Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[CH:3](Cl)(Cl)Cl.[N+:7]([C:10]1[CH:11]=[C:12]([N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)[C:13]([OH:16])=[N:14][CH:15]=1)([O-:9])=[O:8].[N+:22]([C:25]1[CH:26]=[C:27]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[C:28]([OH:31])=[N:29][CH:30]=1)([O-:24])=[O:23]>C(=O)([O-])[O-].[Ag+2].O>[CH3:25][N:14]1[CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[C:12]([N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)[C:13]1=[O:16].[CH3:3][N:29]1[CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=[C:27]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[C:28]1=[O:31]
Reactant: O=[N+]([O-])c1cnc(O)c(-n2ccnn2)c1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(-n2nccn2)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: O
Product: Cn1cc([N+](=O)[O-])cc(-n2ccnn2)c1=O
Product: Cn1cc([N+](=O)[O-])cc(-n2nccn2)c1=O

Procedure:
Silver carbonate (377 mg) and methyl iodide (366 W) were added to a chloroform (10 ml) solution containing the mixture of 5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-ol and 5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2-ol (184 mg) obtained in the 1st step while shielding light, followed by reflux for 2 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:5 to 2:3), and a white solid of 1-methyl-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2(1H)-one (28.1 mg) and a white solid of 1-methyl-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2(1H)-one (23.3 mg) were thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[OH:20])[CH:5]=[C:6]([O:17][CH3:18])[C:7]=1[O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([CH3:16])[N:10]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[OH:20])[CH:5]=[C:6]([O:17][CH3:18])[C:7]=1[O:8][C:9]1[N:14]=[C:13]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=[C:11]([CH3:16])[N:10]=1
Reactant: C1COCCN1
Reactant: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)n1
Solvent: C1COCCO1
Product: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-4-[[4-chloro-6-methyl-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol (3.0 g) in anhydrous 1,4-dioxane (80 mL), morpholine (1.39 mL) was added and the solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in water and extracted with methylene chloride. The extracts were combined and dried over MgSO4. The solvent was stripped under reduced pressure and the residue was purified on silica gel using a 2:1 mixture of ethyl acetate and hexane to yield 3-bromo-4-[[6-methyl-4-(4-morpholinyl)-1,3,5-triazin-2-yl]oxy]-5-methoxy-a,a-dimethylbenzenemethanol as a colorless powder, mp 199-201° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C@H:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@@H:34]([OH:41])[CH2:33]2)=[CH:24]1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCCC.C(OCC)(=O)C>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C@H:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34](=[O:41])[CH2:33]2)=[CH:24]1
Reactant: O[C@H]1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Dess-Martin Periodane (1.08 g, 2.55 mmol ) in 10 mL CH2Cl2 was added to (1S,3R)-3-(1H-Indol-3-yl)-indan-1-ol (2.52 mmol ) in 10 mL CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature and stirred 40 min—TLC showed full conversion. To the reaction mixture ethyl acetate and sat. NaHCO3 was added. The organic phase was isolated, washed with 2N NaOH and brine, dried over MgSO4 and concentrated in vacuo. A quantitative yield of (R)-3-(1H-indol-3-yl)-indan-1-one was obtained after flash chromatography (heptane/ethyl acetate, silica gel).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](=[O:43])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:36]([NH:35][C:34]([C@H:10]1[C@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12][NH:8][CH2:9]1)=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)NCc2ccccc2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2C(=O)NCc2ccccc2)C(C)C)ccc1OC
