Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30]=O)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH2:30][N:37]6[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]6)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CN1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 50 %

Procedure:
To a solution of 264 (300 mg, 0.66 mmol), N-methylpiperazine (74 μl, 0.66 mmol) and AcOH (76 μl, 1.33 mmol) in NMP (10 mL) was added sodium triacetoxyborohydride (422 mg, 1.99 mmol) and the reaction mixture was stirred for 2.5 days at RT. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic extract was successively washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15μ, C18(2) 100A, 250×50.0 mm, 15 μm; 0.05% of formic acid in both MeOH/water:20/80 to 95/5 over 60 min, flow; 30 mL/min) to afford the title compound 266 (180 mg, 0.33 mmol, 51% yield, di-formate salt) as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13].O>C1COCC1>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:16])[CH3:13]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCN(CC)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.2 g, 30 mmol, 1.5 eq., Aldrich) in THF (20 mL) at 0° C. was slowly added a solution of indole (2.4 g, 20 mmol, Aldrich) in THF (20 mL). The resulting mixture was stirred at 0° C. for 20 min, after which N,N-diethylcarbamoyl chloride (2.9 mL, 22 mmol, 1.1 eq., Aldrich) was added. Then, the reaction mixture was stirred at 0° C. for 30 min. H2O (10 mL) was added to quench the reaction and the mixture was transferred to a separatory funnel. The organic and aqueous layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. After purification of the residue by a short silica gel column (silica gel 60, 230-400 mesh) with EtOAc/hexanes as eluent, the product N,N-diethyl-1H-indole-1-carboxamide (4.3 g, 99% yield) was obtained as a light yellow oil. Further purification using flash column chromatography was deemed unnecessary. 1H NMR (400 MHz, CDCl3) δ ppm: 7.67 (d, J=8.17 Hz, 1H), 7.63 (d, J=7.65 Hz, 1H), 7.36-7.26 (m, 2H), 7.21 (t, J=7.24 Hz, 1H), 6.62 (d, J=2.77 Hz, 1H), 3.51 (q, J=7.10 Hz, 4H), 1.27 (t, J=7.11 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ ppm: 154.39, 135.51, 129.27, 125.89, 123.36, 121.55, 120.90, 112.98, 105.35, 42.41, 13.46.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:9]=[C:10]([CH:40]=[CH:41][CH:42]=1)[O:11][C:12]1[CH:13]=[C:14]([CH:37]=[CH:38][CH:39]=1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32](F)[CH:31]=3)[CH:24]=2)[CH:17]=1.[NH2:43][C:44]1[CH:45]=[C:46]([CH:125]=[CH:126][CH:127]=1)[O:47][C:48]1[CH:49]=[C:50]([CH:122]=[CH:123][CH:124]=1)[O:51]C1C=C(C2C(OC3C=CC=C(OC4C=CC=C(F)C=4)C=3)=CC=CC=2OC2C=CC=C(OC3C=CC=C(OC4C=CC=C(F)C=4)C=3)C=2C2C=CC=C(OC3C=CC=C(OC4C=CC=C(N)C=4)C=3)C=2)C=CC=1.C[N:129]1C(=O)N(C)CC1>>[NH2:129][C:8]1[CH:9]=[C:10]([CH:40]=[CH:41][CH:42]=1)[O:11][C:12]1[CH:13]=[C:14]([CH:37]=[CH:38][CH:39]=1)[O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:51][C:50]3[CH:122]=[CH:123][CH:124]=[C:48]([O:47][C:46]4[CH:125]=[CH:126][CH:127]=[C:44]([NH2:43])[CH:45]=4)[CH:49]=3)[CH:31]=2)[CH:24]=1
Reactant: Fc1cccc(Oc2cccc(Oc3cccc(Oc4cccc(Oc5cccc(F)c5)c4)c3)c2)c1
Reactant: Nc1cccc(Oc2cccc(Oc3cccc(-c4c(Oc5cccc(Oc6cccc(F)c6)c5)cccc4Oc4cccc(Oc5cccc(Oc6cccc(F)c6)c5)c4-c4cccc(Oc5cccc(Oc6cccc(N)c6)c5)c4)c3)c2)c1
Reactant: CN1CCN(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1cccc(Oc2cccc(Oc3cccc(Oc4cccc(Oc5cccc(Oc6cccc(Oc7cccc(N)c7)c6)c5)c4)c3)c2)c1
Temperature: 210 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
In a nitrogen atmosphere, 1 g (9 mmole) of maminophenol was dissolved in 20 ml of DMI, and 2 g (15 mmole) of potassium carbonate was added, followed by stirring for 30 minutes. Then, 1 g (2 mmole) of 1,3-bis(3-(3-fluorophenoxy)phenoxy)benzene was added, and the mixture was stirred for 14 hours under heating at 210° C. The progress of the reaction was confirmed by HPLC. When the intermediate product, 3-(3-(3-aminophenoxy)phenoxy)phenyl-3-(3-(3-fluorophenoxy)phenoxy)phenyl ether almost disappeared, the reaction was terminated. Then, liquid separation was carried out in the same manner as in Example 2 to obtain an organic phase, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 1.1 g (1.6 mmole, yield: 86%, purity (HPLC): 98%) of 1,3-bis(3-(3-(3-aminophenoxy)phenoxy)phenoxy)benzene as a yellow oily product. The structure and the properties of the compound are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2C(C#N)[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:32].[K+].[CH2:34]([OH:37])[CH2:35]O.Cl>C(OCC)C>[CH2:1]([O:8][C:9]1[C:14]2[CH:35]([C:34]([OH:37])=[O:32])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C#N
Reactant: [OH-]
Reactant: OCCO
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2.0 g 5-benzyloxy-4-cyano-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran, 20 g potassium hydroxide and 100 ml ethylene glycol are heated under nitrogen at reflux for 18 hours and cooled to ambient temperature. The mixture is acidified to pH 3 with concentrated hydrochloric acid, extracted with ethyl acetate and the extracts dried (MgSO4). Evaporation of solvent gives an oil which is taken up in ethyl ether, washed with water, brine, dried (MgSO4) and the solvent evaporated to give 2.09 g of crude solid. The crude was purified by chromatography on silica gel, eluting with ethyl ether/hexane. The combined product fractions are combined and solvent evaporated to afford 1.69 g of the product, m.p. 137°-138° C.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[C:8]1([O:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[O:14]([C:15]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COP(OC)OC
Reactant: O=C(Cl)Oc1ccccc1
Product: COP(=O)(OC)C(=O)Oc1ccccc1

