Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([F:15])([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>CC(C)=O>[Cl:22][C:23]1[N:28]=[C:27]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:7][C:8]([F:14])([F:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Compound Ethyl 3-(cyclopentylamino)-2,2-difluoropropanoate (396 mg, 1.79 mmol) was solubilized in acetone (40 mL, dry). The solution was cooled in an ice salt bath under a nitrogen atmosphere and K2CO3 (495 mg, 3.58 mmol) added. To this, a solution of 2,4-dichloro-5-nitropyrimidine (378 mg, 1.97 mmol) in acetone (10 mL, dry) was added dropwise. Upon completion of addition the reaction mixture abandoned and allowed to slowly warm to room temperature and stir overnight. The mixture was then filtered through paper, the filter pad washed with acetone, and the filtrate concentrated. The concentrate was then solubilized in EtOAc (10 mL). Hexanes (70 mL) were then added and the solution was put on the rotovap to slowly concentrate. Yellow crystals form and are collected by filtration to yield 360 mg of the desired product Ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate (53%). The filtrate was found to contain a 1:1:1 mixture of the product, dichloronitropyrimidine, and the 2-addition product. This material was concentrated and set aside for future use. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.20 Hz, 3H) 1.36-1.98 (m, 8H) 3.64 (q, 1H) 4.25 (q, J=7.24 Hz, 2H) 4.35 (t, J=13.77 Hz, 2H) 8.94 (s, 1H). [M+H] calc'd for C14H17F2N4O4, 379. found 379.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(C=C)OB([CH:31]=[CH2:32])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([CH:31]=[CH2:32])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=Cc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 110 °C
Yield: 68.4 %

Procedure:
N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.300 g, 0.896 mmol) (as in Example 4) and 2,4,6-trivinyl cyclotriboroxane pyridine complex (0.323 g, 1.34 mmol) were dissolved in dioxane (15 mL) and then cesium carbonate (0.584 g, 1.79 mmol) dissolved in water (2 mL) was added. The reaction mixture was degassed with nitrogen for 15 minutes, then tetrakistriphenylphosphine palladium (0.0520 g, 0.0450 mmol) was added and the resulting reaction mixture degassed for 15 minutes. The reaction mixture was then heated to 110° C. for 14 h, allowed to cool, concentrated under reduced pressure and CH2Cl2 (25 mL) was added. The residue was filtered through a CELITE® bed and the filterate dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 3% methanol in chloroform) to yield N-benzyl-5-phenyl-2-vinylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 34.2%). LCMS Condition B-25: retention time 3.12 min, [M+1]=327.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.72 (d, J=5.6 Hz, 2H), 5.60 (d, J=2.4 Hz, J=10.4 Hz, 1H), 6.36-6.56 (m, 3H), 6.72 (d, J=2.8 Hz, 1H), 7.30-7.37 (m, 5H), 7.42-7.52 (m, 5H), 7.74 (d, J=2.8 Hz, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[CH:15]=[N:14]2)[CH2:9]1.Cl[CH:26]([C:29]1([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][CH:36]=[CH:35]3)[CH2:31][CH2:30]1)[CH:27]=O>>[O:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][C:21]4[N:20]([C:26]([C:29]5([C:32]6[CH:33]=[C:34]7[C:39](=[CH:40][CH:41]=6)[N:38]=[CH:37][CH:36]=[CH:35]7)[CH2:31][CH2:30]5)=[CH:27][N:24]=4)[CH:19]=3)[CH:15]=[N:14]2)[CH2:9]1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2cnn(C3CCOC3)c2)cn1
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2ccc(C3(c4cnc5ncc(-c6cnn(C7CCOC7)c6)cn45)CC3)cc2c1

Procedure:
The title compound was prepared as a TFA salt from the condensation of 5-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde using a procedure analogous to that described for the synthesis of Example 7, Step 8. LCMS: (M+H)=423.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([S:22]Cl)=[O:21].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]1[O:12][C:20](=[O:21])[S:22][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Cl)cc1OCc1ccccc1
Reactant: O=C(Cl)SCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Temperature: 90 °C
Yield: 98.8 %

