Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Li].C([Li])CCC.BrC1C=CC=CC=1C(F)(F)F.[OH:28][C:29]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:30]=1[C:36](=[O:39])[CH2:37][CH3:38].[Cl-].[NH4+]>CCOCC>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:36]([C:30]1[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:29]=1[OH:28])([OH:39])[CH2:37][CH3:38]
Reactant: [Li]c1ccccc1C(F)(F)F
Reactant: CCC(=O)c1ccc(O)cc1O
Agent: FC(F)(F)c1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCC(O)(c1ccc(O)cc1O)c1ccccc1C(F)(F)F
Temperature: 0 °C

Procedure:
To 2-trifluoromethylphenyl-lithium prepared from 18.9 g. of n-butyl-lithium and 65.2 g. of 2-bromobenzotrifluoride in 480 ml. of dry ether, a solution of 8.3 g. of 2',4'-dihydroxy-propiophenone in 85 ml. of dry ether is added dropwise, with stirring at a temperature between 0° C. and -5° C. The reaction mixture is stirred at room temperature for further two hours. After cooling the mixture is poured onto a 10% solution of ammonium chloride in ice water. The phases are separated and the aqueous phase is extracted with ether. The organic phase is washed to neutral with water, dried over anhydrous magnesium sulfate, decolored with activated carbon, filtered, and ether is distilled off under reduced pressure. As a residue 15 g. of an oily product are obtained, which is then chromatographed on a silica gel column by elution with dichloromethane. Dichloromethane is then distilled off under reduced pressure, and the solid residue is crystallized from a mixture of n-hexane and ethyl acetate to yield 6.9 g. of the named compound, melting at 143° to 144° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([F:19])[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.O>[F:7][C:8]1([F:19])[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: OCC1CCC(F)(F)CC1
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.24 g) was slurried in diethyl ether (15 mL), ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g) in diethyl ether (2 mL) was added dropwise, and the reaction was stirred under reflux under nitrogen for 4 hours. The reaction was cooled to 0° C., followed by the careful addition of water (0.24 mL), 4N aqueous NaOH (0.24 mL), and water (0.72 mL). Na2SO4 and diethyl ether (40 mL) were added and the mixture was stirred at room temperature for 30 minutes. Filtration through diatomaceous earth and concentration of the filtrate provided the title compound which was used without purification.
Reaction SMILES: [OH-].[Na+].[C:3]1(C)[CH:8]=CC=[CH:5][CH:4]=1.[C:10]([N:14]1[CH:18]([NH2:19])[CH:17]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[C:16](=[O:28])[NH:15]1)([CH3:13])([CH3:12])[CH3:11]>O>[C:10]([N:14]1[CH:18]([NH2:19])[CH:17]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[C:16](=[O:28])[N:15]1[CH:3]([CH2:4][CH3:5])[CH3:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)N1NC(=O)C(c2c(Cl)cccc2Cl)C1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)N1C(=O)C(c2c(Cl)cccc2Cl)C(N)N1C(C)(C)C
Temperature: 100 °C
Yield: 31 %

Procedure:
To 160 mg of sodium hydroxide (60% oil dispersion) were added 30 ml of toluene and 1.00 g of 1-tert-butyl-4-(2,6-dichlorophenyl)-5-amino-pyrazolin-3-one, and the mixture was heated for 2 hours at 100° C. To this was added 550 ml of isopropyl mathanesulfonate, and the mixture was heated for additional 3 hours at 100° C. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate anhydride, then, the solvent was distilled off under reduced pressure. The residue analyzed by 1H-NMR on the ratio of N-alkyl compound to O-alkyl compound being 31 to 69 was applied to column chromatography to obtain 353 mg (yield: 31%) of 1-tert-butyl-2-sec-butyl-4-(2,6-dichlorophenyl)-5-aminopyrazolin-3-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OCC)(C)[CH3:17]>C(O)C>[CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH2:16][CH3:17])=[O:13]
Reactant: CCOC(=NC(C)C)NC(C)C
Reactant: CC1(C)[C@H](/C=C2\CCOC2=O)[C@H]1C(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1[C@@H](/C=C2\CCOC2=O)C1(C)C
Yield: 56.6 %