Procedure:
From 10.0 ml (85 mmole) of trimethylphosphite and 10.0 g (64 mmole) of phenylchloroformate (100°, 2 hours). Yield 11.0 g (75%). B.p.0.5 125°-7°, nD25 1.4907. NMR (CDCl3)δ: 3.90 and 4.09 (CH3), 7.10-7.60 (C6H5).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccn2)CC1
Reaction time: 8 h
Yield: 38 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with pyridine-2-carbonyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred overnight. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (15 mg, 37%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([CH:32]2[CH2:34][CH2:33]2)[C:29]([C:35]([O:37][CH3:38])=[O:36])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(O)C>[CH:32]1([C:30]2[C:29]([C:35]([O:37][CH3:38])=[O:36])=[CH:28][N:27]=[C:26]([N:9]3[CH2:8][CH2:7][N:6]4[C:10]5[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=5[N:12]=[C:5]4[C@H:4]3[CH:1]([CH3:3])[CH3:2])[N:31]=2)[CH2:33][CH2:34]1
Reactant: COC(=O)c1cnc(Cl)nc1C1CC1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(C2CC2)n1)[C@@H]3C(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
The mixture of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (77 mg, 0.22 mmol), methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (57 mg, 0.26 mmol, 1.2 eq.) and DIEA (172 mg, 1.3 mmol, 6 eq.) in CH2Cl2/i-PrOH (1 mL/1 mL) was stirred at 120° C. for 16 h. TLC showed (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate was consumed completely (PE:EtOAc=1:1). Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-cyclopropyl-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (50 mg, 43% yield) as a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H]>O1CCCC1>[CH2:1]1[CH:13]2[CH:5]([CH:6]3[CH:11]([CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: [H][H]
Solvent: C1CCOC1
Product: C1CCC2C(C1)CC1CCCCC12
Reaction time: 16 h

