Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][CH:23]2[C:56](=[O:57])[N:25]3[C:26]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:27]([CH2:30][S:31][C:32]4[N:36]([CH2:37][C:38]#[CH:39])[N:35]=[N:34][N:33]=4)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO>C(Cl)Cl>[NH2:22][CH:23]1[C:56](=[O:57])[N:25]2[C:26]([C:40]([O:42][CH:43]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:41])=[C:27]([CH2:30][S:31][C:32]3[N:36]([CH2:37][C:38]#[CH:39])[N:35]=[N:34][N:33]=3)[CH2:28][S:29][C@H:24]12
Reactant: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
A mixture of phosphorus pentachloride (5.3 g) in methylene chloride (80 ml) was cooled to 5° C. and thereto was added pyridine (2.0 g). The mixture was stirred for 30 minutes at room temperature and then cooled to 5° C. and thereto was added benzhydryl 7-(2-phenylacetamido)-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (8.0 g) to give a homogeneous solution. The obtained solution was stirred for 30 minutes at 5° C. and added to methanol (40.2 g) precooled to -30° C. The resulting mixture was stirred for 30 minutes without external cooling. The reaction mixture was evaporated and to the residue were added ethyl acetate and water. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The ethyl acetate layer was separated, washed with water (×3), dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressine to give benzhydryl 7-amino-3 -[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (6.17 g).
Reaction SMILES: [Cl:1]([O-:3])=[O:2].[Na+:4].[P:5]([O-:9])([OH:8])([OH:7])=[O:6].[Na+].[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH:21]=[O:22])=[CH:17][NH:18]2)=[CH:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][OH:31])=[C:25]([O:32][CH3:33])[CH:24]=1.CC(=CC)C.S([O-])([O-])=[O:40].[Na+].[Na+]>O.C(OCC)(=O)C.C(O)(C)(C)C.C1COCC1>[Cl:1]([O-:3])=[O:2].[Na+:4].[P:5]([O-:9])([OH:8])([OH:7])=[O:6].[Na+:4].[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:21]([OH:40])=[O:22])=[CH:17][NH:18]2)=[CH:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][OH:31])=[C:25]([O:32][CH3:33])[CH:24]=1
Reactant: COc1cc(-c2cc3c(C=O)c[nH]c3cc2Cl)ccc1CCO
Reactant: O=S([O-])[O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1CCO
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.5M/2.65M of sodium chlorite/sodium dihydrogen phosphate in water was prepared and 1.0 mL (2.5 mmol sodium chlorite and 2.6 mmol sodium dihydrogen phosphate) was added to a vial containing 6-chloro-5-[4-(2-hydroxyethyl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde, 1.0 mL THF, 0.5 mL t-butanol, 0.5 mL 2-methyl-2-butene, and sealed then heated to 30° C. for 3 hours. Sodium sulfite (315 mg, 2.50 mmol) was then added and the mixture stirred for 15 min. Ethyl acetate was then added to extract (3×1 mL). The organic layer was separated and solvents removed by speedvac. The residue was purified by reverse phase HPLC to give the title compound. MS(AP−) 344 (M−H)−. Retention time=1.892 Column Xbridge C18 2.1×50 mm 5 μm, Temperature 50° C. Mobile Phase A=0.05% NH4OH in water. Mobile Phase B=100% acetonitrile. Gradient: Initial 5% B Time 0.00 mins, 5% B Time 0.50 mins, 5% B Time 3.40 mins, 100% B Time 4.20 mins, 100% B Time 4.21 mins, 5% B Time 4.70 mins, 5% B Flow rate, 0.8 mL/min Injection volume 2 μL. Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD Ionization Mode API-ES Polarity Negative
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19]([C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc(C(=O)c2ccccc2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cc(Cc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
30 mg of 5% palladium-carbon was added to a mixed solution of 1.5 mL of methanol and 2 mL of ethyl acetate containing the obtained 0.15 g of 2-(benzamido)-4-benzoylbenzoic acid and stirred under hydrogen atmosphere at room temperature for ten hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 0.11 g of 2-(benzamido)-4-benzylbenzoic acid as white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[C:8]2[CH3:22].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C)C=O>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=2)[C:8]([CH3:22])=[C:9]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2[nH]c3ccc(OC)cc3c2C)cc1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C)c3cc(OC)ccc3n2CCCCCCBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