Procedure:
Using the procedure of Example 17, 7.8 g of (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid and 7 g of ethyl N,N'-diisopropylcarbamimidate were reacted to obtain 5 g of ethyl (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+50°±2° (c=0.5% in ethanol).
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:19]=1[C:20]([N:8]1[C:9](=[O:10])[C:4]2=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]1=[O:7])=[O:21]
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1cc(Cl)cc(Cl)c1Cl)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(2,3,5-trichlorobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:22]=3)=[N:18][N:17]=2)=[CH:11][C:10]=1[CH2:34][CH3:35])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH:29]1([C:23]2[CH:22]=[C:21]([C:19]3[O:20][C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([OH:8])=[C:10]([CH2:34][CH3:35])[CH:11]=4)=[N:17][N:18]=3)[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
Pd/C (150 mg, 10% Pd) is added to a solution of 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-2-cyclopentyl-6-methoxy-pyridine (750 mg, 1.60 mmol) in THF (20 mL) and methanol (20 mL). The mixture is stirred under 1 bar of H2 at rt for 24 h. The catalyst is removed by filtration and the filtrate is concentrated and dried to give 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-phenol (495 mg) as a white solid; LC-MS**: tR=0.91 min, [M+H]+=380.25; 1H NMR (D6-DMSO): δ 1.20 (t, J=7.5 Hz, 3H), 1.65-1.74 (m, 2H), 1.76-1.88 (m, 4H), 1.99-2.09 (m, 2H), 2.29 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 7.26 (d, J=1.0 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([N+:12]([O-:14])=[O:13])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([CH3:1])([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:5][CH:6]=1)[CH3:16]
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A mixture of 4-(2-methyl-2-nitropropyl)phenol (3.0 g, 15.4 mmol), ethylbromoacetate (2.04 mL, 17.0 mmol) and potassium carbonate (6.4 g, 46.2 mmol) was stirred at room temperature for 18 h. The reaction was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (3×). The combined organic layers were washed with water (3×), brine, dried (Na2SO4), and concentrated in vacuo to a brown oil. The material was purified by flash chromatography over silica gel eluting with 5% MeOH/CHCl3 to provide 4.22 g (97%) of a clear oil. NMR
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:29][C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:29][C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(CN(C(=O)OC(C)(C)C)c2cccc(Br)n2)CCOCC1
Yield: 45.9 %

Procedure:
To a solution of tert-butyl 6-bromo-pyridin-2-ylcarbamate (136 mg, 0.50 mmol) in DMF (2 ml) under nitrogen was added NaH (60%, 40 mg, 1.0 mmol) under stirring. The resultant mixture was stirred at room temperature for one hour. A solution of (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate O, 152 mg, 0.506 mmol) in DMF (1.5 ml) was then added. The resulting mixture was then stirred at 85° C. for about 18 hours. The mixture was diluted with 30 ml of ethyl acetate, washed with water (20 ml×3) and dried with sodium sulfate. After concentration the residue was purified by silica gel chromatography using a 12 g column, eluting with 5-20% ethyl acetate in hexane to give the desired title compound as a viscous oil (92 mg, 46% yield), which solidified upon standing overnight. LCMS (m/z): 403.1[M+H]+; Rt=1.026 min.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)(=O)C.O=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]1[NH:4][CH2:3][CH2:1][O:2]1
Reactant: NCCO
Reactant: O=CC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)C1NCCO1

Procedure:
To a 2 liter 3-necked flask equipped with a stirrer, Dean-Stark trap, a condenser and dropping funnel were added 214 g (3.51 moles) ethanolamine and 450 g. toluene. Then 273 g (4.55 moles) of glacial acetic acid were added slowly to keep the temperature (cooling if necessary) at 30°-45° C. Then 568 g (3.85 moles) of chloral were added at 40°-50° C. The reaction mixture was refluxed to remove water and, when complete, the temperature increased to 115°-120° C. The reaction mixture was cooled in an ice bath and the product precipitated after standing for several hours to give 189.5 g (28.5%) m.p. 72°-74° C. The filtrate was washed with 5.0 moles of 20% sodium hydroxide and more product precipitated. Filtration and drying yielded 228.5 g (34.3%), m.p. 73°-75° C. The toluene layer was washed with water and evaporated to give a solid. Washing with water and filtration yielded upon drying 328 g. (49.2%), m.p. 62°-72° C. for a total yield of 556.0 g (83.5%). The analysis was consistent with the assigned structure.
Reaction SMILES: N#N.[CH3:3][N:4]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[C:11]([Cl:16])[C:10]([C:17]([F:20])([F:19])[F:18])=[CH:9][C:8]=1[NH2:21])[CH3:5].[N+]([C:25]1C=C(C(F)(F)F)C=C([N+]([O-])=O)[C:30]=1NN)([O-])=O>[Pd].C(O)C>[NH2:13][C:12]1[C:7]2[N:6]([N:4]([CH3:5])[CH3:3])[C:25]([CH3:30])=[N:21][C:8]=2[CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[C:11]=1[Cl:16]
Reactant: NNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN(C)Nc1c(N)cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: Cc1nc2cc(C(F)(F)F)c(Cl)c(N)c2n1N(C)C

Procedure:
A solution of 5.2g. of N2 -(dimethylamino)-4-chloro-3-nitro-5-trifluoromethyl-1,2-phenylenediamine (prepared by hydrogenation of the corresponding 3,5-dinitro-4-hydrazinobenzotrifluoride in the presence of palladium catalyst) and 7.5g. of ethyl methylcarboximidate hydrochloride in 60 ml. of ethanol was refluxed for 26 hours. The resultant 7-nitrobenzimidazole was separated by fractionation on a silica gel column and then hydrogenated in the presence of platinum oxide catalyst in dimethoxyethane-methanol to give the desired product (2.8g.) m.p. 173°-174°C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[NH:32][C:26]3=[N:27][CH:28]=[C:29]([F:31])[CH:30]=[C:25]3[CH:24]=2)=[CH:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2]>[Pd].CO>[CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:23]2[NH:32][C:26]3=[N:27][CH:28]=[C:29]([F:31])[CH:30]=[C:25]3[CH:24]=2)[CH2:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:2]
Reactant: CCOCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOCCS(=O)(=O)c1ccc(C(CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 58.3 %

