Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([C@H:15]2[NH:20][C@@H:19]([C:21](OC)=[O:22])[CH2:18][CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[F:14].O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([C@H:15]2[NH:20][C@@H:19]([CH2:21][OH:22])[CH2:18][CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: COC(=O)[C@H]1CCC[C@@H](c2ccc(F)c(F)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1CCC[C@@H](c2ccc(F)c(F)c2)N1
Temperature: -15 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
LAH (90 mg) was added in three portions to a solution of methyl(2R,6S)-6-(3,4-difluorophenyl)piperidine-2-carboxylate (300 mg) in THF (5 mL) at −15° C. over 15 minutes. The reaction solution was stirred at −15° C. for one hour, and water (0.1 mL), a 5 N sodium hydroxide solution (0.1 mL), and water (0.3 mL) were sequentially added to the reaction solution. The mixture was heated to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain 267 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C:10]2=[N:9][N:8]=1.C(N(CC)C(C)C)(C)C.[CH3:25][Si:26]([CH3:41])([CH3:40])[CH2:27][CH2:28][O:29][C:30](ON1C(=O)CCC1=O)=[O:31]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14]([C:30]([O:29][CH2:28][CH2:27][Si:26]([CH3:41])([CH3:40])[CH3:25])=[O:31])[CH2:15][C:10]2=[N:9][N:8]=1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: c1cnc(-c2nnc3n2CCNC3)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 3-(pyrazin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (1.0 g, 5.0 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol) in DMF (15 mL) was added 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (1.5 g, 5.9 mmol). Stirred for 18 h and poured into ice cold brine (150 mL). Precipitate filtered and washed successively with water and ether to afford the desired product as a white solid (1.5 g, 89%). MS (ESI): mass calcd. for C15H22N6O2Si, 346.2; m/z found, 347.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.50 (d, J=1.4 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.52-8.48 (m, 1H), 4.91 (s, 2H), 4.60-4.45 (m, 2H), 4.25-4.14 (m, 2H), 3.87 (t, J=5.3 Hz, 2H), 1.07-0.92 (m, 2H), 0.01-0.04 (m, 9H).
Reaction SMILES: C(COC)OC.Br[C:8]1[CH:9]=[N:10][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[NH:26][C:27]4[C:32]([CH:33]=3)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=4)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[N:12][CH:13]=1.[N:35]1[CH:40]=[CH:39][C:38](OB(O)O)=[CH:37][CH:36]=1.[F-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[Cl:34][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([S:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]3[N:10]=[CH:9][C:8]([C:38]4[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=4)=[CH:13][N:12]=3)=[O:15])[CH2:17][CH2:18]1)(=[O:24])=[O:23])=[CH:33]2
Reactant: O=C(c1ncc(Br)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: OB(O)Oc1ccncc1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: O=C(c1ncc(-c2ccncc2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 40 %

Procedure:
In a mixed solvent of dimethoxyethane (10 ml) and methanol (10 ml), 1-[(5-bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (485 mg) and 4-pyridylboric acid (197 mg) were suspended at room temperature, followed by the successive addition of tetrakis(triphenylphosphine) palladium (0) (116 mg) and cesium fluoride (1.00 g). The resulting mixture was heated under reflux for 1 week. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. Dichloromethane and water were added to the concentrate to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (2% methanol—dichloromethane). The pale yellow crystals precipitated in ethanol were collected by filtration and dissolved in dichloromethane. To the resulting solution, 1N aqueous hydrochloride in ethanol was added and the resulting mixture was distilled under reduced pressure to remove the solvent. The yellow crystals precipitated in ethyl acetate were collected by filtration and dried, whereby the title compound (40%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]2([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]2([CH2:29][CH2:28][C:27]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)([OH:30])[CH2:26][CH2:25]2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCC2(CC1)CCN(Cc1ccccc1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCC2(CCN(Cc3ccccc3)C2)CC1
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 3-bromopyridine (290 μl, 2.96 mmol, 1.20 eq.) in dry THF (9 ml) was added dropwise to a solution of n-BuLi (2.47 ml, 4.94 mmol, 2.0 eq., 2M solution in hexane) in THF (9 ml) at −78° C. and the reaction mixture was stirred at same temperature for 1 h. A solution of 2-benzyl-2-azaspiro[4.5]decan-8-one (600 mg, 2.47 mmol, 1.0 eq.) (see step-6 product AMN-39) in THF (10 ml) was added dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (15 ml) while cooling and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 10% MeOH/MC) to yield the desired compound as a light brown semi-solid. Yield: 44% (350 mg, 1.08 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4]3=[C:5]([C:19](=[O:23])[C:20](=[O:21])[N:3]13)[CH:6]=[CH:7][CH:8]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C=C(c2ccccc2)c2ccccc2N1
Solvent: ClCCl
Product: CC1(C)C=C(c2ccccc2)c2cccc3c2N1C(=O)C3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A solution of 1,2-dihydro-2,2-dimethyl-4-phenylquinoline (5.0 g., 21.2 mMole) in 50 ml. dry methylene chloride was added dropwise with stirring to oxalyl chloride (2.77 g., 22.0 mMole) in 200 ml. dry methylene chloride at 30° C. and protected from moisture. Addition required one hour, and when complete the orange solution was stirred 30 minutes at ambient temperature and two hours at reflux. The solvent was removed at reduced pressure and the purple-brown crystalline residue air dried. A single recrystallization from chloroform/60°-110° C. ligroine produced a solid 3.97 g. (63.5%) melting at 210.5°-212° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][C:35]([C:37]([F:40])([F:39])[F:38])=[N:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11]([C:32]4[S:36][C:35]([C:37]([F:40])([F:39])[F:38])=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1ncc(Br)s1
Reactant: C[C@@H](Oc1nc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2cnc(C(F)(F)F)s2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 16.1 %

