Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=O)[C:15]2=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC(OCC)=O.C[Si](C)(C)[O:46][NH2:47]>O1CCCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([NH:47][OH:46])=[O:22])[C:15]2=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(C)C(C(=O)O)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(C(=O)NO)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
2-(3-(4-Benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (50 mg; 0.13 mmol) was dissolved in tetrahydrofuran (THF; 2 ml). At 0° C., diisopropylethylamine (DIEA; 69 μl; 0.39 mmol) and ethyl chloroformate (25 μl; 0.26 mmol) were successively added. The mixture was allowed to reach RT from 0° C. over the course of 2 h, and then O-trimethylsilylhydroxylamine (50 μl; 0.65 mmol) was added. Stirring at RT for a further 3 h was followed by partitioning between dilute HCl (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3×; 5 ml). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. Trituration of the residue with EtOAc (2 ml) resulted in 2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyramide (25 mg; 0.06 mmol). MS: 398.15 (M+H); Rt: 1.30 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:38])(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16][CH:17]=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: C=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 816.6 %

Procedure:
Treat a solution of (R)-4-Benzyl-3-[(S)-2-(6-chloro-2,3-difluoro-4-trifluoromethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one (Preparation 45) (0.72 g, 1.5 mmol) in THF (9 mL) and water (3 mL) with 2.5% OsO4 in tBuOH (1.5 g, 0.15 mmol). Then, add sodium periodate (0.96 g, 4.5 mmol) to the solution and stir the reaction for 4 hr at room temperature. Quench the reaction with water and extract with EtOAc. Wash the organic with 1N sodium thiosulfate and brine. Separate the organic, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.60 g (82%) of desired product. MS (m/e): 490 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>CCO.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-fluoro-4-nitrobenzamide (E335) was dissolved in EtOH under Ar and 10% Pd/C added. The reaction was pump-purged with H2 and left stirring at room temperature overnight. The catalyst was removed by filtration and the reaction concentrated to give pure 4-amino-2-fluorobenzamide (E336).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH3:17])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:18]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH3:17])=[C:8]([CH2:10][O:11][CH3:18])[CH:9]=1
Reactant: CI
Reactant: CC1CCCN1c1ccc(Br)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Br)ccc1N1CCCC1C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of sodium hydride (2.84 g, 119 mmol) in anhydrous DMF (80 mL) was added a solution of [5-Bromo-2-(2-methylpyrrolidin-1-yl)phenyl]methanol (16 g, 59.2 mmol) in DMF (50 mL) drop wise at 0° C. After 30 minutes, methyl iodide (7.3 mL, 119 mmol) was added drop wise at 0° C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL), then diluted with water (200 mL) and extracted with EtOAc (150 ml). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (16.5 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 7.55 (1H, s), 7.29 (1H, m), 6.86 (1H, d), 4.45 (2H, s), 3.55 (1H, m), 3.41 (1H, m), 2.82 (1H, m), 2.12-2.51 (1H, m), 1.91 (1H, m) 1.81 (1H, m), 1.58 (1H, m), 0.99 (3H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:14][C:13]([NH2:15])=[N:12][CH:11]=1)([O-:3])=[O:2].Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(C(C)=O)C>[CH2:22]([O:21][C:19]([C:18]1[N:15]=[C:13]2[N:12]([CH:17]=1)[CH:11]=[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[S:14]2)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ncc(-c2ccccc2[N+](=O)[O-])s1
Solvent: CCC(C)=O
Product: CCOC(=O)c1cn2cc(-c3ccccc3[N+](=O)[O-])sc2n1
Temperature: 25 °C