Procedure:
A sample of 0.5 g (2.8 mmol) 9-fluorenone (Aldrich, 98%), 0.15 g Au—Pd/SiO2/TiO2 catalyst and 5 ml tetrahydrofuran (Fisher, HPLC Grade) were placed in a 20 cc stirred tank reactor and the reactor was sealed. The reactor was connected to a manifold containing a vacuum source, high-pressure hydrogen source, and a high-pressure ballast. After evacuation of residual air from the manifold lines, hydrogen was purged through the reactor to displace the air from the reactor headspace. The mixture was hydrogenated at 110 psia H2 pressure and 70° C. for 16 hours. After cooling the reactor and venting the reactor to atmospheric pressure, the contents of the reactor were filtered to remove the catalyst. GC-MS analysis of the product showed complete conversion of 9-fluorenone to two products: fluorene (53.5%) and hexahydrofluorene (46.5%). To this solution of fluorene and hexahydrofluorene was added 0.15 g of a ruthenium supported on alumina catalyst (Engelhard, 5% Ru) and the slurry was returned to the reactor. The mixture was hydrogenated at 1000 psia H2 pressure and 190° C. for 4 hours. After cooling and venting the reactor to atmospheric conditions, the catalyst was removed by filtration. GC-MS analysis of the product solution showed >99% conversion and >99% selectivity to perhydrofluorene. The cis,cis isomer of perhydrofluorene was obtained with 96% selectivity based on the GC retention time vs. commercial perhydrofluorene (Aldrich, 97%). INADEQUATE 13C NMR of the commercial perhydrofluorene confirmed the cis-cis stereochemistry of the four methine carbons in the central ring: 22.1 ppm (s), 24.3 ppm (s), 24.4 ppm (s), 29.2 ppm (s), 35.3 ppm (s), 37.3 ppm (s), 43 ppm (s), confirmed the cis-cis stereochemistry of the four methine protons in the central ring as reported by R. Meusinger in J. Prakt. Chem. 339, 128 (1997).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[F:36][C:32]1[C:24]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]3)=[O:20])=[N:22][C:23]=2[CH:35]=[CH:34][CH:33]=1
Reactant: C1COCCN1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (207 mg), morpholine (87 μl), HOBt (40 mg) and triethylamine (210 μl) were dissolved in DMF (10 ml), WSC.HCl (180 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (160 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1N)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[CH:37]1([CH2:42][C:43](Cl)=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38]1.[N:46]1C=CC=CC=1>C(Cl)Cl>[Br:33][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:32]=1)[C:26]([N:25]([C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:36])[NH:46][C:43](=[O:44])[CH2:42][CH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:35]
Reactant: c1ccncc1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Product: O=C(CC1CCCC1)NN(C(=O)c1cccc(Br)c1)[C@@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)C(=O)O
Yield: 519.6 %

Procedure:
(S)-(2-Amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.2 g, 0.04 mmlo) in 5 ml of DCM was reacted with cyclopentyl acetyl chloride (82.6 mg, 0.06 mmol) and pyridine (60 mg, 0.08 mmol) as described in general procedure K. The resulting ester was hydrolyzed according to the general procedure C to afford the title compound (0.2 g) as a white solid. LCMS: 642 (M+1)+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13]S(C)=O.OO>O>[CH3:13][O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Solvent: O
Product: CON1C(C)(C)CC(=O)CC1(C)C
Temperature: 30.5 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A 5.0 L 4 neck mechanically stirred flask is charged with 1oxyl-2,2,6,6-tetramethyl-4-piperidone (300 g, 1.76 moles), ferrous sulfate heptahydrate (513.7 g, 1.85 moles) and dimethylsulfoxide (1450 g). Hydrogen peroxide, 30% (279.2 g, 2.46 moles), is added over a 1 hour 45 min span. The temperature is maintained at 29-32° C. The content is stirred for an additional 30 min at 25-30° C. and then chilled below 1° C. Water (1250 ml) is added and the mixture is extracted with four 750 ml portions of ethyl acetate. The combined extracts are washed, 2×1.0 L of H2O, then 1×500 ml of saturated NaCl and then dried over anhydrous MgSO4. Ethyl acetate is evaporated and the product is distilled (82-84° C. 10.33×10−2 bar), yielding 254 g of a pale yellow oil (yield: 78% of theory; IR-spectrum: Ketone carbonyl, 1710 cm-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C[Si](C[Li])(C)C>>[CH:9]([N:4]1[CH2:3][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:10].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:1]=[O:2]
Reactant: COc1ccccn1
Reactant: COc1ccncc1
Agent: [Li]C[Si](C)(C)C
Product: COc1ccncc1C=O
Product: O=CN1CCCCC1

