Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:18])[CH:13]=[CH:12][C:11]=1[C:30]([CH3:33])([CH3:32])[CH3:31])=O)(C)(C)C>CC#N>[NH2:8][CH2:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:18])[CH:13]=[CH:12][C:11]=1[C:30]([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)ccc1C(C)(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)cc1CN

Procedure:
N-[3-(Aminomethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide (390) was synthesized following the general scheme above starting from [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenyl]methylaminoformic acid tert-butyl ester (465). HPLC ret. time 2.44 min, 10-99% CH3CN, 5 min gradient; ESI-MS m/z 350.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7][CH2:8][C:9](=[O:13])[NH:10][C:11]=2[N:12]=1.C1COCC1>ClCCl.[O-2].[O-2].[Mn+4]>[O:13]=[C:9]1[CH2:8][S:7][C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[N:12][C:11]=2[NH:10]1
Reactant: O=C1CSc2ccc(CO)nc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of 6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (330 mg) in dichloromethane (30 mL)/THF (30 mL) was treated with manganese dioxide (730 mg) and stirred at room temperature. Further manganese dioxide was added after 1 h (730 mg) and 16 h (300 mg). After a total of 20 h the mixture was filtered through kieselguhr and the filtrate evaporated. The product was triturated with EtOAc/hexane (1:1) and collected to give a solid (180 mg): LC/MS (APCI−) m/z 195 ([M−H]−, 95%), 165 (100%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[O:27]CC1C=CC=CC=1)[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16])=[N+:2]=[N-:3].C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>C(Cl)Cl>[N:1]([CH2:4][C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:12]=1[CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]2[N:24]([C:25](=[O:35])[C:26]=1[OH:27])[CH2:23][CH2:22][O:21][C:20]2([CH3:37])[CH3:36])=[O:16])=[N+:2]=[N-:3]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(OCc1ccccc1)c2=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CN=[N+]=[N-])c(O)c2=O
Temperature: 23 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of intermediate 195, (R)-N-(2-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide, (0 030 g, 0.052 mmol) in CH2Cl2 (1 mL) was added CF3CO2H (1 mL) at 23° C. The reaction mixture was stirred at 23° C. for 3 h. Toluene (20 mL) was then added and the solvents evaporated in vacuo. The residue was purified by preparative HPLC (YMC-Pack C-18) to afford the title compound (0.008 g, 31%): 1H NMR (400 MHz, MeOD) δ ppm: 7.55 (1H, dd, J=6.6 Hz), 7.16 (2H, m), 4.47–4.24 (2H, m), 4.05 (2H, m), 3.98 (2H, m), 3.56 (2H, s), 2.70–2.45 (4H, m), 2.11 (1H, m), 1.64 (3H, s), 1.61 (3H, s). HRMS calcd for C22H25N7O5F: 486.1901. found 486.1923.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=O)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH:14]=[C:11]([C:12]#[N:13])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:21]
Reactant: COc1ccc(C(C#N)C=O)cc1OC
Reactant: CCOC(N)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC=C(C#N)c1ccc(OC)c(OC)c1

Procedure:
To the mixture of 2-(3,4-Dimethoxy-phenyl)-3-oxo-propionitrile (20.5 g, 0.1 mol), urethane (8.9 g, 0.1 mol) in toluene (400 mL) was added concentrated sulfuric acid (0.5 mL, 10 mmol). The mixture was refluxed and was concentrated by slow distillation to a volume to about 50 mL. The cooled mixture was filtered and the precipitate was washed with benzene and dried. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% methylenechloride) afforded [2-Cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-carbamic acid ethyl ester as a solid: LC-MS m/e calcd for C14H16N2O4 (MH+) 277, found 277. 1H NMR (300 MHz) compatible.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([C:12]#[N:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@@H:10]([CH2:12][NH2:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](CN)CN1C(=O)OC(C)(C)C