12.5 mmol (300 mg) of NaH are added to 40 ml of absolute dimethylformamide and cooled to 0° C. With vigorous stirring, 7.5 mmol of 5-methoxy-2-(4-methoxy-phenyl)-3-methyl-indole dissolved in 25 ml of absolute dimethylformamide are slowly added dropwise and stirred for 30 minutes at 0° C. This suspension is added dropwise with stirring and ice-cooling to a solution of 11.0 mmol of 1,6-dibromohexane in 25 ml of absolute dimethylformamide and stirred for 30 minutes at 0° C. Excess NaH is destroyed with water and stirring continues for a further 2.5 hours at room temperature. The mixture is shaken with dichloromethane, dried over MgSO4 and the solvent removed. The brown oily crude product is chromatographed on silica gel with dichloro-methane and recrystallized from ethanol. Yield 84%. M.P. 60° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)(Cl)=O.O=C1CCCN1CCC(Cl)=O.[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>>[O:11]=[C:9]([CH:29]1[C:30](=[O:33])[CH2:31][CH2:32][O:27][CH2:28]1)[CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C1CCOCC1
Reactant: O=C(O)CCN1CCCC1=O
Agent: O=C(Cl)CCN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: O=C1CCOCC1C(=O)CCN1CCCC1=O
Yield: 25.6 %

Procedure:
3-(2-Oxopyrrolidin-1-yl)propanoic acid (519 mg, 3.3 mmol) was heated to reflux in thionyl chloride (0.365 ml, 5.00 mmol) for 30 min. The excess of thionyl chloride was evaporated and the product, (3-(2-oxopyrrolidin-1-yl)propanoyl chloride (3.3 mmol)) used as such in the next step. 1-(3-oxo-3-(4-oxotetrahydro-2H-pyran-3-yl)propyl)pyrrolidin-2-one (202 mg, 15%) was synthesised from dihydro-2H-pyran-4(3H)-one (0.462 ml, 5.00 mmol) and 3-(2-oxopyrrolidin-1-yl)propanoyl chloride (3.3 mmol) by the general procedure for the preparation of diketones.
Reaction SMILES: Br[C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH:35]=[C:36]([C:2]2[C:23]([O:24][CH3:25])=[CH:22][C:5]3[C:6]([CH3:21])([CH3:20])[C:7]4[NH:8][C:9]5[C:14]([C:15]=4[C:16](=[O:17])[C:4]=3[CH:3]=2)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=5)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cc2c(cc1Br)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C1=CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 80 °C
Reaction time: 1.33 h

Procedure:
To 9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 300 mg, 0.759 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (282 mg, 0.911 mmol, 1.2 eq.), Pd(PPh3)2Cl2 (26.6 mg, 0.0379 mmol, 0.05 eq.) and sodium carbonate (241 mg, 2.28 mmol, 3.0 eq.), DME (5 ml) and water (1 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by flushing with nitrogen gas. This procedure was repeated five times and then degassed. The mixture was stirred at 80° C. for 80 min under nitrogen atmosphere. Pd(PPh3)2Cl2 (26.6 mg, 0.0379 mmol, 0.05 eq.) was added and the mixture was further stirred at 80° C. for 20 min. Then, the mixture was cooled to room temperature, and added with water and ethyl acetate. The insoluble matters were filtered through Celite. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to obtain the title compound as a crude product (gray powder).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCCNC1
Reaction time: 0.01 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (500 mg, 2.18 mmol) in CH2Cl2 (10 mL) was added TFA (5 ml). The reaction mixture was stirred for an hour. Excess TFA was removed under reduced pressure, and the piperidine-3-carboxylic acid was used without neutralization for the next step. LC/MS: m/z 1303 (M+H)+ at 0.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(F)cc3)CC1)O2
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(F)cc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-[2-(4-Fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (300 mg, 0.673 mmol) was suspended in DCM (10 ml). TEA (0.14 ml, 1 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (230 mg) as a yellow solid. The protected hydroxamic acid derivative was dissolved in DCM (10 ml) and treated with 4 M HCl in dioxane (1 ml, 4 mmol). After 1 h the solvents were evaporated, the residue was worked up with 1 M NaHCO3, extracted with DCM, which was dried and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1 to 90:10) to give an orange solid (95 mg) as free base.
