Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(F)(OC)(=O)=O.[F:7][C:8]([F:25])([F:24])[C-:9]([C:20]([F:23])([F:22])[F:21])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].[CH3:26]N([S+](N(C)C)N(C)C)C.FC(F)(F)C(C(F)(F)F)=C(F)C(F)(F)C(F)(F)F>C(#N)C1C=CC=CC=1>[F:18][C:10]([F:19])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:9]([C:20]([F:21])([F:22])[F:23])([C:8]([F:24])([F:25])[F:7])[CH3:26]
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C)[S+](N(C)C)N(C)C
Agent: COS(=O)(=O)F
Agent: FC(=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: N#Cc1ccccc1
Product: CC(C(F)(F)F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 60 %

Procedure:
Methyl fluorosulfate (7.6 g, 0.0665 mol) was added dropwise at 0° to a stirred solution of tris(dimethylamino)sulfonium 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-2-pentanide, prepared by dissolving 20.2 g (0.073 mol) of tris(dimethylamino)sulfonium difluorotrimethylsilicate and 20.0 g (0.0665 mol) of 1,1,1,3,4,4,5,5,5-nonafluoro-2-trifluoromethyl-2-pentene in 75 mL of benzonitrile. The reaction mixture was warmed at 25°, and the most volatile portion of the reaction mixture was distilled out under reduced pressure. The distillate was redistilled at atmospheric pressure to give 13.27 g (60%) of 3,3,4,4,5,5,5-heptafluoro-2,2-bis(trifluoromethyl)pentane as a colorless liquid: b.p. 88°-89°; 19F NMR (CCl3F) δ -67.7 ppm (t,t, 6F), -81.1 ppm (t, 3F), -110.5 ppm (m, 2F) and -123.7 ppm (m, 2F); 1H NMR (CCl3F) δ1.72 ppm. Anal. Calcd. for C7H3F13 : C, 25.17; H, 0.91; F, 73.93. Found: C, 24.88; H, 0.87; F, 73.64.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7](Cl)=[O:8])=[O:4].O[NH:11][C:12](=[NH:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(#N)C.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[N:11]=[C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[O:8][N:22]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1ccc(CC(=N)NO)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)CCc1nc(Cc2ccc(OC)cc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
3-Methoxycarbonylpropionyl chloride (4.5 g) was added dropwise to a mixed solution of N-hydroxy-2-(4-methoxyphenyl)ethaneimidamide (3 g) in acetonitrile (20 ml) and pyridine (5 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, which was diluted with ethyl acetate. The reaction mixture was washed twice with 2N hydrochloric acid and water, then dried and concentrated. The obtained residue was dissolved in pyridine (20 ml) and stirred under heating at 100° C. for 18 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain methyl 3-[3-(4-methoxyphenyl)methyl-1,2,4-oxadiazol-5-yl]propionate (2.5 g).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH:74]([O:77][CH3:78])[O:75][CH3:76])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=2[N:63]([CH3:73])[S:64]([C:67]1[N:68]([CH3:72])[CH:69]=[CH:70][N:71]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.O>[CH3:78][O:77][CH:74]([O:75][CH3:76])[CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=3[N:63]([CH3:73])[S:64]([C:67]2[N:68]([CH3:72])[CH:69]=[CH:70][N:71]=2)(=[O:66])=[O:65])=[N:46][CH2:45]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
Triphenylphosphine oxide (0.9 g) was dissolved in dichloromethane (10 mL), trifluoromethanesulfonic anhydride (0.55 mL) was added under ice-cooling, and the mixture was stirred for 10 min. A solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-5-(2-methoxyethoxy)-7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxamide (1.9 g) and thioanisole (0.7 mL) in dichloromethane (10 mL) was added dropwise under ice-cooling, and the mixture was stirred for 25 min, and then at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography (ethyl acetate:hexane=10:90-80:20) to give the title compound (620 mg, yield 39%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[O:12])[CH2:9][CH2:10][CH3:11].[CH2:13]=[O:14].[CH:15]([O-:17])=O.C([NH+](CC)CC)C>>[CH2:8]([C:9]([CH2:15][OH:17])([CH2:13][OH:14])[CH2:10][CH3:11])[OH:12]
Reactant: C=O
Reactant: O=C[O-]
Reactant: CCCC=O
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Product: CCC(CO)(CO)CO
Yield: 84 %