Procedure:
5-(2-Nitro-phenyl)-thiazol-2-ylamine (100 mg, 0.452 mmol) was mixed with 10 mL of methyl ethyl ketone along with 1.5 equivalents of ethyl bromopyruvate. The reaction mixture was stirred under reflux for 5 hours. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by chromatography (Isco, gradient elution, CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford 60 mg of 2-(2-nitro-phenyl)-imidazo[2,1-b]thiazole-6-carboxylic acid ethyl ester (MS, M++H=318).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][CH:8]=[C:7]([F:22])[C:3]=1C(O)=O.C(Cl)(C(Cl)=O)=O.[N-:29]=[N+]=[N-].[Na+].OS(O)(=O)=O>C(Cl)Cl.CN(C=O)C.CC(C)=O.O.CCO>[NH2:29][C:3]1[C:2]([F:1])=[C:10]([OH:11])[CH:9]=[CH:8][C:7]=1[F:22]
Reactant: CC(C)[Si](Oc1ccc(F)c(C(=O)O)c1F)(C(C)C)C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a solution of 2,6-difluoro-3-triisopropylsilyloxy-benzoic acid (18.4 g, 0.056 mol, 1.0 eq) in DCM (180 mL) and DMF (3 drops) at 0° C. was added (COCl)2 (21.19 g, 0.167 mmol, 3.0 eq) dropwise. The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was evaporated in vacuo and the residue obtained dissolved in acetone (100 mL). The resultant solution was added dropwise to a cooled solution of NaN3 (14.5 g, 0.223 mol, 4.0 eq) in acetone (160 mL) and water (100 mL) at 0° C. The reaction was stirred for 1 h at 0° C. Further water was then added (200 mL) and the reaction heated at 70° C. overnight. The acetone was removed under reduced pressure and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained dissolved in EtOH (94 mL) and water (30 mL). Concentrated H2SO4 (30 mL) was added and the reaction heated at 110° C. overnight. The ethanol was removed under reduced pressure and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 20:1 to 6:1) to give the title compound as a white solid (4.0 g, 50%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)[C:7]=2[C:8]1=[O:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Yield: 74.2 %

Procedure:
A solution of cis-tert-butyl 2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (135.8 mg, 0.247 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (154 mg, 0.742 mmol) and bis(triphenylphosphine)palladium chloride (174 mg, 0.247 mmol) in dioxane (2 mL) and saturated aq Na2CO3 (2 mL) was heated at 120° C. for 30 min. After filtering out the solids, the solvent was removed and the residue was dissolved in MeOH and DCM and the mixture was purified by preparative HPLC. The fractions were collected and the solvent was stripped to dryness via rotary evaporation to give the title compound (109 mg, 74%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.97-1.98 (m, 10H), 2.28-2.44 (m, 3H), 2.56-2.72 (m, 4H), 3.63-3.99 (m, 11H), 4.36 (d, J=18.06 Hz, 2H), 4.56 (br s, 2H), 6.50 (br s, 1H), 6.61 (br s, 1H), 6.65-6.81 (m, 1H), 7.08 (br s, 1H), 7.70 (br s, 1H), 8.30 (br s, 1H), 8.75-9.02 (m, 1H). [M+H] calc'd for C31H39FN6O5, 595. found, 595.
Reaction SMILES: C(OC(CO[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1(=[O:15])[NH:10][C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]12
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 2.77 g of N-(t-butoxy carbonylmethoxy) phthalimide (Compound (13)) in 10 ml of anhydrous methylene chloride was added dropwise 1.37 g of trifluoro acetic acid, and the mixture was followed by stirring at room temperature over night. After the reaction was completed, the resultant was filtrated to give 520 mg of N-(corboxy methoxy) phthalimide (Compound (11)) in the form of white crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([OH:24])=O)[C:17]=1[CH3:25].[N:26]1([CH2:33][CH2:34][OH:35])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:29]2[CH2:30][CH2:31][CH2:32][N:26]([CH2:33][CH2:34][OH:35])[CH2:27][CH2:28]2)=[O:24])[C:17]=1[CH3:25]
Reactant: OCCN1CCCNCC1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCCN(CCO)CC2)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a suspension of 0.060 g (0.18 mmol) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid in 2 ml of CH2Cl2 was added 0.031 g (0.22 mmol) of 2-(1,4-diazepan-1-yl)ethan-1-ol, diluted in 1.7 ml of CH2Cl2. This solution was treated at 0° C. with 0.048 g (0.23 mmol) of DCC. The reaction was allowed to warm up over night to RT, then partitioned between aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, dried (Na2SO4) and evaporated. The residue was suspended in EtOAc and filtered to remove the DCC urea. Purification by flash chromatography (SiO2—NH2, n-heptane/EtOAc 1:4) gave 0.033 g (39%) of [5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-methanone as white oil. MS: 459.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.COC1C=CC([N+:19]#N)=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[C:10]([NH2:19])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: COc1ccc([N+]#N)cc1
Reactant: Nc1cc2ccccn2n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1nn2ccccc2c1N