Reaction SMILES: [BH4-].[Na+].CC1C2C(C)(C)C(C2)CC=1.[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:24][CH:23]=[CH:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH:31]O.[OH-].[Na+]>O1CCCC1>[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:24][CH2:23][C@H:22]([OH:31])[CH2:21]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1=CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: OO
Agent: CC1=CCC2CC1C2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 79 %

Procedure:
Sodium borohydride (0.235 mg) was suspended in tetrahydrofuran (2.0 mL) in an argon flow, and the suspension was cooled with ice. Optically active α-pinene (0.63 mL) and boron trifluoride-ether complex (0.25 mL) were added dropwise to the suspension, and the mixture was stirred for 12 hours. 1-Diphenylmethyl-3-pyrroline (0.24 g) was added to the reaction mixture, and the resultant mixture was allowed to react for 9 hours. Thereafter, 30% aqueous hydrogen peroxide (2 mL) and 6 mol/L aqueous sodium hydroxide (2 mL) were added dropwise to the reaction mixture. After 3 h, the reaction mixture was extracted with methylene chloride, and the formed organic layer was dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystalline residue. The residue was subjected to silica gel chromatography, to thereby give the target compound (0.200 g, yield 79%). HPLC analysis (through use of a Daicel Chiral Pack AD-RH) of the thus-obtained compound indicates that the compound has an optical purity of 72% ee.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C([Li])CCC.Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[OH:8])[S:5][CH:6]=1
Reactant: CCc1ccc(Br)cc1
Reactant: O=Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(C(O)c2cc(Br)cs2)cc1
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
Under a nitrogen stream, to a solution of 4-bromo-2-thiophenecarboxaldehyde (10.0 g, 52.3 mmol) in anhydrous THF (100 ml), a hexane solution of n-butyllithium (1.6 M, 34.35 ml, 55.0 mmol) was added dropwise at −78° C. over 5 minutes. After stirring at the same temperature for 10 minutes, a solution of 1-bromo-4-ethylbenzene (10.2 g, 55.0 mmol) in THF (50 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours and, after addition of saturated aqueous ammonium chloride, was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:10)) to give the titled compound (7.1 g, 45%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C=CC(O)=CC=1)O.[CH:15](O)=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:1]([O:6][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCCCCCC=CO
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Product: C=CCCCCCCCCCOC(=O)C(=C)C
Yield: 51.2 %

Procedure:
Monomer synthesis. In a 3 neck round bottom flask, methacrylic acid (51.4 g, 0.515 mol) and benzene (60 ml) were combined. P-TSA (0.90 g, 2.6 mmol), hydroquinone (1.56 g, 13.6 mmol) and undecene-1-ol (25.8 g, 0.150 mol) were added into the flask and a Dean Stark adapter was attached. The reaction was heated at reflux overnight. The benzene was removed from the solution by rotary evaporation at reduced pressure and ether (200 ml) was added. NaHCO3 (50 g) was added to the ether solution to remove any excess methacrylic acid. The product was decanted from the NaHCO3 and washed with H2O (200 ml) 3 times, with 5% by weight NaHCO3 (200 ml) solution 3 times, and again with H2O (200 ml) 3 times. The product was dried over MgSO4 and the ether was removed by rotary evaporation. The product was distilled at 110° C. at 150 mTorr to yield 18.3 g (51% yield) of undec-10-enyl methacrylate.
