Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:6]([C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccccc2[N+](=O)[O-])c1C

Procedure:
o-Nitroaniline (15 mmol, 2.1 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (15 mmol, 3.7 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over three silica gel columns to yield the named product, 1H-NMR (CDCl3, ppm): 1.36 t (3H), 2.36 s (3H), 4.31 q (2H), 6.80 s (1H), 7.03-7.66 bm (6H), 7.68 dt (2H) 7.97 dd (1H)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[Cl:20][C:21]1[C:28]([Cl:29])=[C:27]([OH:30])[CH:26]=[CH:25][C:22]=1[CH:23]=O>>[Cl:20][C:21]1[C:28]([Cl:29])=[C:27]([OH:30])[CH:26]=[CH:25][C:22]=1[CH:23]=[CH:16][C:15]([C:13]1[S:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:19])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: CC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)-ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is crystallized from acetonitrile.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=3)=[CH:27][C:26]([O:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[N:25]2)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[N:24]([C:21]3[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[N:25]=[C:26]([O:36][CH2:37][C:38]([F:40])([F:39])[F:41])[CH:27]=2)=[CH:34][CH:33]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(O)cc2)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2nc(OCC(F)(F)F)cc2-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cn1
Reaction time: 1 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (207 μl) in CH2Cl2 (1 mg) was added to a solution of 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenol (300 mg) and pyridine (199 μl) in CH2C12 (3 ml) under ice-bath cooling. The mixture was stirred at same temperature for 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride solution (5 ml) The mixture was partitioned between AcOEt and 1M HCl. The mixture was washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 4-[l-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-yl]phenyl trifluoromethane-sulfonate (439 mg) as an oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([SiH2:27][O:28][C:29]([CH3:42])([CH3:41])[C:30]1[CH:31]=[C:32]([CH2:39][OH:40])[CH:33]=[C:34]([N:36]([CH3:38])[CH3:37])[CH:35]=1)([CH3:26])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:23]([SiH2:27][O:28][C:29]([CH3:42])([CH3:41])[C:30]1[CH:31]=[C:32]([CH:33]=[C:34]([N:36]([CH3:38])[CH3:37])[CH:35]=1)[CH:39]=[O:40])([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)c1cc(CO)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)c1cc(C=O)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A suspension of Dess-Martin periodinane (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 538 mg, 1.27 mmol) in methylene chloride (10 mL) was pipetted into a magnetically stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-5-dimethylamino-phenyl]-methanol (288 mg, 0.986 mmol) in methylene chloride (20 mL). The mixture was stirred for 15 min. Powdered sodium bicarbonate (˜500 mg) was added and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography, eluting with 10-40% ethyl acetate/hexanes, to give 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-dimethylamino-benzaldehyde (187 mg, 65%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:16]=[CH:15][C:9]4[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=4[CH:7]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-acetamide (Example 153a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 209-211° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Yield: 36 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-difluorophenyl isocyanate in a similar manner as described in Example 1.53, providing 26.7 mg (36%) of Compound 29: LCMS m/z (%)=395 (M+H37Cl, 35), 393 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 8.43 (s, 1H), 8.03 (m, J1=12 Hz, J2=4 Hz, 1H), 7.56 (s, 1H), 7.50 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.34 (d, J=4 Hz, 1H), 7.28 (m, J1=12 Hz, J2=4 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.01 (m, J1=8 Hz, J2=2 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2([C:12](Cl)=[O:13])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH2:17][C:18]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][N:21]=[C:20]2[O:31][CH:32]=[CH:33][C:19]=12>>[NH2:17][C:18]1[N:23]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:12]([C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=4)[CH2:11][CH2:10]3)=[O:13])=[CH:28][CH:29]=2)[CH2:22][N:21]=[C:20]2[O:31][CH:32]=[CH:33][C:19]=12
Reactant: O=C(Cl)C1(c2cccc(C(F)(F)F)c2)CC1
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in making Example 474, using 1-(3-Trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine of choice. MS(ES) m/e 436 [M+H]+.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(Cl)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(Cl)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cn1cncn1
Yield: 37 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-chlorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 79, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-chlorophenoxy)phenyl)pyrrolidine-2-carboxamide (187 mg, 37%). 1H-NMR (400 MHz, CDCl3): σ 9.04 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.43 (d, 2H), 7.31 (d, 2H), 7.27-7.18 (m, 4H), 6.93 (d, 2H), 6.88 (d, 2H), 5.03 (d, 1H), 4.95 (d, 1H), 4.81 (d, 1H), 3.63 (dd, 1H), 3.25 (dd, 1H), 3.05-2.90 (m, 3H), 2.70-2.63 (m, 2H). MS (EI) for C28H26ClN5O3. found 515.9 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:23]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:33])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 7 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 6 g of 2-methoxy-4-nitrobenzenesulfonyl chloride. The expected product is obtained after crystallization from a DCM/iso ether/THF mixture. m=9.4 g. M.p.=229° C.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:24])([C:20]([F:23])([F:22])[F:21])[CH2:18]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][C:17]([F:24])([F:16])[C:20]([F:23])([F:22])[F:21])(=[O:8])=[O:9]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 90 °C
Yield: 97 %