Procedure:
A solution (4S)-1-(tert-butyloxycarbonyl)-4-cyano-L-proline tert-butyl ester (470 mg, 1.59 mmol) in 90% ethanol (22 mL) was hydrogenated in the presence of 10% palladium-on-charcoal (225 mg) at 450 psi for 24 hours. The catalyst was removed by filtration through Celite, the filter washed with ethanol, and the combined filtrate and washings evaporated. Purification was achieved by flash silica gel chromatography eluting with 95:5:0.5 chloroform-methanol-ammonia; yield 284 mg (60%). 400 MHz 1H NMR (CD3OD): δ1.41-1.48 (3s, 18H); 1.58 (m, 1H); 2.28 (m, 1H); 2.48 (m, 1H); 2.66 (m, 2H); 3.05 (dd, 1H); 3.71 (dd, 1H); 4.12 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19]([C:20]([OH:22])=[O:21])[C:18]=1[OH:26]>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[C:18]([OH:26])=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2O)sc2ccc(Cl)cc12
Yield: 72 %

Procedure:
A solution of 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (17 mg, 0.060 mmol) and 3-aminosalicylic acid (14 mg, 0.090 mmol) in 1200 μL of water/dioxane (1:6) was shaken at 35° C. for 5 days. The product was purified by reversed phase chromatography (ACE C8, 4 μm, 21×50 mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 72% yield (17.2 mg). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.48 (s, 3 H) 6.85 (t, J=7.92 Hz, 1 H) 7.46 (dd, J=7.69, 1.64 Hz, 1 H) 7.55 (dd, J=8.66, 2.05 Hz, 1 H) 7.63 (dd, J=7.92, 1.64 Hz, 1 H) 8.00 (dd, J=2.05, 0.47 Hz, 1 H) 8.04 (dd, J=8.66, 0.47 Hz, 1 H) 10.17 (br. s., 1 H). MS (ESI+) m/z 398 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][CH2:14]OC>>[Cl:13][CH2:14][C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH:9]=[O:10]
Reactant: COCCl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Product: O=Cc1cc([N+](=O)[O-])c(CCl)cc1O

Procedure:
5-nitrosalicylaldehyde was obtained upon reaction of salicylaldehyde with nitric acid according to the method described by G. Miller in Chem. Ber., 20, 1928 (1888). This 5-nitrosalicylaldehyde was made to react with chloromethyl-methyl ether according to D. Taylor and B. Davis, J. Org. Chem., 28, 1713 (1963) to form 4-chloromethyl-5-nitro-salicylaldehyde, which was converted into the 4-hydroxymethyl derivative by refluxing the chloromethyl derivative for 3 hours in water. The 4-hydroxymethyl-5-nitro-salicylaldehyde had a melting point of 135°C.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[C:3]1[C:16]([F:17])=[C:15]([F:18])[C:6]([CH2:7][O:8]C2CCCCO2)=[C:5]([F:19])[C:4]=1[F:20].C(OCC)(=O)C.C(OCC)C>CO.Cl>[CH3:1][Si:2]([CH3:22])([CH3:21])[C:3]1[C:16]([F:17])=[C:15]([F:18])[C:6]([CH2:7][OH:8])=[C:5]([F:19])[C:4]=1[F:20]
Reactant: C[Si](C)(C)c1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: C[Si](C)(C)c1c(F)c(F)c(CO)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude tetrahydropyranyl ether prepared in Stage (i) was dissolved in methanol (20 cm3), and to the stirred solution was added concentrated hydrochloric acid (3 drops). After stirring for 16 hours at the ambient temperature (ca. 25° C.), the reaction mixture was poured into ethyl acetate, washed with water and brine, and dried. Evaporation of the solvent under reduced pressure gave a yellow oil which was subjected to column chromatography on silica gel using petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% gradually increased to 40% by volume) as eluent to give 4-trimethylsilyl-2,3,5,6-tetrafluorobenzyl alcohol (0.79 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>>[CH:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:22](=[O:23])[N:21]([CH3:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=S(=O)(NCCC1CCCCC1)c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(S(=O)(=O)NCCC2CCCCC2)cc1)c1ccccc1