Procedure:
2.66 g. 2-Aminopyrazolo[1,5-a]pyridine (see Chem. Pharm. Bull., 21, 2146/1973) are reacted with p-methoxybenzenediazonium salt analogously to Example 12.3.1, the resultant azo compound is reduced with sodium dithionite and the crude product obtained is purified to give 2,3-diaminopyrazolo[1,5-a]pyridine; m.p. 190° C.; Rf =0.6 (silica gel, ligroin/acetone/glacial acetic acid 60:40:1 v/v/v).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22]([C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH:30]=O)(=[O:24])=[O:23].ClC(Cl)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:30][C:26]2[S:27][CH:28]=[CH:29][C:25]=2[S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:23])=[O:24])=[C:6]1[CH3:15]
Reactant: O=Cc1sccc1S(=O)(=O)c1cccs1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.14 g), 3-(thiophene-2-sulfonyl)thiophene-2-carbaldehyde (0.12 g) and dichloroethane (5.0 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (1.4 mL), trifluoroacetic acid (0.35 mL) and dichloroethane (2.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C., diluted with saturated aqueous sodium hydrogen carbonate solution and the phases separated. The aqueous phase was extracted with dichloromethane and the combined organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume), to afford the title compound as a yellow solid (0.17 g).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[O:15][C:16](=[O:18])[NH2:17])([CH2:3][CH3:4])[CH3:2]>CCCCCC.C(OCC)(=O)C>[C@H:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C@@H:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[O:15][C:16](=[O:18])[NH:17][C@@H:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cccc(C(C)CC)c1OC(N)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC[C@@H](C)c1cccc([C@H](C)CC)c1OC(=O)N[C@H](C)c1ccccc1
Yield: 53 %

Procedure:
To an Agilent HPLC system fitted with a diode array detector and a 0.46 cm ID×25 cm long 10 mm KROMASIL Silica Column was charged 714 mg of racemic R-(+)-1-phenyl-ethyl)-carbamic acid-2,6-di-sec-butylphenyl ester dissolved in 10 ml of hexane/ethyl acetate (98:2) to give a 71.4 g/l feed solution. The sample was eluted with hexane/ethyl acetate (98:2) at 2 ml/min at 25° C. Fractions containing (R,R,R)-1-phenylethylcarbamic acid-2,6-di-sec-butylphenyl ester were collected and evaporated under reduced pressure at <55° C. At the highest loading, the (R,R,R)-stereoisomer was collected with a chiral purity of 98.7% diastereomeric excess (de) and a total yield of 53%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@H:8]2[CH2:9][C@H:5]([CH2:6][CH2:7]2)[C@H:4]1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C@H:3]2[C@H:8]3[CH2:9][C@H:5]([CH2:6][CH2:7]3)[C@H:4]2[C:10]([O:12][CH3:13])=[O:11])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
Methyl (1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (prepared as described in Example 6c, 0.5 g, 2.43 mmol) was dissolved in methanol (12 mL). Sodium acetate (0.4 g, 4.86 mmol) was added followed by 4 Å powdered molecular sieves (0.5 g) and 4-fluoro-benzaldehyde (0.302 g, 2.43 mmol). Sodium cyanoborohydride (0.305 g, 4.86 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (300 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, methyl (1S,2R,3S,4R)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (0.663 g, 2.39 mmol, 98%), as a clear oil. LC-MS (ESI) calcd for C16H20FNO2 277.15. found 278.2 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: [H][H]
Reactant: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Reaction time: 15 h
Yield: 75.3 %