Procedure:
A mixture of trifluoromethanesulfonic anhydride (40 mL, 0.24 mol) and 2,2,3,3,3-pentafluoropropanol (25 mL, 0.24 mol) was heated under argon at 90° C. overnight. Then, the crude mixture was distilled at atmospheric pressure to give the desired product as a colourless oil (97% yield).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3].[N:25]1([C:32]2[S:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:32]3[S:33][C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)[CH2:26][CH2:27]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Product: CCCNC(=O)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-propylamide and 2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:23])[C:14]2[C:19]([C:20]=1[CH:21]=O)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>[Si:1]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:23])[C:14]2[C:19]([C:20]=1[CH2:21][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-1H-isochromene-4-carbaldehyde (Intermediate B59.2, 0.5 g, 1.5 mmol) and morpholine (0.12 ml, 1.35 mmol) in DCM (20 ml), dry Na2SO4 was added and the mixture stirred RT for 10 min. Sodium triacetoxyborohydride (0.286 g, 2.25 mmol) and acetic acid (0.09 ml, 1.5 mmol) were added and the reaction mixture was stirred for 24 h at RT. The reaction was quenched by the addition of 2M HCl (3 ml), the heterogeneous mixture was filtered and the filtrate was purified by flash chromatography on silica NH cartridge (cyclohexane:EtOAc=90:10 to 80:20) affording 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (Intermediate B59.3, 0.183 g, 0.45 mmol, 30%).
Reaction SMILES: [CH:1]1([C:6]([OH:19])([C:17]#[CH:18])[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1.C(NC(C)C)(C)C>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.CN(C=O)C>[CH:1]1([C:6]([OH:19])([C:17]#[C:18][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH2:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C=C(CC(O)(C#Cc2nccs2)C2CCCC2)O1
Yield: 81 %

Procedure:
To a degassed solution of 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (264.1 mg, 1.0; prepared as described in Example 1, Step 2), 2-bromothiazole (99.1 μL, 1.1 mmol), diisopropylamine (1.5 mL), and DMF (0.5 mL), under argon, was added Pd(PPh3)2Cl2 (28.1 mg, 0.04 mmol) and Cul (15.2 mg, 0.08 mmol). The resulting mixture was vacuum-flushed with argon (3×), then placed in 100° C. oil bath for 5 minutes, during which time the reaction becomes black/brown in color. The mixture was filtered through a plug of silica eluted with ethylacetate, concentrated, and purified by flash chromatography using 30% EtOAc/Hex as the eluent. The yield of product was 280 mg (81% yield). 1H NMR (CDCl3): δ 1.63 (m, 4H), 1.72 (s, 3H), 1.73 (s, 3H), 2.23 (pentet, 1H, J=8.0 Hz), 2.54 (s, 1H), 2.65 (s, 2H), 3.81 (s, 3H), 5.47 (s, 1H), 6.83 (d, 2H, J=8.7 Hz), 7.31(d, 2H, J=8.1 Hz), ESIMS (M+Na+): 393.2.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][S:7][CH3:8])[C:3]#[N:4].S(=O)(=O)(O)[OH:10]>>[OH:1][CH:2]([CH2:5][CH2:6][S:7][CH3:8])[C:3]([NH2:4])=[O:10]
Reactant: CSCCC(O)C#N
Reactant: O=S(=O)(O)O
Product: CSCCC(O)C(N)=O

Procedure:
A process as set forth in claim 1 wherein 2-hydroxy-4-methylthiobutanenitrile is hydrolyzed in the presence of sulfuric acid to produce an intermediate hydrolyzate comprising 2-hydroxy-4-(methylthio)butanamide; and
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:30])[C:4]1[CH:29]=[CH:28][C:7]([CH2:8][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[C:31](O)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[C:31]([O:1][NH:2][C:3](=[NH:30])[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:28][CH:29]=1)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=N)NO)cc1)Cc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCC(=O)ONC(=N)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1
Yield: 95 %

