Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:40]([O:41]CC2C=CC=CC=2)[C@H:39]([O:49][C@@H:50]2[O:79][C@H:78]([CH3:80])[C@@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]([O:61]CC3C=CC=CC=3)[C@H:51]2[O:52]CC2C=CC=CC=2)[C@@H:38]([CH2:81][O:82]CC2C=CC=CC=2)[O:37][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@H:13]1[CH2:35][F:36])C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-].[C]>[C@@H:50]1([O:49][C@@H:39]2[C@@H:38]([CH2:81][OH:82])[O:37][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[CH2:15][NH:14][C@H:13]3[CH2:35][F:36])[C@H:9]([OH:8])[C@H:40]2[OH:41])[O:79][C@H:78]([CH3:80])[C@@H:69]([OH:70])[C@H:60]([OH:61])[C@H:51]1[OH:52]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@H]3[C@H](OCc4ccccc4)CN(C(=O)OCc4ccccc4)[C@H]3CF)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)CN[C@H]3CF)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 8.2 %

Procedure:
The compound (53 mg, 43.9 μmol) synthesized in Example 10 (10d) was dissolved in 1% hydrochloric acid methanol solution (5 mL) and 20% palladium hydroxide-carbon (30 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 3 hours. After the catalyst was removed by celite filtration, 28% ammonia water (0.2 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and it was passed through ion exchange resin column with water (30 mL), 1% ammonia water (30 mL) was flowed through. The ammonia water containing the desired compound was concentrated under reduced pressure and the residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (1.6 mg, 8%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:22](OCC)=[O:23])([F:21])([F:20])[F:19].CC[O-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][C:22](=[O:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
45.2 g 1-(4-Benzyloxy-phenyl) ethanone (200 mmol) was taken up in THF (250 mL) and treated with CF3CO2Et (30 ml, 250 mmol). The solution was cooled to 0° C. and treated with 2.66 M NaOEt (94 ml, 250 mmol) solution over 1 h. The ice bath was removed and the solution was stirred at room temperature for 4 h. The reaction was poured into 1N HCl (1000 ml) and extracted with EtOAc (1500 ml). The organic layer was washed with brine, dried and evaporated to yield 64.2 g 1-(4-Benzyloxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (200 mmol, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>O>[CH:21]([O:20][C:18]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A stirred suspension of 2,5-diaminonitrobenzene (60 g.) in a solution of sodium bicarbonate (49.4 g) in water (780 ml) at 10° C. was treated dropwise with isopropyl chloroformate (48 g) and the mixture was stirred at room temperature for 3 hours. The crude brown solid was filtered off, washed well with water and dried to give 4-isopropoxycarbonylamino-2-nitroaniline (90.0 g), m.p. 158°-160° C., which was used in the next stage of the synthesis without further purification being necessary. Recrystallization of a sample from toluene gave pure 4-isopropoxycarbonylamino-2-nitroaniline, m.p. 161°-163° C.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:26][CH2:27]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of di-tert-butyl [{4-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidin-1-yl}methylylidene]biscarbamate 66 (0.26 g, 0.42 mmol) and Pd/C (0.080 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 67 (0.21 g, 98%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1I)=[O:24].[CH3:40][NH2:41]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1[NH:41][CH3:40])=[O:24]
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c(I)ccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Reactant: CN
Product: CNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Yield: 36 %