Procedure:
98.7 ml (0.71 mole)/hour of triethylamine, 42.9 ml (0.49 mole)/hour of n-butyraldehyde and 308.7 ml/hour of 15.2% strength formaldehyde solution (1.7 moles/hour of formaldehyde) are passed into a continuous reaction cascade which consists of three flasks connected in series, the reaction volume of each flask being 900 ml and the reaction temperature in each flask being 80° C. The reacted mixture from the cascade is fed to a continuous hydrogenation apparatus and is hydrogenated at 115° C. and under 60 bar, the catalyst consisting of 81.47% of NiO and 18.53% of Al2O3. Low boilers, and triethylammonium formate formed in the course of the reaction, are then separated off by distillation under reduced pressure (20 mbar). Fractional distillation of the residue under 3 mbar gives 125 g (84% yield) of trimethylolpropane per of hydrogenated mixture and 18 g (13% yield) of di-trimethylolpropane per of hydrogenated mixture, the stated % yields being based on n-butyraldehyde.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:27])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:19][C:17](=[O:18])[C:16]2[CH:36]=[CH:37][C:38]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)=[CH:39][C:15]=2[O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:27])=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1ccncc1NC(=O)c1ccc(N2CCCC2)cc1OC1CCNCC1
Yield: 89 %

Procedure:
The 3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-pyridine-4-carboxamide (109 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 mL) with anisole (1 mL). The solution was treated with trifluoroacetic acid (1 mL) at room temperature for 2 h. The mixture was concentrated to dryness under vacuum, rinsed with hexanes, and sonicated with diethyl ether (5 mL) for 5 min to give 120 mg (0.16 mmol, 89%) of the title product.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:8]=2[CH:7]=1>ClCCl.CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1
Reactant: COCn1c(=O)c2cccnc2c2cc(OCCN(C)C)ccc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COCn1c(=O)c2c(c3cc(OCCN(C)C)ccc31)NCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
The compound (40 mg, 0.122 mmol) prepared in step 6 was dissolved in dichloromethane/methanol (5 ml), added with 10%-palladium (Pd) (4 mg). The resulting mixture was stirred under hydrogen gas for one day at room temperature. Once the reaction was completed, the solution was filtered with celite and the filtrate was concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (40 mg, yield: 99%, white solid).
Reaction SMILES: O[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.S(Cl)([Cl:15])=O>N1C=CC=CC=1>[Cl:15][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: OCC1COc2ccccc2O1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: ClCC1COc2ccccc2O1

Procedure:
0.42 mole of 2-hydroxymethyl-1,4-benzodioxane, 0.42 mole of thionyl chloride and 600 ml of dry pyridine were heated at 100° C. for 3 hours. After the mixture had been cooled, ice-cold dilute hydrochloric acid was added and the mixture was extracted with ether. After drying, the solvent was removed and the residue was distilled in vacuo. Boiling point: 80° C. (0.9 mbar).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16]Br)[C:7]1=2)C.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl>[CH2:20]([N:22]([CH2:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:3])=[O:19])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:18])[CH:14]=1)[CH2:23][CH3:24])[CH3:21]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CBr)c21
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-Bromomethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.5 mmol) in DCM (5 mL) was added diethylamine (5 mmol) and the mixture was stirred overnight at r.t. The crude product was evaporated, LiOH (75 mg) in THF/water/methanol (2:1:1, 5 mL) was added and stirred at r.t. for 1 h. The solvent was evaporated to give a residue, which was purified by HPLC, yielded 5 mg of desire product. MS (ESI) m/z: 294 [M+1]+; 1H NMR (300 MHz, CD3OD) δ 7.18 (s, 2H), 5.72-5.76 (dd, 1H), 4.20-4.45 (dd, 2H), 3.05-3.22 (m, 3H), 2.36-2.44 (dd, 1H), 1.40-1.45 (t, 3H), 1.30-1.34 (t, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4].[N-:27]=[N+:28]=[N-:29].[Na+]>C(#N)C.C(OCC)(=O)C>[N:27]([CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4])=[N+:28]=[N-:29]
Reactant: O=C(CCl)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: [N-]=[N+]=NCC(=O)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide (70 mg, 0.19 mmol) in acetonitrile (2 mL) was added sodium azide (62 mg, 0.95 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL). The ethyl acetate fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 65 mg of product as a white powder (yield was 91.8%). MS obsd. (ESI+) [(M+H)+] 373.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C:23]([O:25]CC=C)=[O:24])[C:10]([O:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10](=[O:11])[O:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14])[CH2:22][C:23]([OH:25])=[O:24])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
Pd(Ph3p)4 (210 mg, 0.181 mmol) was added to a solution of 4-allyl 1-(2-phenylpropan-2-yl) (S)-2-((tert-butoxycarbonyl)amino)succinate (Compound 108) (710 mg, 1.81 mmol) in dichloromethane (20 ml)-acetic acid (1.08 ml)-N-methylmorpholine (0.541 ml), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→30/70) to afford (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-4-((2-phenylpropan-2-yl)oxy)butanoic acid (Compound 109) (525 mg, 82%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])=[CH:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccn(Cc2ccccc2)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Yield: 19.5 %