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of (3S*,4R*)-3-benzylcarbamoyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (61 mg, 0.098 mmol) in 2 mL CH2Cl2, TFA (113 μL, 1.46 mmol) is added. The mixture is stirred at 30° C. for 2 h, then overnight at RT, and poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on an NH2 Isolute SPE Flash column (eluent: CH2Cl2:MeOH 100:0 to 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 9:1)=0.2. MS (LC-MS): 498 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.38 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](S(C)=O)[N:8]([CH3:15])[C:7]2=[O:16].IC1C=CC=C2C=1N=C(S(C)(=O)=[O:29])N(C)C2=O.O[Li].O>C1COCC1.O>[OH:29][C:9]1[N:8]([CH3:15])[C:7](=[O:16])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cn1c(S(C)=O)nc2c(I)cccc2c1=O
Reactant: Cn1c(S(C)(=O)=O)nc2c(I)cccc2c1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(O)nc2c(I)cccc2c1=O
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
A suspension of 8-iodo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (700a; 15 g, 45.2 mmol) in 400 mL of DCM was set stirring at 0° C. before adding 3-chlorobenzoperoxoic acid (15.59 g of 77% max. Aldrich, 70 mmol) portion wise over 10 min. The ice bath was removed; and the reaction mixture was stirred at RT for 30 min. It was diluted with 200 mL of DCM, washed sequentially with ice cold 2×50 mL of saturated Na2CO3 followed by sat. Na2SO3 solution and 15 mL of brine. The organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give yellow crystalline solid (700b) containing a mixture of 8-iodo-3-methyl-2-(methylsulfinyl)quinazolin-4(3H)-one and 8-iodo-3-methyl-2-(methylsulfonyl)quinazolin-4(3H)-on. The crude material of yellow crystalline solid (700b) in 40 mL of THF and 40 mL of water at RT was treated with LiOH—H2O (6.60 g, 275 mmol). The reaction mixture was stirred in an oil bath at 75° C. for 2.5 h. It was concentrated to half of its volume under reduced pressure. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether. The off-white crystalline solid was dried in a vacuum oven at 45° C. for 48 h to give 2-hydroxy-8-iodo-3-methylquinazolin-4(3H)-one (700c; 12.79 g, 42.3 mmol, 94% yield). The crude material was used in the next step. m/z (ES, +ve) 302.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][C@@H:36](O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C@@H:36]([CH3:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.8 %

Procedure:
To an argon-flushed flask containing a solution of 3.01 g (15 mmol) of p-benzyloxy-phenol and 1.25 eq of triphenylphosphine in 220 ml in dry dichloromethane, was added a solution of 4.91 g (15.14 mmol) of (R)-2-octanol in 30 ml of dry dichloromethane via syringe. Then 1.20 eq of diethyl azodicarboxylate dissolved in 60 ml of dry dichloromethane was added dropwise for 30 min. The reaction mixture was stirred at room temperature for 19 h, Then 5 drops of water were added and the mixture was stirred for 1 h. The solvent was then evaporated and the residual crude product was triturated in a mixture of hexanes/ethyl acetate [70/30] for 1 h and filtered through a short silica gel pad. The filtrate was evaporated and the product was purified by flash chromatography on silica gel using dichloromethane/hexanes [10/90] as eluent, affording 3.32 g (71%) of (S)-p-Benzyloxy-(1-methylheptyloxy)benzene (Compound 18, Scheme III, R2 =(S)-OCH(CH3)C6H13) as a colorless liquid: Rf [dichloromethane/hexanes 10/90]: 0.13; 1H NMR (300 MHz, CDCl3): δ 0.87(t, 3H, J=6.6 Hz), 1.20-1.60(m, 12H), 1.70(m, 1H), 4.21(m, 1H), 5.00(s, 2H), Distorted AA'BB' System [6.82(d, 2H) 6.88(d, 2H)], 7.30-7.46(m, 5H); 13C NMR (300 MHz, CDCl3): δ 14.02, 19.77, 22.55, 25.52, 29.26, 31.77, 36.51, 70.63, 74.95, 115.77, 117.35, 127.49, 127.87, 128.55, 137.39, 152.53, 153.01; IR (CHCl3): 3010, 2940, 2850, 1600, 1500, 1475, 1450, 1375, 1230, 1200, 1125, 1025, 925, 825 cm-1 ; Mass spectrum, m/z (rel.Intensity): 312(M+ 7), 212(15), 91(100), 71(5), 57(8), 43(10).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([CH:25]3[CH2:27][CH2:26]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[C:6]([OH:8])=O)[CH2:3][CH2:2]1.[Cl-].[NH4+:29]>>[NH2:29][C:6](=[O:8])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])[C:16]([CH:25]2[CH2:27][CH2:26]2)=[CH:15][N:14]=1)=[O:12])([CH3:9])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-methyl-propanoic acid (example 186d) and ammonium chloride as starting materials and isolated (16 mg, 32%); MS (ESI, m/z): 386.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=O)[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].[CH2:32](Cl)Cl>C(=O)([O-])[O-].[K+].[K+]>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([CH:32]2[S:31][CH2:27][CH2:28][CH2:29][S:30]2)[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: ClCCl