Procedure:
A mixture of Example A5 (100 mg, 0.155 mmol) in a methanolic solution of MeNH2 (10 mL) was heated at 80° C. for 3 h. The mixture was concentrated to dryness and purified by HPLC to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide (31 mg, 36%). 1H-NMR (400 MHz, CD3OD): δ 8.64 (br, s, 1H), 8.49 (br, s, 1H), 8.42 (br, s, 1H), 8.13 (br, s, 1H), 7.64 (br, s, 3H), 7.56 (br, s, 2H), 7.37-7.16 (m, 4H), 6.33 (br, s, 1H), 3.98 (s, 3H), 3.09 (s, 3H); MS (ESI) m/z: 547.2 (M+H+).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH3:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:22][CH2:21]1
Reactant: CC1CCC(N)CC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: C[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, white solid, MS: m/e=292.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and 4-methyl-cyclohexylamine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC(C)(C)C
Yield: 49.2 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (400 mg, 1.225 mmol) with 3-methoxy-2-neopentyloxybenzaldehyde (353 mg, 1.50 mmol) in the presence of sodium ethoxide (163 mg, 2.40 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to afford 320 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (s, 9H), 3.52 (s, 2H), 3.77 (s, 3H), 6.82 (d, J=16.2 Hz, 1H), 6.92-6.94 (m, 1H), 6.99 (s, 2H), 7.48 (m, 5H), 7.98 (d, J=5.1 Hz, 1H), 8.22 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 531.35 (M+H)+.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>>[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccsc1I
Product: N#Cc1ccsc1-c1ccc(C=O)cc1

Procedure:
In a manner analogous to the procedure set forth in example A-239, the title compound is prepared from 2-iodo-3-cyano-thiophene and 4-formylphenyl boronic acid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:28]([N:25]1[CH2:24][CH2:23][N:22]([C:20]([N:11]2[CH2:12][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([NH:7][CH3:6])[CH2:10]2)=[O:21])[CH2:27][CH2:26]1)(=[O:30])=[O:29]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (640 mg, 1.37 mmol) in CH2Cl2 (10 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 500 mg (99%) of the title product as a white solid. ES-MS m/e: 367.1 (M+H+).
Reaction SMILES: [OH-].[Na+].C([C:10]1[C:11]([N+:33]([O-:35])=[O:34])=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]3C=CC=CC=3)C=2[N+]([O-])=O)[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.C1(S[CH2:43][C:44]#[N:45])C=CC=CC=1.Cl>CS(C)=O>[CH2:17]([O:16][C:12]1[CH:13]=[C:14]([CH2:43][C:44]#[N:45])[CH:15]=[CH:10][C:11]=1[N+:33]([O-:35])=[O:34])[C:22]1[CH:21]=[CH:20][CH:19]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1c(Cc2ccccc2)cccc1Oc1cccc(Cc2ccccc2)c1[N+](=O)[O-]
Reactant: N#CCSc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CCc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a suspension of NaOH (68.44 g 1.71 mol, Aldrich, 20-40 mesh beads) in 171 mL of DMSO a solution of benzyl-2-nitrophenyl ether (39.23 g, 0.171 mol) and (phenylthio)acetonitrile (25.54 g, 0.171 mol, Lancaster) in 171 mL of DMSO was added dropwise for 10 min and stirred at r.t. for another 25 min. A mixture of 430 g of ice and 430 g of conc. HCl was added. The product precipitated and crystallized. The reaction mixture was cooled down in a refrigerator and filtered. The precipitate was dried on air (hood!) and recrystallized from EtOAc-hexanes. Yield 32.03 g (70%), mp 78-80° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][NH2:16]>O1CCCC1>[CH3:15][NH:16][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: CN
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A suspension of 3.38 g of 5-chlorosulfonyl-2-oxindole in 10 mL 2M methylamine in tetrahydrofuran was stirred at room temperature for 4 hours during which time a white solid formed. The precipitate was collected by vacuum filtration, washed twice with 5 mL of water and dried under vacuum at 40° C. overnight to give 3.0 g (88% yield) of 5-methylaminosulfonyl-2-oxindole.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(SC)oc3c2)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the 4-(2-(methylthio)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide (1.26 g, 4.0 mmol, 1.0 eq) in 40 mL of methylene chloride was added 3-chloroperoxybenzoic acid (70%, 989 mg, 4.4 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 5 hours and then was diluted with 200 mL of methylene chloride. The resulting mixture was washed with aqueous sodium bicarbonate and brine then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was used to next step without further purification. MH+=332.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:9][C:8]=1[F:24])[CH3:2].C(O[CH2:32][N:33]([CH2:41][Si](C)(C)C)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)CCCC.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@@H:5]1[C@@H:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:9][C:8]=2[F:24])[CH2:41][N:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32]1)=[O:25])[CH3:2]
Reactant: CCCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)OCc2ccccc2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 0.17 h