Procedure:
The title compound was prepared from N-(2-cyclohexyl-ethyl)-4-hydroxy-benzenesulfonamide and N-methyl-N-phenyl carbamoylchloride, preparative HPLC (Method C) (14%, light yellow oil). HPLC-MS m/z=417.3 (M+1), Rt: 4.89 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12](=[O:16])[CH2:13][CH2:14][OH:15])[C:5]2=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-]>CN(C)C(=O)C.C(O)C.O.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].C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12](=[O:16])[CH2:13][CH2:14][OH:15])[C:5]2=[O:17]
Reactant: O=C(CCO)n1cnc2ccc(Br)cc2c1=O
Reactant: COc1cccc(Cl)c1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cccc(Cl)c1-c1ccc2ncn(C(=O)CCO)c(=O)c2c1
Yield: 24.3 %

Procedure:
To a solution of 6-Bromo-3-(3-hydroxy-propionyl)-3H-quinazolin-4-one (11.6 mg, 0.039 mmol) dissolved in 1 ml N,N-dimethylacetamide in a 20 ml vial, 2-chloro-6-methoxy-phenylboronic acid (14.55 mg, 0.078 mmol) dissolved in 0.5 ml ethanol and potassium carbonate (5.92 mg, 0.043 mmol) dissolved in 0.5 ml water were added. Triphenylphosphine (1 mg, 3.8 umol) and tris(dibenzylideneacetone)dipalladium (0) (0.7 mg, 0.78 umol) were added to the mixture which refluxed overnight. The crude product was poured into 5 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 3.4 mg product was obtained. Yield: 24.3%; 1H NMR (500 MHz, DMSO-d6): δ 2.75538–2.78226(t, J=6.835 Hz, 2H), 3.70334(s, 3H), 4.15877–4.18594 (t, J=6.785 Hz, 2H), 7.13724–7.15535 (dd, J1=8.68 Hz, J2=0.75 Hz, 1H), 7.18337–7.20169 (dd, J1=8.375 Hz, J2=0.885 Hz, 1H), 7.41001–7.44275 (dd, J1=8.215 Hz, J2=8.185 Hz, 1H), 7.66453–7.68523 (dd, J1=8.38 Hz, J2=2.0 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.96 (d, J=1.9 Hz, 1H), 8.41 (s, 1H); ESI-MS: m/z 359 (M++1)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C@@H:12]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[CH2:13][OH:14].C(N(CC)CC)C>ClCCl.O>[CH3:11][C@@H:12]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[CH:13]=[O:14]
Reactant: C[C@H](CO)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C=O)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A 2 M solution of oxalyl dichloride in dichloromethane (4.96 mL; 13.2 mmol) is diluted with dichloromethane (35 mL); is cooled to −70° C. and dimethylsulfoxide (0.94 mL; 13.2 mmol) is added. The resulting mixture is stirred for 20 minutes. The temperature is allowed to reach −60° C. and a solution of (S)-2-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propan-1-ol (2.0 g; 6.6 mmol, prepared in accordance with Example 65) in dichloromethane (20 mL) is added over 5 minutes. The resulting mixture is stirred at −60° C. for 2 hours before triethylamine (4.61 mL; 33.1 mmol) is added. After 10 minutes reaction time, the reaction mixture is allowed to slowly reach room temperature. The reaction is treated with water (100 mL), the organic layer is separated and is washed with water (2×100 mL) and concentrated to afford the desired product (1.99 g; 6.6 mmol). The crude product is engaged in the next step without further purification.
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:40](=[O:41])[C@H:39]([S:42][CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)=[O:45])[C@H:38]2[C:53]2[CH:67]=[CH:66][C:56]([O:57][CH2:58][C:59]([NH:61][CH2:62][C:63](O)=[O:64])=[O:60])=[CH:55][CH:54]=2)=[CH:33][CH:32]=1.[NH2:68][C:69]1([C:72]([OH:74])=[O:73])[CH2:71][CH2:70]1.[BH4-].[Na+]>CN(C=O)C.CO>[F:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[C:40](=[O:41])[C@H:39]([S:42][CH2:43][CH:44]([C:46]3[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=3)[OH:45])[C@H:38]2[C:53]2[CH:54]=[CH:55][C:56]([O:57][CH2:58][C:59]([NH:61][CH2:62][C:63]([NH:68][C:69]3([C:72]([OH:74])=[O:73])[CH2:71][CH2:70]3)=[O:64])=[O:60])=[CH:66][CH:67]=2)=[CH:35][CH:36]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)NC1(C(=O)O)CC1
Reaction time: 1 h