Procedure:
A reaction scheme according to embodiments of the present invention is illustrated in FIG. 1. As illustrated in FIG. 1, methoxypyridine is deprotonated using the alkylmetal reagent (trimethylsilylmethyl)lithium. According to embodiments of the present invention, 4-methoxypyridine may be reacted with (trimethylsilylmethyl)lithium then N-formylpiperidine to produce 4-methoxy-3-pyridinecarboxaldehyde (MPC). The reaction is carried out at a temperature of about −20° C. or less in the presence of tetrahydrofuran (THF). HCONR2 is also added to the reaction mixture, wherein R is an alkyl group, for example, dimethylformamide or 1-formylpiperidine. The resulting 4-methoxy-3-pyridinecarboxaldehyde is crystallized directly from the reaction mixture with yields between about 60 percent to about 100 percent MPC, depending on temperature used. For example, in the reaction scheme of FIG. 1, a 60 percent yield was achieved at −10° C. and a 100 percent yield was achieved at −30° C. Yields may be higher at temperatures below about −20° C. but are still acceptable at higher temperatures, for example at about −12° C. or higher. The presence of directed ortho metallating groups gives typical selectivity for deprotonation on the aromatic rings. Likewise, lateral lithiation, where side chains on the aromatic ring are metallated, is possible with these bases.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:11]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1ccccc1Br
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: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccccc1-c1ccsc1

Procedure:
The reaction was repeated on a 50 mmol scale with 2-bromobenzaldehyde (5.8 mL), thiophene-3-boronic acid (7.03 g, 0.0555 mol) in ethanol (55 mL), Pd(PPh3)4 (1.7 g, 3 mol %), 2 M aqueous Na2CO3 (55 mL) in toluene (275 mL) to yield crude 2-(3-thienyl)benzaldehyde as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)\[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.Cl.[NH2:54][C@@H:55]1[C:80](=[O:81])[N:57]2[C:58]([C:64]([O:66][CH:67]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[C:59]([CH2:62][Br:63])[CH2:60][S:61][C@H:56]12>ClCCl.O>[Br:63][CH2:62][C:59]1[CH2:60][S:61][C@@H:56]2[C@H:55]([NH:54][C:12](=[O:13])/[C:11](=[N:10]\[O:9][CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])/[C:15]3[N:16]=[C:17]([NH:20][C:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[S:18][CH:19]=3)[C:80](=[O:81])[N:57]2[C:58]=1[C:64]([O:66][CH:67]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)=[O:65]
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.08 h
Yield: 85.6 %

Procedure:
(Z)-2-(t-Butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (1.1 g) (described in Example 3 of South African Specification No. 78/1630) was added to a stirred solution of phosphorus pentachloride (0.46 g) in dichloromethane (20 ml) at -20°. The solution was kept at -15°±5° for 40 35 minutes. More phosphorus pentachloride (0.05 g) was added after 30 minutes. The solution was cooled to -20° and triethylamine (0.6 ml) was added. The solution was stirred at -20° for 5 minutes and then added to a stirred solution of diphenylmethyl (6R,7R)-7-amino-3-bromomethylceph-3-em-4-carboxylate, hydrochloride salt (1 g) in dichloromethane (20 ml) containing triethylamine (0.3 ml) at -20°. The temperature did not exceed -20° during the addition. The mixture was stirred at -20° for 10 minutes and then warmed to 22° over 45 minutes. The mixture was diluted with water (25 ml) and dichloromethane (20 ml) and shaken. The organic phase was separated and the aqueous layer was backwashed once with dichloromethane. The organic phase was washed with dilute sodium bicarbonate solution and the aqueous phase was backwashed. The combined organic solutions were washed with dilute brine, dried over sodium sulphate, and evaporated to a foam. This was triturated with diisopropyl ether, filtered, and dried in vacuo at 60° for 2 hours followed by room temperature overnight to give the title compound, (1.7 g), [α]D21 -28° (c 1.0 CHCl3); λinf. (ethanol) 239 nm, E1 cm1% 252; 260 nm, E1 cm1% 196; 265.5 nm, E1cm1% 193; 273 nm, E1 cm1% 181.