Procedure:
To a solution of 4.5 g of 3-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-acrylic acid ethyl ester (13.1 mmol) and 7.68 g N-[(pentyloxy)methyl]-N-[(trimethylsilyl)-methyl]-benzenemethanamine (26.2 mmol) in 50 ml dichloromethane was added 10 μL. trifluoroacetic acid. The reaction was monitored by TLC. The reaction was complete after 10 min. The mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate solution and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by filtration over a short silica column, using a 7/3 hexane/ethyl acetate mixture as eluent.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]([NH:26][C:27]([C@H:29]1C[C@@H:30]1C1SC=CC=1)=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.O.NN>C(O)C>[NH2:3][CH2:12][C@H:13]([NH:26][C:27](=[O:28])[C@H:29]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:30])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC[C@H](C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 60 °C
Yield: 102.6 %

Procedure:
A mixture of (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic acid {(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide (330 mg, 0.66 mmol) and ethanol (20 mL) was treated dropwise with hydrazine monohydrate (0.32 mL, 6.6 mmol), and the resulting reaction was maintained at 60° C. overnight. The mixture was allowed to cool to room temperature and the solids were removed by filtration. The filtrate was concentrated to dryness, and triturated with ethyl acetate (15 mL), and the mixture was filtered. The collected solids were air dried, then dissolved in diethyl ether (5 mL). The resulting solution was treated with concentrated HCl (0.1 mL), and the precipitate was collected by filtration to afford (2S)-N-((1R)-2-amino-1-[4-((S)-2-methylbutoxy)phenyl]-ethyl)-2-phenylpropionamide (120 mg, 52% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 7.33 (d, J=8.6 Hz, 2H), 7.16 (dd, J=5.1, 1.3 Hz, 1H), 6.98 (d, J=8.6 Hz, 2 H), 6.89 (dd, J=5.1, 3.5 Hz, 1H), 6.85 (d, J=3.3 Hz, 1H), 5.17 (dd, J=8.7, 5.9 Hz, 1H), 3.86 (dd, J=9.1, 5.8 Hz, 1H), 3.79 (dd, J=9.1, 6.3 Hz, 1H), 3.27-3.31 (m, 2H), 2.57 (ddd, J=9.3, 5.7, 4.2 Hz, 1H), 2.00 (ddd, J=8.3, 5.2, 4.2 Hz, 1H), 1.85 (dq, J=13.1, 6.6 Hz, 1H), 1.55-1.64 (m, 2H), 1.25-1.34 (m, 2H), 1.03 (d, J=6.8 Hz, 3 H), 0.97 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 373.1 [(M+H)+, calcd for C21H29N2O2S 373.2].
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](Br)=[C:4]([Br:8])[C:3]=1[Br:9].C([Li])CCC.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:5]1[S:6][C:2]([Br:1])=[C:3]([Br:9])[C:4]=1[Br:8])=[O:21])[CH3:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1sc(Br)c(Br)c1Br
Agent: [Li]CCCC
Product: CCOC(=O)C(=O)c1sc(Br)c(Br)c1Br
Temperature: -18 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
To tetrabromothiophene (2.0 g, 5.0 mmol) in an oven dried 50 mL flask, evacuated and flushed with nitrogen, was added anhydrous diethyl ether (12 ml). The resulting solution was cooled to −18° C., then n-butyllithium (1.6 M in hexane) (3.1 ml, 5.0 mmol ) was added dropwise via a syringe. After stirring for 10 min at −18° C., diethyl oxalate (0.75 ml, 5.5 mmol) was added dropwise. Stirring was continued for 30 min, then the reaction mixture was quenched with 1N HCl. The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. Purification was performed by column chromatography using hexane/ethyl acetate (20:1) to yield (3,4,5-tribromothiophen-2-yl)-oxo-acetic acid ethyl ester as a yellow solid (1.5 g, 71%). MS (M+H)+: 422.55; 1H NMR (300 MHz, CDCl3) δ4.45 (2H, q, J=7.1 Hz), 1.44 (3H, t, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ173.89, 161.64, 133.35, 124.81, 123.05, 122.54, 63.75, 14.11.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][N:4]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][O:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccnc(CO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccnc(COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
The 2-hydroxymethyl-4-methoxypyridine, (3.48 g, 0.024 mol) was dissolved in 50 ml CH2Cl2 and cooled to 0° C. The p-toluenesulfonyl chloride (5.7 g, 0.03 mol) was added followed by triethylamine (5 g), in 10 ml of CH2Cl2. After 15 minutes, the reaction was stirred at room temperature for one hour. The reaction was diluted with CH2Cl2 (200 ml) and washed with water. The organic layer was separated and dried with MgSO4, filtered and concentrated to afford 7.3 g of crude subtitle compound suitable for further use.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])(=[O:14])=[O:13].Cl.N1C=CC=CC=1>C(#N)C>[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[CH:1]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)CCOCCn1cnc2cnc3ccccc3c21
Reaction time: 0.33 h
Yield: 67.9 %