Procedure:
N-Methyl morpholine (0.037 g, 0.370 mmol) and TBTU (0.039 g, 0.120 mmol) were added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.025 g, 0.046 mmol) in DMF (2 ml) at 30° C. After 1 h, 1-aminocyclopropane carboxylic acid (0.019 g, 0.185 mmol) was added. After 1 h, the reaction was quenched by the addition of water (1 ml). After 10 minutes, MeOH (2 ml) and NaBH4 (0.035 g, 0.925 mmol) were added. Full conversion to the corresponding alcohol was obtained after 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml). The product was purified by preparative HPLC (eluent 0-50% CH3CN in 0.1M NH4OAc buffer). Freeze-drying of the pure fractions afforded the title compound (0.045 g, 78%) as a colourless solid. 1H NMR [(CD3)2SO), 400 MH] δ 0.78-0.88 (m, 2H), 1.08-1.22 (m, 2H), 2.84-2.94 (m, 2H), 3.63-3.72 (m, 2H), 4.24-4.29 (m, 1H), 4.48-4.52 (m, 2H), 4.68-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.96-7.37 (m, 12H), 7.78-8.36 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1c(C)cc(F)cc1C(C)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1c(C)cc(F)cc1C(C)=O
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 1-(5-Fluoro-2-methoxy-3-methylphenyl)ethanol (1.3 g 7.13 mmol) in acetone (15 mL) at room temperature was added pyridinium chlorochromate (3.8 g, 17.64 mmol). The reaction was stirred for 3 hours, diethyl ether was added (30 mL). The resultant sludge was filtered through celite. The organic phase was dried over Na2SO4, filtered over silica gel, and concentrated to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford 1-(5-fluoro-2-methoxy-3-methylphenyl)ethanone (1.2 g, 98%): 1H NMR (400 MHz, CDCl3): δ 7.18 (dd, 1H), 7.05 (dd, 1H), 3.63 (s, 3H), 2.61 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:22][OH:23])[CH2:20][CH3:21])=[C:15]([OH:24])[C:14]=1[CH2:25][CH2:26][CH3:27].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:22][O:23][C:33](=[O:35])[CH3:34])[CH2:20][CH3:21])=[C:15]([OH:24])[C:14]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc(C(CC)=NO)c1O
Reactant: CC(=O)OC(C)=O
Product: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc(C(CC)=NOC(C)=O)c1O

Procedure:
A solution of methyl 3-chloro-4-(3-(2-propyl-3-hydroxy-4-(1-hydroxyiminopropyl)phenoxy)propylthio)phenyl acetate (Step C; 5.96 grams) in acetic anhydride (50 mL) was stirred for 16 hours. The solvent was removed in vacuo. The remaining residue was dissolved in isopropyl acetate and washed with pH 7 buffer. The organic phase was dried over magnesium sulfate, filtered and evaporated. The title compound was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCCC1
Product: COc1ccc2c(c1)CCN(C1CCCCC1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 52.8 %