Procedure:
The same procedure as employed in the preparation of Example 10 (step a) but using tert-butyl 4-[(hydroxyamino)(imino)methyl]benzyl[4-(trifluoromethyl)benzyl]carbamate and dodecanoic acid gave the title compound as a colorless oil (95%). 1H NMR (CD3OD, 300 MHz) δ 7.68 (d, 2H, J=7.9 Hz), 7.59 (d, 2H, J=8.0 Hz), 7.27 (m, 4H), 5.08 (br s, 2H), 4.42 (m, 4H), 2.49 (m, 2H), 1.72 (m, 2H), 1.49 (s, 9H), 1.27 (br s, 16H), 0.88 (m, 3H). HPLC (Condition A), Rt: 7.06 min (HPLC purity: 86.0%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]([O:13][CH3:14])=[O:12].[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][NH:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][N:26]([C:11]([O:13][CH3:14])=[O:12])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: COC(=O)Cl
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (0.19 mL, 1.1 mmol, 6.0 equiv) and methyl chloroformate (0.014 uL, 0.18 mmol, 1.0 equiv) were added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5, 0.18 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was stirred for 1 hour, then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (40 mL) and ethyl acetate (2×35 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide methyl 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (1-6) as an off-white solid. 1H NMR (500 MHz, CD3OD) one rotamer: δ 7.32 (m, 3H), 7.25 (m, 2H), 7.20 (m, 1H), 7.16 (m, 1H), 7.07 (m, 1H), 6.38 (br s, 1H), 5.67 (m, 1H), 4.74 (br s, 2H), 3.70 (s, 3H). LRMS m/z (M+H) 316.0 found, 316.1 required.
Reaction SMILES: C([N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[NH:16][C:15]1=[O:27])(C1C=CC=CC=1)C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[C:20]1([C:18]2[C:17](=[O:26])[NH:16][C:15](=[O:27])[NH:14][CH:19]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-Benzhydryl-5-phenyl-pyrimidine-2,4-dione (0.13 g, 0.35 mmol) was added to solution of triflic acid (0.09 mL, 0.99 mmol) in TFA (0.87 mL) cooled to 0° C. The reaction mixture was stirred for 2 hrs and then quenched by addition of ice. The white precipitate was filtered and dried. The filtrate was diluted with EtOAc and the two phases were separated. The aqueous layer was further extracted with EtOAc (3×15 mL), the combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was taken up with a 1:1 dichloromethane/diethyl ether mixture; the product precipitated as white solid that was filtered and combined to the first fraction isolated (0.06 g, 65%). Analytical data were consistent with those reported in the literature (J. Org. Chem. 1990, 55, 1396-1399); 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.30 (m 1H), 7.32-7.39 (m, 2H), 7.51-7.56 (m 2H), 7.60 (s 1H), 11.10 (br s, 1H), 11.22 (br s, 1H). MS (ESI) m/z: 187 [M-H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18](OCC)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][CH2:18][OH:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 7 h
Yield: 66 %

Procedure:
To a cooled, −78° C., solution of ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, 50 mg, 0.14 mmol) in THF (1.5 mL), under an atmosphere of nitrogen, was added LiAlH4 (2.4 M in THF, 0.1 mL, 0.24 mmol). The reaction was stirred for 7 h before being quenched with 1N NaOH (aq.). The crude reaction mixture was filtered through CELITE® and the aqueous layer was extracted with EtOAc. The combined organic fractions were concentrated onto silica and purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a yellow solid (29 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=2.0 Hz, 1H), 7.92 (s, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.38-7.27 (m, 4H), 5.18 (s, 2H), 4.02-3.90 (m, 2H), 3.02 (t, J=6.3 Hz, 2H). [M+H]=314.3.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH:5]([CH2:13][CH3:12])[CH2:6][CH3:7])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Solvent: O=S(Cl)Cl
Product: CCC(CC)OC(=O)c1ccc(OC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.0 Gram of 4-acetoxy-2-fluorobenzoic acid was added to 7 ml of thionyl chloride, and the mixture was allowed to react under reflux for 5 hours. Thereafter, excessive thionyl chloride was distilled off, and a mixture comprising 1 ml of pyridine, 4 ml of dry ether and 0.6 g of 3-pentanol was added dropwise to the above mixture. After the addition, the resulting mixture was stirred at room temperature for one day and diluted with 200 ml of ether, and an organic layer was washed consecutively with diluted hydrochloric acid, a 1N sodium hydroxide aqueous solution and water, and dried over magnesium sulfate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O/[N:30]=[C:31](\[NH2:39])/[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>CN(C=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][C:31]2[N:39]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:30]=2)[CH:34]=1
Reactant: N/C(Cc1cccnc1)=N\O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Cc3cccnc3)no2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
1-(Tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.29 g, 0.010 mmol) was treated with 1,1′-carbonyldiimidazole (1.62 g, 0.010 mmol) in DMF (5 mL) at ambient temperature for 30 min. Following this activation period, the crude (1Z)-N′-hydroxy-2-pyridin-3-ylethanimidamide (0.010 mmol) was added and the reaction mixture heated at 70° C. for 6 h followed by 120° C. for an additional 6 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic phase was separated, washed successively with saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give tert-butyl 4-[3-(pyridin-3-ylmethyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate. 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.53 (m, 1H), 7.67 (d, 1H, J=7.7 Hz), 7.28 (m, 1H), 4.20-4.05 (m, 2H), 4.08 (s, 2H), 3.08 (m, 1H), 2.94 (m, 2H), 2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.47 (s, 9H). ES-LCMS m/z 367.36 (M+Na).