Procedure:
Triethyl orthoformate (2 mL, 12 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.1 g, 10 mmol) in acetonitrile (50 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 20 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide a viscous oil. The oil was triturated with ethyl acetate. The resulting solid was isolated by filtration and washed with ethyl acetate to provide 2.17 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as an off-white powder.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[Cl:6][CH2:7][N+:8]12[CH2:15][CH2:14][N:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2.[F:16][B-:17]([F:20])([F:19])[F:18].[Na+].[F:22]F>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:6][CH2:7][N+:8]12[CH2:15][CH2:14][N+:11]([F:22])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: FF
Reactant: ClC[N+]12CCN(CC1)CC2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: F[N+]12CC[N+](CCl)(CC1)CC2
Yield: 89 %

Procedure:
Treatment to a vigorously-stirred cold (-35° C.) solution of the slightly impure 1-chloromethyl-4-aza-1-azoniabicyclo [2.2.2]octane tetrafluoroborate (1.01 g, 7.28 mmol) and sodium tetrafluoroborate (0.80 g, 7.28 mmol) in dry acetonitrile (200 cm3) with neat fluorine at 10-20 mmHg (1.3-2.7 kPa) pressure until its uptake appeared to cease provided 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (2.20 g, 6.51 mmol, 89%), almost pure according to elemental analysis (C, 24.4: H, 4.6: N, 7.9%. Calc. C, 23.7; H, 3.95; N, 7.9%) and n.m.r. analysis [δF (solution in D2O; ext. CF3CO2H ref.) 125.5 (br. s; FN+), -72.0 (s; BF4-) p.p.m. (a trace of F- impurity caused an absorption at -50.7 p.p.m.); δH (same soln.) 4.53 (m; 3×CH2), 4.97 (m; 3×CH2), 5.50 (s; CH2Cl) p.p.m. (residual H in D2O, 4.70 p.p.m.)](isolated by filtering the product to remove NaF then evaporating the filtrate to remove CH3CN). This bis(tetrafluoroborate) melted with decomposition at 170° C. (turning brown at about 160° C.) after recrystallisation from an acetonitrile-diethyl ether mixture; rapidly liberated iodine from potassium iodine (moist starch-iodide paper); and converted phenol in warm acetonitrile to a mixture of ortho- and parafluorophenol.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(F)(F)F.CCOCC>O1CCOCC1>[C:15]1([C:14]2[O:11][N:10]=[C:8]([C:7]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=NO)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(-c2noc(-c3ccccc3)n2)cc1

Procedure:
A solution of 10.8 g. (0.06 mole) of p-nitrobenzamidoxime and 8.5 g. (0.06 mole) of benzoyl chloride in 250 ml. of dioxane is heated on a steam bath for one hour, followed by the addition of 2 ml. of BF3 -Et2O. After refluxing the solution overnight, the reaction mixture is cooled and the material which precipitates is collected by filtration to yield 8.1 g. (50%) of 5-phenyl-3-(4-nitrophenyl)-1,2,4-oxadizole.