Reaction SMILES: [OH:1][CH:2]([CH:16]1[CH2:20][CH2:19][S:18][C:17]1=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.O>O1CCOCC1>[OH:1][CH:2]([CH:16]1[CH2:20][CH2:19][S:18][C:17]1=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)c1ccc(C(O)C2CCSC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C(=O)O)c1ccc(C(O)C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
Ethyl 2-{4-[hydroxy(2-oxothiolan-3-yl)methyl]phenyl}propionate (106 mg) obtained in Example 32 was dissolved in 1,4-dioxane (2.0 ml), and to the solution was added 30% aqueous sulfuric acid (2.0 ml), and the solution was stirred overnight at room temperature. After completion of the reaction, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (64 mg, 66%).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH3:11])[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: COc1ccccc1C(=O)Cl
Agent: O=C(Cl)c1ccccc1F
Product: COc1ccccc1C(=O)Nc1cc(C(=O)NCc2ccccc2)ccn1
Yield: 76 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-methoxybenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(2-methoxybenzamido)isonicotinamide was obtained as a colorless solid in 76% yield: mp 205-207° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 10.56 (s, 1H), 8.70 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.20 (dd, J=7.8, 1.8 Hz, 1H), 7.58-7.49 (m, 2H), 7.37-7.25 (m, 5H), 7.14-7.02 (m, 2H), 6.81 (s, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.08 (s, 3H); MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30]([OH:32])=[O:31]>>[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30]([O:32][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:31]
Reactant: CC(CC(=O)O)C(F)(F)F
Reactant: ON=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(CC(=O)OC1(N=O)CCCCC1)C(F)(F)F

Procedure:
1-Nitrosocyclohexyl 4,4,4-trifluoro-3-methylbutanoate was prepared from cyclohexanone oxime, lead tetraacetate and 4,4,4-trifluoro-3-methyl butanoic acid using conditions of General Method 3. 1H NMR (250 MHz, chloroform-d) δ 2.69-2.92 (1H, m), 2.69-2.92 (1H, m), 2.47 (1H, d, 6.5 Hz), 1.71-2.05 (4H, m), 1.42-1.63 (2H, m), 1.27 (3H, d, 6.9 Hz), 1.10-1.39 (2H, m), 0.87 (1H, d, 7.0 Hz), 0.78-0.99 (1H, m).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:16]#[N:17])[CH2:10][CH2:9][CH:8]([S:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:18][Mg]Br.C1(C)C=CC=CC=1.CCCCCC.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH:1]1([CH2:4][C:5]2([CH:16]([NH2:17])[CH3:18])[CH2:6][CH2:7][CH:8]([S:11][CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: C[Mg]Br
Reactant: N#CC1(CC2CC2)CCC(SCC2CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(N)C1(CC2CC2)CCC(SCC2CC2)CC1
Reaction time: 0.25 h

Procedure:
1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile (2 g; 8.0321 mmol) was dissolved in toluene (30 mL) and methylmagnesium bromide (8.6 ml; 12 mL of a 1.4M solution in 3:1 toluene/hexane) was added and the reaction mixture was heated to reflux for 16 hours. The reaction was cooled to OC and methanol (12 mL) was added and the mixture was stirred for 15 minutes before adding sodium borohydride (0.315 g; 8.514026 mmol) and stirring for 0.5 hours at room temperature. The reaction was carefully quenched with 1 M hydrochloric acid (24 mL) and then extracted into ethyl acetate and purified using a 40M Biotage cartridge using 5% (2M ammonia in methanol)/DCM to yield (1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl)amine. (1.6 g, 75%)
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CC(=O)C.S(=O)(=O)(O)O.CO>O.[O-2].[O-2].[O-2].[Cr+6]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: OC1CCC(Oc2ccc(F)cc2)CC1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(Oc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a stirred and cooled mixture of 8.9 parts of 4-(4-fluorophenoxy)cyclohexanol and 160 parts of 2-propanone were added dropwise 13 parts of a solution of 26.7 parts of chromium trioxide in 42.3 parts of concentrate sulfuric acid diluted with water till a volume of 100 parts at a temperature below 5° C. Upon completion, stirring was continued for 3 hours at room temperature. After the addition of a few parts of methanol, the reaction mixture was poured onto water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 8.4 parts (96.1%) of 4-(4-fluorophenoxy)cyclohexanone as a residue (140).
Reaction SMILES: Br[C:2]1[N:3]([CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CCN(CC)CC>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]3[CH2:19][CH2:20][CH2:21]/[C:22](=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])/[C:2]=23)=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/CCCn1c(Br)c(Cc2ccc(Cl)cc2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C1/CCCn2c1c(Cc1ccc(Cl)cc1)c1ccccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred solution of 0.13 g of the product from Step 5 in 4 mL of DMF under N2 atmosphere was added sequentially 0.75 g of n-Bu4NCl, 0.1 mL of Et3N and 0.022 g of Pd(AcO)2. The mixture was stirred for 1 hour at 75° C. and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluted with 6:1 hexane/EtOAc to give 0.07 g of the more mobile isomer followed by 0.06 g of the less mobile isomer.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccccc1N=C=O
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: COc1ccccc1NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=425.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 2-methoxyphenyl-isocyanate.