Reactant: SCCCS
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(C2SCCCS2)CCC3(C)C)cc1
Reaction time: 4 h

Procedure:
To a cold solution (0° C.) of 140 mg (0.40 mmol) of ethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2), in 6.0 mL of methylene chloride was added dropwisel 30 mg (0.12 mL, 1.2 mmol) of 1,3-propanedithiol and 0.17 g (0.15 mL, 102 mmol) of borontrifluoride diethyl etherate. The reaction stirred between 0° C. and room temperature for 4 h. The mixture was diluted with aqueous sat. potassium carbonate, and extracted with ether (2×). The organic phase was washed with brine, dried over MgSO4 and then concentrated in vacuo. The crude product was purified by flash chromatography (silica, 10% ethyl acetate in hexane) to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:21]1[N:25]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[N:29][C:24]2=[N:23][CH:22]=1)CCC>>[F:15][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[N:29][C:24]3=[N:23][CH:22]=2)=[CH:7][C:6]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccnc(-c2cc(Br)ccc2F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: Cc1ccnc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1

Procedure:
2-(5-Bromo-2-fluorophenyl)-4-methylpyridine was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from ethyl acetate/isohexane, gave 3-[4-fluoro-3-(4-methylpyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow powder: δH (400 MHz, CDCl3) 8.87 (1H, d, J 7), 8.58 (1H, d, J 5), 8.24 (1H, dd, J 7 and 2), 8.12 (1H, s), 7.71 (1H, s), 7.53-7.58 (1H, m), 7.38 (1H, dd, J 11 and 8), 7.26 (1H, d, J 7), 7.16 (1H, d, J 5), 2.46 (3H, s); m/z (ES+) 373 (M++H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O.O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3ccsc3c(=O)n2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc2nc3ccsc3c(=O)n2c1
Temperature: 95 °C

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide (1.4 g, 0.006 mol), p-toluenesulfonyl chloride (1.6 g, 0.008 mol), and pyridine (1.4 ml, 0.017 mol) in dimethylformamide (10 ml) is heated at 95° C. for 75 minutes. The mixture is cooled, diluted with water (5 ml) and stirred. The precipitate is filtered, washed with water, with ethanol and dried. Recrystallization from dimethylformamide gives the product (0.8 g.), mp 263°-264° C. (dec).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:3][CH:4]([OH:6])[CH3:5]>[Pd].CCCCCC>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5]
Reactant: CC(C)=CCCC(C)=CC(C)O
Agent: [Pd]
Solvent: CCCCCC
Product: CC(C)CCCC(C)CC(C)O
Temperature: 80 °C
Yield: 94.6 %

Procedure:
A mixture of 671.2 g of citral and 185.6 g of diethyl ether is added to an addition funnel. The citral mixture is then added dropwise over a five hour period to a nitrogen blanketed, stirred, 5 L, 3-neck, round bottom flask equipped with a reflux condenser containing 1.6 L of 3.0 M methylmagnesium bromide solution and an additional 740 ml of diethyl ether. The reaction flask is situated in an ice water bath to control exotherm and subsequent ether reflux. After addition is complete, the ice water bath is removed and the reaction allowed to mix for an additional 2 hours at 20-25° C. at which point the reaction mixture is added to 3.5 Kg of cracked ice with good mixing. To this mixture is added 1570 g of 30% sulfuric acid solution. The aqueous acid layer is drained and the remaining ether layer washed twice with 2 L of water. The ether layer is concentrated by evaporation of the ether under vacuum to yield 720.6 g of 4,8-dimethyl-3,7-nonadien-2-ol. To a glass autoclave liner is added 249.8 g of the 4,8-dimethyl-3,7-nonadien-2-ol, 5.8 g or 5% palladium on activated carbon and 200 ml of n-hexane. The glass liner is sealed inside a 3 L, stainless steel, rocking autoclave and the autoclave purged twice with 250 psig N2, once with 250 psig H2 and then charged with 100 psig H2. Upon mixing, the reaction initiates and begins consuming H2 and exotherms to 75° C. The autoclave is heated to 80° C., boosted to 500 psig with H2, mixed for 3 hours and then cooled to 30° C. The reaction mixture is removed from autoclave, filtered to remove catalyst and concentrated by evaporation of n-hexane under vacuum to yield 242 g of 4,8-dimethyl-2-nonanol.