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (133.6 mg, 0.324 mmol), 5-bromo-2-(trifluoromethyl)thiazole (90.2 mg, 0.389 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.97 mL, 0.97 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (18.7 mg, 0.016 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH: DCM=5:95) to give off-white solids, 22.8 mg (yield 16.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.74 (m, 1H), 8.38 (d, J=0.5 Hz, 1H), 8.09 (s, 1H), 7.57 (broad s, 1H), 5.43 (p, J=6.0 Hz, 1H), 3.71 (m, 1H), 3.41 (m, 1H), 3.26-3.18 (m, 1H), 2.82-2.87 (m, 1H), 2.35-2.31 (m, 2H), 1.42 (d, J=6.2 Hz, 3H), 1.14 (m, 2H), 1.11-0.98 (m, 2H) ppm; MS (ESI+) m/z 438 (M+H).
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[C:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][C:8]=1[CH3:18]>C1COCC1>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:3]=[O:2])=[C:8]([CH3:18])[O:9][C:10]=2[CH:15]=1
Reactant: COc1ccc2c(C3OCCO3)c(C)oc2c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(C=O)c(C)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2N HCl (5 mL) was added to 3-[1,3]dioxolan-2-yl-6-methoxy-2-methyl-benzofuran in THF (5 mL) at 0° C. After stirring for 1 h at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3×20 mL). The organic layers were combined and dried over anhydrous MgSO4. After the solvent was removed, the residue was purified on a silica gel column eluting with EtOAc/hexane (1:9) to give 6-methoxy-2-methylbenzofuran-3-carbaldehyde (0.090 g, 81%).
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].CC(C)=O.[CH3:11][C:12]1[C:16]([S:17](Cl)(=[O:19])=[O:18])=[C:15]([CH3:21])[O:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:11][C:12]1[C:16]([S:17]([O-:19])=[O:18])=[C:15]([CH3:21])[O:14][N:13]=1.[Na+:5]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1noc(C)c1S(=O)[O-]
Temperature: 80 °C
Yield: 101.1 %

Procedure:
A solution of sodium sulfite (680 mg, 5.40 mmol) in water (5 mL) was added to an acetone (5 mL) solution of 3,5-dimethylisoxazole-4-sulfonyl chloride (530 mg, 2.70 mmol). The mixture was heated to 80° C., then a solution of sodium carbonate (430 mg, 4.05 mmol) in water (5 ml) was added dropwise. The mixture was refluxed for 16 hours then evaporated to dryness. The residue was refluxed with ethanol (20 mL), the inorganics were removed by filtration. Evaporation of the filtrate afforded 500 mg of crude sodium 3,5-dimethylisoxazole-4-sulfinate. It was used in the next steps without further purification. 1H NMR (400 MHz, DMSO-d6): δ 2.37 (s, 3H) and 2.22 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:7]([CH3:26])=[N:6][C:5]=1[CH3:27])(=[O:3])[NH2:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:24][CH2:23][CH2:22][C@H:19]1[CH2:18][CH2:17][C@H:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]([CH3:27])=[N:6][C:7]=3[CH3:26])=[CH:11][CH:12]=2)[CH2:21][CH2:20]1
Reactant: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc2)nc1C(N)=O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CCO)CC3)cc2)nc1C(N)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of Example 1 (50 mg, 0.14 mmol) and NMM (71 μL, 0.64 mmol) in THF (1 mL) at 0° C. was added a solution of ethyl chloroformate (61 μL, 0.64 mmol) in THF (0.5 mL). The reaction was stirred at 0° C. for ˜3 h, but additional equivalents of NMM and ethyl chloroformate were needed during this time to drive the reaction. The reaction mixture was added dropwise to a solution of NaBH4 in water at 0-5° C. and the combined mixture was stirred for 30 min. The mixture was partitioned between EtOAc and 1M HCl and the organic layer was washed with water, dried through a phase separator and concentrated. The crude was dissolved in DMSO and purified by HPLC (neutral). Freeze-drying of pure fractions gave the title compound (8 mg, 17%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1I.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].[F-].[K+]>CN(C)C=O.C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[C:14]([F:17])([F:16])[F:15]
Reactant: O=[N+]([O-])c1ccc(I)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(Cl)c1