Procedure:
To a solution of 2-(benzyloxy)-4-chlorobenzamide (0.103 g, 0.38 mmol) in toluene (5 ml) was added chlorocarbonylsulfenyl chloride (63 μL, 0.76 mmol) under nitrogen atmosphere and the resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring) water was added followed by extraction with ether (3×25 ml). The combined organics was then sequentially washed with water, 10% NaHCO3 (aqueous solution) and finally again with water. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated to get desired product (0.12 g, 94%) that was carried forward as such without further purification. MS: 320.21 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:18](=[NH:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:18](=[N:31][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH:9]=2)[C:3]=1[F:17])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN(C)C1CC=C(c2cccc(Br)c2F)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C)C1CC=C(c2cccc(N=C(c3ccccc3)c3ccccc3)c2F)CC1
Yield: 87.7 %

Procedure:
Combine (4-(3-bromo-2-fluoro-phenyl)-cyclohex-3-enyl)-dimethyl-amine (preparation 7, 1.70 g, 6.84 mmol), benzophenone imine (1.24 g, 6.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.104 g, 0.11 mmol), racemic BINAP (0.142 g, 0.228 mmol), and sodium t-butoxide (0.767 g, 0.8 mmol) with toluene (5 mL) and heat at reflux for 2 hr. Dissolve the reaction mixture in MeOH and filter through a SCX column (Bond Elut™, 10 g), wash with MeOH, elute the product with 2M NH3 in MeOH, evaporate the solvent, and further purify on a silica gel column (DCM:2M NH3 in MeOH, gradient) to give pure benzhydrylidene-(3-(4-dimethylamino-cyclohex-1-enyl)-2-fluoro-phenyl)-amine (2.39 g): MS (ES): m/z=399 (M+H)+. 1H NMR (CDCl3): δ 7.76 (m, 2H), 7.46 (m, 1H), 7.40 (m, 2H), 7.25 (m, 4H), 7.13 (m, 2H), 6.85 (m, 1H), 6.73 (m, 1H), 6.65 (m, 1H), 5.70 (m, 1H), 3.05 (m, 1H), 2.61 (s, 6H), 2.6-2.2 (m, 5H), 1.75 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[CH3:23][O:24][C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(-n2cnc3c(Cl)nc4ccccc4c32)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2cnc3c(OC)nc4ccccc4c32)cc1

Procedure:
A mixture of 3.6 g (0.0116 mole) of 4-chloro-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline (from Example 109), 25.1 g (0.116 mole) of 25% sodium methoxide in methanol and 50 ml of methanol was heated its reflux temperature for one hour. Evaporation provided a residue which was diluted with 75 ml of water. The precipitate was separated by filtration, washed with water and recrystallized from ethanol to provide 4-methoxy-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline, m.p. 180°-182° C. Analysis: Calculated for C18H15N3O2 : %C, 70.8; %H, 5.0; %N, 13.8; Found: %C, 70.6; %H, 5.0; %N, 13.9.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: Clc1ccccn1
Reactant: C[C@@H]1CNCCN1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2ccccn2)CCN1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.3 %

Procedure:
To a solution of (R)-2-methyl piperazine (6.6 g, 0.066 mol) in xylene (100 mL) at 140° C. under nitrogen was added 2-chloro pyridine (4 g, 0.035 mol) slowly over a period of 1 h. The heating was continued for additional 12 h and cooled to RT. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography using chloroform methanol (8/2) as eluent to afford the title product as a liquid (2.5 g, 40%). TLC—Chloroform/MeOH (8/2); Rf=0.2. HPLC purity: 97%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([F:17])=[CH:10][C:9]2[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C)c(F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(5-dimethyl-aminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-fluoro-phenyl)-carbamic acid tert.-butyl ester (Example M39) (170 mg, 0.32 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (34 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[S:18]>ClCCl>[CH3:15][NH:16][C:17]([NH:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[S:18]
Reactant: Cc1cccc(N2CCOCC2)c1N
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1c(C)cccc1N1CCOCC1