Procedure:
Benzyl 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylate (1.08 g, 3.38 mmol) obtained in Step 2 was dissolved in a mixed solvent of methanol (7 mL) and water (7 mL), and sodium hydroxide (0.680 g, 16.9 mmol) was added thereto, followed by stirring under heating and reflux for 30 minutes. The reaction mixture was poured into water (50 mL), and 10% hydrochloric acid was added thereto to adjust the pH to 4.5, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration to afford the entitled Compound w (151 mg, 20%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=O)[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:22][C:23]4[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of the hydrochloride salt of 7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.99 g), tert-butyl [3-amino-5-(trifluoromethyl)-benzyl]carbamate (1.98 g, 6.82 mmol), and DMAP (0.834 g, 6.82 mmol) in DMF (60 mL) was added EDCI (1.31 g, 6.82 mmol). The reaction mixture was allowed to stir at rt overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give tert-butyl [3-[({7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)-amino]-5-(trifluoromethyl)benzyl]carbamate (2.45 g, 71%). LCMS: (FA) ES+ 557.9, ES+ 554.6.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.Br[CH2:27][C:28]([NH2:30])=[O:29]>CCN(CC)CC>[NH2:30][C:28](=[O:29])[CH2:27][NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNCC(N)=O)no1

Procedure:
Method as for preparation 106 using tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (250 mg, 0.71 mmol) and 2-bromoacetamide (98 mg, 0.71 mmol) as starting materials and Et3N as the base.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:13]=[C:14]1[N:20]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C@@H:30]([C:43](O)=[O:44])[CH2:31][C:32]3[CH:41]=[C:40]([CH3:42])[C:35]4[NH:36][C:37](=[O:39])[O:38][C:34]=4[CH:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:19][CH2:18][C:17]2[CH:46]=[CH:47][CH:48]=[CH:49][C:16]=2[NH:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:13]=[C:14]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C@H:30]([CH2:31][C:32]3[CH:41]=[C:40]([CH3:42])[C:35]4[NH:36][C:37](=[O:39])[O:38][C:34]=4[CH:33]=3)[C:43](=[O:44])[N:10]3[CH2:11][CH2:12][N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:28])[CH2:25][CH2:26]2)[CH2:19][CH2:18][C:17]2[CH:46]=[CH:47][CH:48]=[CH:49][C:16]=2[NH:15]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc2oc(=O)[nH]c12
Reaction time: 8 h

Procedure:
30 mg (0.18 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added at RT to a solution of 70 mg (0.14 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 50 mg (1.12 mmol) TBTU and 25 μL (0.18 mmol) triethylamine in 1 mL DMF and the reaction solution was stirred overnight. It was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=[O:3].N1C=CC=CC=1.[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:48]O)=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:31]=1[CH2:32][O:33][C:34]1[C:35]2[N:36]([C:40]([C:44]([NH:46][C@@H:47]([CH2:50][CH2:51][CH2:52][CH:53]=[O:3])[CH3:48])=[O:45])=[C:41]([CH3:43])[N:42]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@H](C)CCCC=O
Temperature: -30 °C
Reaction time: 4 h