Reaction SMILES: [F:1][C:2]1[C:7]([B:8](C2C(F)=C(F)C(F)=C(F)C=2F)[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].[OH2:35]>CCCCCCC.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([B:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])[OH:35])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34]
Reactant: O
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: OB(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
20 g (39 mmol) of tris(pentafluorophenyl)borane are suspended in 150 ml of heptane and, under reflux, a solution of 1.8 ml (97.5 mmol) of water in 40 ml of toluene is then added over a period of 30 minutes. The mixture is subsequently stirred for another five hours under reflux. The solution is subsequently cooled to 0° C. Over a period of 30 minutes, the product precipitates as a white solid. The product is isolated and washed three times with 50 ml each time of pentane and subsequently dried in an oil pump vacuum. This gives 11.5 g (80%) of colorless bis(pentafluorophenyl)hydroxyborane. The boroxin content is 10%. 1H-NMR(C6D6, 400 MHz): −133.1 (m, 4 F, o-B(C6F5)2), −147.9 (m, 2 F, p-B(C6F5)2), −161.1 (m, 4 F, m-B(C6F5)2) ppm.
Reaction SMILES: [N+](C1C=C[C:7]([C:8](Cl)=[O:9])=CC=1)([O-])=O.C(N)(C)C.[CH:17]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=1)([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:8](=[O:9])[CH3:7])=[CH:24][CH:23]=1)([CH3:19])[CH3:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)N
Product: CC(=O)Nc1ccc(C(=O)NC(C)C)cc1

Procedure:
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and iso-propyl amine in the amidation step. This yields N-iso-propyl-4-nitrobenzamide (CPI1026).
Reaction SMILES: [C-:1]1([O:6][CH2:7][C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].P(Cl)(Cl)[Cl:18]>N1C=CC=CC=1.C1C=CC=CC=1>[C-:1]1([O:6][CH2:7][C:8]([Cl:18])=[O:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: O=C(O)CO[c-]1cccc1
Reactant: ClP(Cl)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)CO[c-]1cccc1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To ferrocenyloxyacetic acid (1.56 g, 0.006 m) and pyridine (4 drops) in benzene (100 cm3) was added dropwise phosphorous (III) chloride (5.4 cm3). The mixture was stirred for 3 hours at 60° to 70° C. After this time the benzene solution was decanted and the benzene removed under vacuum. The residue was taken up in benzene and the benzene again removed under vacuum. This procedure was repeated. Recrystallization from light petroleum (40° to 60°) gave 1.40 g (83.8%) of ferrocenyloxyacetyl chloride. The chloride (1.40g, 0.005 m) was taken up in dichloromethane (5cm3) and added dropwise to a mixture of 6-aminopenicillanic acid (1.08 g, 0.005 m) and triethylamine (1.01 g, 0.01 m) in dichloromethane (25 cm3) at 0° C. The mixture was stirred for 15 minutes at 0° C. and for 1 hour at 15° C. The solution was then filtered and the solvent removed under vacuum. The residue was taken up in a mixture of water (100 cm3) and ethyl acetate (25 cm3) and the aqueous layer adjusted to pH 2.5 with 2M HCl. The layers were separated and the ethyl acetate layer washed with water, dried, filtered and a 40% solution of SEH in 4-methylpentan-2-one (2 cm3) added. Worked up as previously the yield was 1.53 (67%) of the sodium