Procedure:
Reaction of 6-methyl-2-morpholinoaniline (8.75 g) with methyl isothiocyanate (4.7 g) in dichloromethane (50 ml ) at room temperature for four days yielded N-methyl-N-'-(6-methyl-2-morpholinophenyl)thiourea (m.p. 182°-183° C.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH:27][CH2:28][CH2:29][NH2:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([OH:18])[CH2:16][CH2:15][CH:14]([NH:30][CH2:29][CH2:28][NH:27][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CCC(O)(CC(=O)OCc2ccccc2)CC1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC1CCC(O)(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Titanium ethoxide (0.47 mL, 2.24 mmol) was added to a solution of (1-Hydroxy-4-oxo-cyclohexyl)-acetic acid benzyl ester (1.22 g, 4.65 mmol) and 2-(Boc-amino)ethylamine (0.97 g, 6.05 mmol) in DCM (5.0 mL) under argon. The reaction was stirred at RT for 5 hr. The reaction was concentrated in vacuo. The residue was diluted with methanol (23 mL) under argon and cooled to −78° C. Sodium triacetoxyborohydride (1.49 g, 7.03 mmol) was added in one portion and the reaction allowed to slowly warm to RT overnight. The reaction was quenched with 10% Na2CO3 and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 407 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:8]3([CH2:10][CH2:9]3)[S:7][C:6]=2[CH:13]=1.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C>[C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:8]3([CH2:10][CH2:9]3)[S:7][C:6]=2[CH:13]=1)(=[O:16])[CH3:15]
Reactant: Nc1ccc2c(c1)SC1(CC1)C2=O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)SC1(CC1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In 2 ml of acetic acid and 2 ml of acetic anhydride was dissolved 9.5 mg of 6-aminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one as obtained in Example 6, and the solution was stirred at room temperature for 10 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the residue was chromatographed on a column of silica gel. Recrystallization of the resultant crude crystals from ethanol-water (1:2) yielded colorless needles of 6-acetylaminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting point: 195°-196.5° C.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:14]2[O:13][CH2:12][CH2:11][C:10]=2[C:9]([NH:15][C:16](=[O:18])[CH3:17])=[CH:8][CH:7]=1)=O>CO>[C:16]([NH:15][C:9]1[C:10]2[CH2:11][CH2:12][O:13][C:14]=2[C:6]([C:4]([NH2:1])=[O:3])=[CH:7][CH:8]=1)(=[O:18])[CH3:17]
Reactant: N
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCC2
Solvent: CO
Product: CC(=O)Nc1ccc(C(N)=O)c2c1CCO2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ammonia gas was bubbled through a solution of 4-acetylamino-2,3-dihydro-benzofuran-7-carboxylic acid methyl ester (12 g, 51 mmol, prepared as described in Takuji Kakigami et al, Chem. Pharm. Bull, 46 (1), 42-52, (1998)) in CH3OH (200 mL) in a pressure bottle at 0-5° C. until the solution was saturated. The bottle was sealed and stirred at 60° C. overnight. After cooling to 0-5° C., the reaction mixture was charged one more time with NH3 gas, then the sealed bottle stirred at 60° C. for another 24 h. After cooling to rt, white precipitates were collected by filtration, and dried under vacuum to furnish the title compound (10.5 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4]>O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:2]([C@@H:3]([CH2:5][OH:6])[OH:4])[OH:1])[OH:6])[OH:4]
Reactant: OCC(O)CO
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The enzymatic solution was prepared by adding carboxymethylcellulose at ambient temperature, and with constant stirring, to glycerine, glucose and water to form a solution, and thereafter adding glucose oxidase, with continued stirring, to obtain the enzymatic coating composition. The viscosity of the solution was 8,000 centipoises.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].N.C(OCC)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 20 h

Procedure:
Combine Raney nickel (twice washed with water and twice washed with ethanol, 3.6 kg), 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (1260 g, 3.51 mol), ethanol (9 L), and an aqueous concentrated ammonia solution (1.6 L) in a 5 gallon autoclave. Hydrogenate at 55 psi. After 20 hours, vent the vessel, purge with nitrogen, and filter. Rinse the solids with ethanol (about 1 L). Evaporate the filtrate in vacuo to give a residue. Combine the residue and ethyl acetate (10 L) and extract twice with water (1 L) and then with brine. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Crystallize the residue from ethyl acetate (about 1.8 L) and heptane (about 7.2 L) to give a solid. Collect the solid to give the title compound: mp; 98-99° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([Cl:19])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+]>O.CC(C)=O>[C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([Cl:19])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(Cc1cc(C)c(O)c(Cl)c1)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@@H](Cc1cc(C)c(O)c(Cl)c1)NC(C)=O
Temperature: 37 °C