Procedure:
The title compound was prepared as described in Example 14. C, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.5 g, 1.39 mmol) and cyclohexanone (0.588 g. 6.0 mmol) to provide the title compound (0.324 g, 53% yield): ES-MS (m/z) 442 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:8]([CH3:14])=[N:9][N:10]([CH3:13])[C:11]=1[CH3:12])C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:13][N:10]1[C:11]([CH3:12])=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[C:8]([CH3:14])=[N:9]1
Reactant: CCOC(=O)CCc1c(C)nn(C)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1CCC=O
Temperature: -78 °C

Procedure:
Dissolve 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-propionic acid ethyl ester (1.94 g, 9.23 mmol) in tetrahydrofuran (78 mL). Cool to −78° C. in a dry ice/acetone bath and treat dropwise with 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for one hr. and add 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for one hr. and add 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for 1 hr. and add 1 M diisobutylaluminum hydride in toluene (10.15 mL). Stir reaction mixture at −78° C. for 1 hr. and quench with aqueous saturated potassium sodium tartrate tetrahydrate solution. Add ethyl acetate (150 mL), and stir for 3 hr. at room temperature. Separate organic layer, extract aqueous layer 3 times with ethyl acetate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 1:1 to 100% ethyl acetate:hexanes), to give the title preparation (760 mg, 51%). GC-MS m/z=166 [M+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:38]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:37])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH2:35][CH3:36])[C:20]=2[N:21]2[CH2:27][CH2:26][CH2:25][CH:24]([NH:28]C(=O)C(F)(F)F)[CH2:23][CH2:22]2)[N:13]=1.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[NH2:38][C:11]1[S:10][C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH2:35][CH3:36])[C:20]=1[N:21]1[CH2:27][CH2:26][CH2:25][CH:24]([NH2:28])[CH2:23][CH2:22]1)=[O:37]
Reactant: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(NC(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC(N)CC1
Temperature: 60 °C
Reaction time: 40 h
Yield: 98.3 %

Procedure:
A solution of tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.17 g, 0.26 mmol) in HCl in 1,4-dioxane (4 M, 5 mL) was allowed to stand at room temperature for 40 hr. The reaction mixture was concentrated under reduced pressure and the residue dissolved in 50% aqueous MeOH (20 mL). K2CO3 (1.22 g, 8.84 mmol) was added and the mixture heated at 60° C. for 3 hr. The mixture was allowed to cool, concentrated to approximately 5 mL and extracted with DCM. The combined organic layers were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue by passing through an SCX column washing with DCM and MeOH and eluting with 1 N ammonia in MeOH gave 241 as a cream solid (118 mg, 99%). 1H-NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.92 (s, 1H), 7.36-7.28 (m, 1H), 7.06-6.97 (m, 2H), 6.14 (s, 2H), 4.05 (q, J=7 Hz, 2H), 3.29-3.12 (m, 5H), 2.02-1.88 (m, 3H), 1.75-1.60 (m, 3H), 1.43 (t, J=7 Hz, 3H). RNH2 not seen. LCMS (ES+) m/z 462.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:4].[H][H]>O1CCOCC1.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(C(=O)O)cc1

Procedure:
8 g (38.8 mmol) of 4-(2-methoxycarbonylvinyl)benzoic acid (step a) were suspended in 250 ml of dioxane and hydrogenated under 1 bar of hydrogen over palladium/charcoal (10%) at room temperature for 7 h. The mixture was filtered and the solvent was evaporated in vacuo. Yield: 8.05 g (100%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH2:23])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>>[NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH:23][C:37]([NH:36][C:27]4[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=4[F:25])=[O:38])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Product: Nc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c4ccccc34)c2[nH]c1=O
Yield: 38 %

Procedure:
Method F2 was used with 3-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a yellow/orange solid (31 mg, 38%).