(C)CCON=O
Reactant: COc1ccc(-n2nccc2N)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-n2ncc(N=O)c2N)cc1

Procedure:
17.4 g (92 mmol) of 5-amino-1-(4-methoxyphenyl)pyrazole [sic] from Step 1.1 was dissolved in 200 mL of tetrahydrofuran, 52.4 g of 32% hydrochloric acid was added, and the mixture was cooled to 0–5° C. Then 11.8 g (101 mmol) of isopentyl nitrite was added dropwise with agitation so that the temperature did not exceed 5° C. Gradually, a brownish precipitate formed which after an additional 2-hour agitation period in an ice bath was removed by suction filtration and washed with a small amount of tetrahydrofuran. Drying gave 16.4 g (64 mmol, 70% of the theoretical) of 5-amino-1-(4-methoxyphenyl)-4-nitrosopyrazole hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:22]([OH:25])[C:23]#[CH:24]>O1CCCC1.CCOCC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:24]#[C:23][CH2:22][OH:25])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: C#CCO
Reactant: Brc1ccc(C2CC2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC#Cc1ccc(C2CC2)cc1
Temperature: 50 °C

Procedure:
To a degassed solution of 1-bromo-4-cyclopropylbenzene (4.4 g, 22.3 mmol; prepared according to J. Org. Chem. 1976, 41, 2262) in anhydrous tetrahydrofuran (22 mL), copper(I) iodide (134 mg, 0.70 mol) and tetrakis(triphenylphosphine)palladium (773 mg, 0.67 mmol) were added and the mixture was cooled down with ice bath. 1,8-Diazabicyclo[5.4.0]-undec-7-ene (4 mL, 26.8 mmol) was added and the reaction mixture was degassed again. A degassed solution of prop-2-yn-1-ol (1.56 mL, 26.8 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise afterwards and the reaction mixture was stirred at 50° C. over night under nitrogen. After cooling, the mixture was diluted with ether (100 mL) and washed with water (40 mL) and 15% hydrochloric acid (2×40 mL). The aqueous layer was extracted with ether (5×40 mL). Combined organic extracts were finally washed with 10% aqueous solution of sodium hydrogen carbonate (40 mL) and brine (2×40 mL) and dried with anhydrous magnesium sulfate. The crude product was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1-8:1) yielding 3-(4-cyclopropylphenyl)prop-2-yn-1-ol as yellow oil, which solidified in refrigerator.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38](C(OC(C)(C)C)=O)[CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:39]3[NH:38][N:37]=[CH:36][CH:35]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1cccnc1)c1cc(-c2ccn[nH]2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 60; 120 mg, 0.29 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (93 mg, 0.32 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.57 ml, 0.57 mmol) and tetrakis(triphenylphosphine)palladium(0) (19.85 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 65 mg.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]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.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CC(O)(C)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[S:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=2)[CH2:16][CH2:15]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
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: BrCCOc1ccccc1-c1nc2ccccc2s1
Solvent: CC(C)(C)O
Product: c1ccc(C(c2ccccc2)N2CCN(CCOc3ccccc3-c3nc4ccccc4s3)CC2)cc1
Yield: 40.6 %

Procedure:
1-Benzhydryl-piperazine (2.26 g, 8.98 mmol) and 2-[2-(2-bromoethoxy)phenyl]-benzothiazole (0.75 g, 2.24 mmol) were stirred in t-BuOH (20 mL) at about 50° C. under N2 (g) for 24 hours. The mixture was concentrated in vacuo and flash chromatographed on silica (15% acetone/hexanes) to afford 460 mg (41%) of the free base of the product. mp 67-72° C.; LSIMS m/z 506 (MH+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([NH:25][C:26]([NH2:28])=[NH:27])[NH:24][C:20]=2[CH:19]=1.[OH-].[Na+]>CO.O>[CH3:17][C:18]1[CH:30]=[CH:29][C:21]2[N:22]=[C:23]([N:25]=[C:26]3[NH:28][C:7]4([C:5]5[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=5)[NH:28][C:26](=[N:25][C:23]5[NH:24][C:20]6[CH:19]=[C:18]([CH3:17])[CH:30]=[CH:29][C:21]=6[N:22]=5)[NH:27][C:9]4([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=4)[NH:27]3)[NH:24][C:20]=2[CH:19]=1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Reactant: Cc1ccc2nc(NC(=N)N)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(N=C3NC4(c5ccccn5)NC(=Nc5nc6ccc(C)cc6[nH]5)NC4(c4ccccn4)N3)[nH]c2c1