Procedure:
A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g), trimethyl(trifluoromethyl)silane (5.68 g), copper(I) iodide (2.28 g), and potassium fluoride (0.56 g) in N,N-dimethylformamide (8 mL) is heated in a sealed tube to 80° C. for 40 hours. The solution is then cooled, diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate is washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil.
Reaction SMILES: COC1C=C(O)C=CC=1OC.BrCCCCCCCCCO.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38].COC1C=C(C=CC=1OC)OCCCCCCCCC(O)=O.Cl.Cl.[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH2:83])[CH2:79][N:80]([CH3:82])[CH3:81])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH:83][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]1[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:25]([O:24][CH3:23])[CH:26]=1)[CH2:79][N:80]([CH3:81])[CH3:82])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: COc1ccc(OCCCCCCCCCO)cc1OC
Agent: COc1ccc(O)cc1OC
Agent: COc1ccc(OCCCCCCCCC(=O)O)cc1OC
Agent: Cl
Product: COc1ccc(OCCCCCCCCC(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1OC

Procedure:
The title compound, m/e=439.4 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, 3,4-dimethoxyphenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(3,4-dimethoxy-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(3,4-dimethoxy-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(3,4-dimethoxy-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:68]([SH:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH2:68]([S:75][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC(OC(c2cccc(SCc3ccccc3)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (200 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), Diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 24 h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5) to afford 2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:10]([O:12][CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])=[C:6]([Br:9])[CH2:7][S:8][C@H:3]12.[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[O:28]([CH2:35][C:36]([NH:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:10]([O:12][CH:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])=[C:6]([Br:9])[CH2:7][S:8][C@H:3]12)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CS[C@H]12
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CS[C@H]12

Procedure:
Diphenylmethyl 7-amino-3-bromo-3-cephem-4-carboxylate is reacted with phenoxyacetyl chloride in the presence of pyridine to provide diphenylmethyl 7-phenoxyacetamido-3-bromo-3-cephem-4-carboxylate.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][O:40][CH2:41][CH2:42][NH2:43]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:43][CH2:42][CH2:41][O:40][CH3:39])=[O:34])(=[O:29])=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCN
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: COCCNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 45.9 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](Cl)(=[O:24])=[O:23])=[C:6]1[CH3:26].[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:24])(=[O:23])[N:29]([CH3:28])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:6]1[CH3:26]
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Reactant: CNc1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 20c using [3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester and N-methylaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.C(Cl)Cl.O.[CH3:22][CH2:23]O>>[CH2:22]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:23]
Reactant: O=C(O)Cc1cc(Cl)cc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)cc(Br)c1

Procedure:
(3-Bromo-5-chloro-phenyl)-acetic acid (14 g, 56 mmol) in EtOH (150 mL) was treated with sulfuric acid (2 mL) at 50° C. for 2 hours. The mixture was worked-up with CH2Cl2 and H2O, and the organic layer was concentrated to give the title compound.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH:16]2[CH2:21][CH2:22][CH2:23][CH:24]=O)[O:14][CH2:13][CH2:12]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([CH:16]1[CH2:17][O:18][CH2:19][CH2:20][C:15]21[O:11][CH2:12][CH2:13][O:14]2)[CH2:22][CH2:23][CH:24]=[CH2:1]
Reactant: O=CCCCC1COCCC12OCCO2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Product: C=CCCCC1COCCC12OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyltriphenylphosphonium bromide (0.920 g, 2.58 mmol) in TI IF (10 mL) under N2 at it was added NaHMDS (2M in THF, 1.30 mL, 2.58 mmol). The mixture was stirred at rt for 1 hr. 4-(1,4,8-trioxaspiro[4.5]dec-6-yl)butanal (0.276 g, 1.29 mmol) was then added and the reaction was stirred at it for 1 hr. It was quenched with sat'd. aq. NH4Cl and extracted 3× with Et2O. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.75-5.86 (m, 1H), 4.91-5.03 (m, 2H), 3.91-4.05 (m, 4H), 3.78-3.90 (m, 2H), 3.62-3.71 (m, 1H), 3.43 (dd, 1H, J=9.0 Hz, 11.2 Hz), 1.98-2.12 (m, 2H), 1.11-1.81 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Product: Clc1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 2-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-264.5° C. (dec.) (corr.), from ethanol-ether.