Procedure:
655 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane; 97%, Aldrich; 1.5 mmol) were initially charged in 10 ml of anhydrous dichloromethane and cooled to about −30° C. 83 μl (1.03 mmol) of pyridine and 430 mg 8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (1.03 mmol) in 20 ml of dichloromethane were added successively to this suspension. The reaction solution was warmed to room temperature and stirred for a further 4 h. With ice cooling, 1N aqueous sodium hydroxide solution was then added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered off and concentrated. The residue obtained was used without further purification for subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][OH:5].[F:11][C:12]([F:18])([F:17])[S:13](Cl)(=O)=[O:14].C(N(CC)CC)C.COP(OC)OC>CCOCC>[F:11][C:12]([F:18])([F:17])[S:13]([O:5][CH2:4][C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:14]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OCc1c(F)cccc1Cl
Agent: COP(OC)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=S(OCc1c(F)cccc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-6-fluorobenzyl alcohol (0.50 g, 3.1 mmol) in ether (5 mL) at −10 C was added trifluoromethyl sulphonyl chloride, followed by a mixture of triethylamine (0.411 mL, 3.88 mmol) and trimethylphosphite (0.458 mLm, 3.88 mmol)) in ether (5 mL). The resulting mixture was stirred for 16 hours at room temperature and then partitioned between ether and water. The organic extract was washed with aq. HCl (0.5N), sat. aq. NaHCO3 and dried (MgSO4). The solvent was evaporated in vacuo to afford 2-chloro-6-fluorobenzyl trifluoromethanesulfinate as an oil. 1H NMR (400 MHz, CDCl3)2δ 7.38 (1H, dt, J=6 and 8 Hz) 7.28 (1H, d, J=8 Hz), 7.08 (1H, dt, J=1, 8 Hz), 5.53 (1H, dd, J=1.8 and 11.1 Hz), 5.30 (1H, dd, J=0.7 and 11.1 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:31]=[CH:30][C:19]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[C:18]([F:32])[CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.B(Br)(Br)Br>>[ClH:1].[NH2:22][CH2:21][CH2:20][C:19]1[CH:30]=[CH:31][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:33])=[CH:17][C:18]=1[F:32]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Agent: BrB(Br)Br
Product: Cl
Product: NCCc1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1F
Yield: 87.3 %

Procedure:
Following General Procedure F, tert-butyl 4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-2-fluorophenethylcarbamate (70 mg, 0.14 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 6 mL, 6 mmol) to afford the desired product as a white solid (26 mg, 48%); 1H NMR (500 MHz, CD3OD) δ 7.67 (d, J=5.4 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.30 (s, 1H), 7.17-7.11 (m, 2H), 6.18 (d, J=5.4 Hz, 1H), 3.35-3.20 (m, 2H), 3.14-3.04 (m, 1H); ESI MS m/z 389 [C19H14ClFN2O2S+H]+; HPLC >99% (AUC), tR=8.93 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@H:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1>>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C@H:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:15][CH2:14]2)[CH:17]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(C)(=O)=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using methanesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide. ESMS m/e: 458.6 (M+H)+.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.ClCCl>[CH3:11][NH:12][C:13]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:14]
Reactant: CN=C=O
Reactant: CC1=NC(=NO)SC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1N=C(C)C(C)(C)S1

Procedure:
15.8 g (0.1 mol) of 2-oxo-4,5,5-trimethyl-3-thiazoline-oxime and 8.5 g. (0.15 mol) of methyl isocyanate were dissolved in 100 ml. of anhydrous dichloromethane. After a few drops of triethylamine were added to this solution, the mixture warmed to 40°-45° C. The mixture was warmed to 50°-60° C. for a short time and then the solvent was distilled off under vacuum. The residue was dissolved in 50 ml. of hot ethyl acetate, treated with carbon and filtered. The hot filtrate was concentrated to 20-30 ml. and treated with 20-30 ml. of hexane. The precipitated crystals were filtered off under vacuum, washed with ether and dried to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 123°-125° C.