Procedure:
6.0 mL Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd) was added to a warm solution (37° C.) of 7.2 g (40.4 mmol) Na2HPO4 dihydrate in 100 mL water and by the addition of NaH2PO4 dihydrate the pH was adjusted to 7.5. Then a solution of 5.5 g (19.2 mmol) methyl 2-acetylamino-3-(3-chloro-4-hydroxy-5-methyl-phenyl)-propionate in 50 mL acetone was added dropwise with stirring at 37° C. The pH value of the reaction mixture was kept constantly in the range from pH 7.4-7.6 by the addition of 1 M NaOH. After the addition had ended the mixture was stirred for 4 h at 37° C. After cooling to RT the reaction mixture was exhaustively extracted with MTBE, the combined organic extracts were washed with 15% K2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the crude product (1.6 g) was further reacted without purification.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[C:4](/[N:6]=[C:7]1\[S:8][C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][N:11]\1[CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1)=[O:5].C(N(CC)CC)C.[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:9]1[S:8]/[C:7](=[N:6]\[C:4](=[O:5])[C:3]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:2]=2/[CH:42]=[CH:41]/[S:38]([CH3:37])(=[O:40])=[O:39])/[N:11]([CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH:10]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2/C=C/S(C)(=O)=O)s1
Temperature: 140 °C
Yield: 47 %

Procedure:
To a solution of Example 386B (172 mg, 0.350 mmol), triethylamine (53 mg, 0.525 mmol) and methylvinylsulfone (55.7 mg, 0.525 mmol) in acetonitrile (1 mL) was added palladium acetate (4.72 mg, 0.021 mmol) and tri(o-tolyl)phosphine (23.44 mg, 0.077 mmol). This mixture was heated in a microwave at 140° C. for 30 min. The reaction was heated another 30 min at 180° C. The reaction mixture was cooled to room temperature and filtered. The residue was purified by preparative HPLC on a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm), using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to provide the title compound (85 mg, 47%). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H) 1.62-1.71 (m, 1H) 1.76-1.92 (m, 2H) 2.02-2.14 (m, 1H) 3.08 (s, 3H) 3.73-3.87 (m, 2H) 4.22-4.34 (m, 2H) 4.50 (d, J=11.10 Hz, 1H) 6.80 (d, J=15.47 Hz, 1H) 6.97 (s, 1H) 7.59-7.72 (m, 2H) 8.52 (s, 1H) 8.83 (d, J=15.47 Hz, 1H); MS (DCI/NH3) m/z 517 (M+H)+.
Reaction SMILES: F[C:2](F)(F)S(OC)(=O)=O.[F:10][C:11]([F:30])([C:13]([F:29])([O:18][C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:14]([F:17])([F:16])[F:15])[O-:12].CN([S+](N(C)C)N(C)C)C>C(#N)C1C=CC=CC=1>[F:10][C:11]([O:12][CH3:2])([F:30])[C:13]([F:29])([O:18][C:19]([F:27])([F:28])[C:20]([F:26])([F:25])[C:21]([F:22])([F:24])[F:23])[C:14]([F:17])([F:16])[F:15]
Reactant: [O-]C(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COS(=O)(=O)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: N#Cc1ccccc1
Product: COC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Methyl trifluoromethanesulfonate, 4.92 g (0.03 mol), was added dropwise to 0.03 mol of tris(dimethylamino)sulfonium 1,1,2,3,3,3-hexafluoro-2-(heptafluoropropoxy)propoxide (prepared as in Example 13) in 30 mL of benzonitrile. The reaction mixture was stirred for 1.5 h and then the more volatile portion of the reaction mixture was distilled out at reduced pressure and redistilled at atmospheric pressure to give 6.39 g (58%) of methyl 1,1,2,3,3,3-hexafluoro-2-(heptafluoropropoxy)propyl ether as a colorless liquid: bp 94°-96°; 1H NMR (CDCl3) δ3.70 ppm (s); 19F NMR (CD3Cl) δ-81.0 ppm (m, 3F), -82.1 ppm (m, 3F), -82.4 ppm (m, 2F), -88.7 ppm (m, 2F), -130.3 ppm (m, 2F) and -144.8 ppm (m, 1F). Anal. Calcd. for C7H3F13O2 : C, 22.96; H, 0.82. Found: C, 22.95; H, 0.78.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([C:44]([F:47])([F:46])[F:45])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([C:44]([F:47])([F:46])[F:45])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C(F)(F)F)cc1-c1cccc-3c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C(F)(F)F)cc1-c1cccc-3c1

Procedure:
A mixture of methyl (2S)-2-(tert-butoxy)-2-[(22S)-4,22,28-trimethyl-17-(trifluoromethyl)-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9. 110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (38 mg, 0.054 mmol), NaOH (0.268 mL, 0.268 mmol) in MeOH (2 mL) was refluxed for 3 h. It was then filtered and purified by prep HPLC to isolate the desired product as a white solid. LCMS (M+1)=695.3.