Procedure:
Following the procedure of Example 1, 2,2'-pyridil (603 mg, 2.84 mmol) and 5-methyl-2-guanidinobenzimidazole (489 mg, 2.58 mmol) in methanol (17 mL) was treated with a solution of sodium hydroxide (113.6 mg, 2.84 mmol) in 2.8 mL of water. The title compound was isolated as a grey powder (450 mg, 63% yield). mp: 290-291 ° C. (dec); 1H NMR (300 MHz, d6 -DMSO) δ 11.3 br s, NH, 2 H), 10.0 (br s, NH, 2 H), 8.5 (br s, NH, 2 H), 8.32 (d, J=4.2 Hz, 2 H), 7.54 (t, J=7.6 Hz, 2 H), 7.31 (d, J=7.6 Hz, 2 H), 7.16 (d, J=7.8 Hz, 2 H), 7.16-7.09 (m, 2 H), 7.09 (s, 2 H), 7.14 br s, 2 H), 6.86 (d, J=7.8, Hz, 2 H), 2.34 (s, 6 H); MS (ESI) m/z 555 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][CH3:29]>>[CH3:29][N:28]([CH2:27][C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH3:23])[CH:25]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: CNCc1cccc(C)c1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: Cc1cccc(CN(C)CCn2cnc(-c3cc(C(=O)O)ccn3)c2)c1
Yield: 57 %

Procedure:
The title compound was prepared in 57% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 3-methyl-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.20 (3H, s), 2.29 (3H, s), 2.68 (2H, t, J=6 Hz), 3.85 (2H, s), 4.02 (1H, t, J=5.9 Hz), 4.15 (1H, t, J=6.0 Hz), 6.96 (1H, m), 7.11 (2H, t, J=9.0 Hz), 7.18-7.27 (2H, m), 7.51 (1H, d, J=3.6 Hz), 7.74 (1H, s), 8.28 (1H, s), 8.47 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H22N4O2, 351. Found, 351.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38]CC3C=CC([N+]([O-])=O)=CC=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].Cl.[O:52]=[C:53]1[NH:58][CH2:57][CH2:56][N:55]([C:59](=[NH:62])[CH2:60][SH:61])[CH2:54]1>C(#N)C.CS(C)=O.O1CCCC1.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[O:52]=[C:53]1[NH:58][CH2:57][CH2:56][N:55]([C:59](=[NH:62])[CH2:60][S:61][C:32]2[C@H:33]([CH3:34])[C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]3[C:31]=2[C:36]([OH:38])=[O:37])[CH2:54]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: N=C(CS)N1CCNC(=O)C1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCNC(=O)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
0.28 ml of diisopropylethylamine and 0.29 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 500 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 6 ml of anhydrous acetonitrile, after which the mixture was stirred for one hour with ice-cooling. 0.20 ml of diisopropylethylamine and a suspension of 452 mg of 2-(3-oxopiperazin-1-yl)-2-iminoethylmercaptan hydrochloride in 3.6 ml of dimethylsulfoxide were added to the reaction mixture, and the whole mixture was stirred for 30 minutes with ice-cooling. The reaction mixture was poured into 200 ml of anhydrous ether and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 40 ml of tetrahydrofuran and 46 ml of 0.1M phosphate buffer (pH 7.0), and the solution was subjected to hydrogenation for 2 hours at room temperature in the presence of 662 mg of 10% palladium-carbon. The hydrogenated mixture was filtered over "Celite" (Trade Mark) filter aid, and the filtrate was extracted with 80 ml of ether. The aqueous layer was concentrated under reduced pressure, and the concentrate was subjected to chromatography through a 160 ml column of "Dowex 50W" (Trade Mark) cation exchange resin (Na+ type), giving 58 mg of the title product from the fraction eluted with water.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][NH2:21]>CCOC(C)=O>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][NH:21][C:2]1[CH:7]=[C:6]([I:8])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(F)cc1I
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(I)c(C)cn2)c(OC)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 2-fluoro-4-iodo-5-methylpyridine (60 g, 253 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (190.6 mL, 1270 mmol) was allowed to stir at 110° C. overnight. The mixture was allowed to cool to rt and was then diluted with EtOAc (190 mL). The resulting solid was filtered and washed with EtOAc and then purified by column chromatography to give N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine (55.0 g, 57%).