salt of 6-(2-ferrocenyloxyacetamido) penicillanic acid. I.r. spectrum showed strong β-lactam absorption at 1770 cm-1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH:17][C:18](=[O:28])[C:19]3[C:24]([OH:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][N:20]=3)[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:45][O:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:45][O:46][CH2:47][CH2:48][C:49]([O:25][C:24]1[C:19]([C:18](=[O:28])[NH:17][C@H:11]2[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C@@H:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[C@H:14]([CH3:15])[O:13][C:12]2=[O:16])=[N:20][CH:21]=[CH:22][C:23]=1[O:26][CH3:27])=[O:50]
Reactant: COCCC(=O)Cl
Reactant: COc1ccc(C[C@H]2CCC[C@H](NC(=O)c3nccc(OC)c3O)C(=O)O[C@@H](C)[C@@H]2OCC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCC(=O)Oc1c(OC)ccnc1C(=O)N[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](OCC2CC2)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a 4 mL vial were added N-((3S,7R,8R,9S)-8-(cyclopropylmethoxy)-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (85 mg, 0.166 mmol), CH2Cl2 (1 mL) and NEt3 (0.069 mL, 0.497 mmol), 3-methoxypropanoyl chloride (30.5 mg, 0.249 mmol), and DMAP (3 mg, 0.02 mmol), and the resulting light yellow solution was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography on SiO2 (0→100% EtOAc/hexanes) to provide the title compound as a colorless semi-solid (77.8 mg, 78%): IR (neat) 3381, 2936, 1769, 1742, 1678, 1511, 1246, 1111 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=7.3 Hz, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.09 (d, J=8.6 Hz, 2H), 6.98 (d, J=5.5 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 4.91 (dq, J=9.1, 6.4 Hz, 1H), 4.55 (ddd, J=10.9, 8.4, 7.0 Hz, 1H), 3.88 (s, 3H), 3.81 (t, J=6.6 Hz, 2H), 3.78 (s, 3H), 3.57 (dd, J=9.7, 7.0 Hz, 1H), 3.44 (dd, J=9.7, 6.8 Hz, 1H), 3.41 (s, 3H), 3.15 (t, J=9.0 Hz, 1H), 3.07 (dd, J=13.4, 3.3 Hz, 1H), 2.98 (t, J=6.6 Hz, 2H), 2.35-2.20 (m, 2H), 1.87-1.77 (m, 1H), 1.61-1.47 (m, 2H), 1.48-1.37 (m, 1H), 1.45 (d, J=6.4 Hz, 3H), 1.22-1.05 (m, 2H), 0.90-0.79 (m, 1H), 0.63-0.49 (m, 2H), 0.29-0.14 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.61, 169.39, 162.32, 159.40, 157.82, 146.76, 141.45, 137.29, 132.66, 129.73, 113.77, 109.78, 83.79, 78.71, 75.22, 67.58, 58.78, 56.30, 55.22, 51.47, 46.17, 35.92, 34.62, 33.89, 26.55, 18.73, 18.08, 11.18, 3.16, 3.00; HRMS-ESI (m/z) ([M]+) calcd for C32H42N2O9, 598.2890; found, 598.2914.
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.C1COCC1>[C:4]([O:3][C:1]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1)=[O:8])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
1.39 g of tert-butyl dicarbonate was added to a solution in which 1.00 g of ethyl 2-amino-1,3-thiazole-4-carboxylate, 0.88 g of triethylamine, and 0.07 g of DMAP were dissolved in THF, under ice cooling. Then, after the reaction mixture was stirred at room temperature for 1 hr, it was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous 2N-hydrochloric acid solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained crude product was washed with a mixed solvent of hexane and t-butyl methyl ether to obtain 1.5 g of the aimed ethyl 2-(tert-butoxycarbonyl)amino-1,3-thiazole-4-carboxylate.