Procedure:
A Parr hydrogenation vessel was charged with ethyl 6-(3-nitroquinolin-4-ylamino)hexanoate (14.4 g, 43.2 mmol), 10% palladium on carbon catalyst (1.0 g), and ethanol (250 mL); placed on a Parr shaker; and the system pressurized to 40 psi (2.7×105 Pa) hydrogen. After shaking for 15 hours, the reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate as a dark oil (9.8 g) that was used directly in the next step without further purification. This step was repeated several times to provide material for the subsequent step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.20 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: CC(N1CCC(=O)CC1)(C)CC(C)(C)C.[CH2:16]([CH:18]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22])[CH3:17].[NH:30]([CH2:37][C:38]([NH2:40])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([N:30]2[C:26]3([CH2:27][CH2:28][N:23]([CH:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)[NH:40][C:38](=[O:39])[CH2:37]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)CNc1ccccc1
Reactant: CCCCC(CC)N1CCC(=O)CC1
Agent: CC(C)(C)CC(C)(C)N1CCC(=O)CC1
Product: CCCCC(CC)N1CCC2(CC1)NC(=O)CN2c1ccccc1

Procedure:
Example 1 was repeated except that 1-(1,1,3,3-tetramethylbutyl)piperidin-4-one which was used in Example 1 was replaced with 1-(1-ethylpentyl)piperidin-4-one as obtained in Production Example 5, and 4-{[tert-butyl(diphenyl)silyl]oxy}-(2S*)-2-[(3-fluorophenyl)amino]butanam was replaced with 2-anilinoacetamide as obtained in Production Example 4, to provide the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].O=[C:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:32]1.Cl>C1COCC1.O>[CH:2]([CH:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:32]1)=[O:3]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.8 %

Procedure:
To a cooled (0° C.) solution of (methoxymethyl)triphenylphosphonium chloride (60.4 g, 176 mmol) in THF (250 mL) was added KOtBu (1 M in THF, 176 mL, 176 mmol) at such a rate that the internal temperature did not exceed 5° C. When the addition was complete, the resulting mixture was stirred for 1 h at which point ethyl 4-oxocyclohexanecarboxylate (20 g, 118 mmol) was introduced as a solution in THF (200 mL). The reaction mixture was allowed to warm slowly to room temperature where it was stirred for 18 h. The vessel was then immersed in an ice bath and water (100 mL) was added followed by 6N HCl (250 mL). The cooling bath was removed and the reaction stirred until hydrolysis was complete by TLC (˜2 h) at which point it was diluted with water and EtOAc. The layers were separated, the organics dried with MgSO4, filtered, and concentrated in vacuo to afford ethyl 4-formylcyclohexanecarboxylate (23 g) as a 3:2 mixture of trans:cis isomers. This colorless oil was used directly in the subsequent step without further manipulation.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-:10].[Na+]>>[CH2:2]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [OH-]
Reactant: CCCCCCCCBr
Agent: [Na+]
Product: CCCCCCCCOCCCCCCCC
Yield: 75 %

Procedure:
The use of quaternary salt catalysts in the production of symmetrical ethers is also known. A. W. Herriott and D. Picker (Tet. Lett. 44, p. 4,521 (1972)) teach that the reaction of 1-bromooctane with 2N sodium hydroxide in the presence of a quaternary ammonium salt catalyst produces di-n-octyl ether in 75% yield. R. D. Gordon (U.S. Pat. No. 3,824,295) also teaches that the reaction of an alkyl halide, sulfate or sulfonate with aqueous caustic in the presence of a quaternary salt catalyst produces a symmetrical ether.