Procedure:
A mixture of 2-[1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (250 mg, 0.54 mmol) and 10% palladium on activated carbon (74 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% dichloromethane/ethyl acetate) afforded 2-[1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-ethyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (145 mg, 57%): LC/MS m/e calcd for C24H29FN2O4S [M+H]+ 461.57, observed 461.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:36]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:34])[N:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH3:26])=[O:17])=[CH:11][C:10]=1[F:35].CO.Cl.[OH-].[Na+]>CC(OC)(C)C.O>[NH2:36][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:34])[N:20]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[O:24][CH2:25][CH3:26])=[O:17])=[CH:11][C:10]=2[F:35])[CH:6]=[CH:5][N:4]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(N)c2Cl)c(F)c1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 40.7 %

Procedure:
To a 250 mL vessel, N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (100.0 g, 147.7 mmoles, 1.0 eq) and methanol (900 mL) were charged. The white slurry was cooled to 10° C. and concentrated HCl (16.3 g, 163.3 mmoles, 1.105 eq) was added, maintaining the reaction temperature below 10° C. The reaction mixture was held at 10° C. for approximately 2.5 h, until HPLC indicated ≦0.5 relative area percent of starting material. Water (500 mL) and MTBE (500 mL) were added and the reaction mixture was warmed to 20° C. Next, 1N NaOH (184.08 g, 177.0 mL, 177 mmoles, 1.20 eq), was added dropwise over 20 minutes while maintaining the temperature between 15 and 20° C. The resulting slurry was cooled to 10° C. and aged for at least 10 minutes. The precipitate was filtered off, and the cake washed with water (2×350 mL), followed by a mixture of methanol:MTBE (10:90) (1×300 mL). Next, the cake was dried in a vacuum oven at 50-60° C. until LOD analysis indicated less than 1 wt % of volatiles. N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide: 79.5 g (95% yield with 98.1 AP and 99.4 wt % potency). The resulting product (35.0 g) was subsequently re-crystallized from THF (367.2 mL)/EtOH (200 proof, 244.8 mL)/n-heptane (350 mL) to obtain N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30.8 g) in 88% yield with >99.9 AP and 99.7 wt % potency.
Reaction SMILES: [CH3:1][N:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH2:5][C@H:4]([NH:15]C(=O)OCC2C=CC=CC=2)[C:3]1=[O:26]>[OH-].[OH-].[Pd+2].CCO>[NH2:15][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:2]([CH3:1])[C:3]1=[O:26]
Reactant: CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)CC=C[C@H]1c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)[C@@H](N)CCC[C@H]1c1ccccc1
Yield: 90 %

Procedure:
A mixture of benzyl [(3S,7S)-1-methyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (2c) (216 mg) and Pearlman's catalyst (40 mg) in EtOH (7 mL) was hydrogenated at 45 psi overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3, brine, dried (Na2SO4), filtered and concentrated to a viscous oil. The aqueous layer from above were extracted 3×50 ml DCM. The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to a viscous oil (60 mg). The two isolated oils were combined to give a 90% yield of the desired product. 1H NMR (300 MHz, CDCl3) δ 1.57-2.12 (m, 9H), 2.53 (s, 3H), 4.92 (d, 1H), 7.26-7.41 (m, 5H). APCI, m/z=219 (M+1). LC/MS 1.82 min., Method A
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH:12]1([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([OH:23])[C:16]=2[F:24])[CH2:14][CH2:13]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:22]1[C:15]([CH:12]2[CH2:13][CH2:14]2)=[C:16]([F:24])[C:17]([OH:23])=[C:18]([CH:21]=1)[CH:19]=[O:20]
Reactant: O=Cc1ccc(C2CC2)c(F)c1O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(C2CC2)c(F)c1O
Reaction time: 3 h
Yield: 134 %

Procedure:
Dibromoisocyanuric acid (1.43 g) was added at room temperature to a DMF (50 mL) solution of 4-cyclopropyl-3-fluoro-2-hydroxybenzaldehyde (1.50 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.73 g)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[NH:8][C@@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@H:6]3[C:5]=2[CH:4]=1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[OH:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9](=[O:14])[NH:8][C@@H:7]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@H:6]3[C:5]=2[CH:4]=1
Reactant: COc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(O)cc2c1C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 160 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a solution of (±)-trans-tert-butyl 8-methoxy-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 72, Part C (0.43 g, 1.29 mmol) in 8 mL of N-methylpyrrolidinone was added thiophenol (0.15 mL, 1.42 mmol) and potassium carbonate (27 mg, 0.19 mmol). The resulting mixture was stirred in a sealed vial at 160° C. for 4 h. The solution was allowed to cool and was partitioned between ether and 1N NaOH. The aqueous layer was washed with ether. The combined organic layers were discarded. The aqueous layer was acidified with 12 N HCl, whereby a solid precipitated out of solution. The mixture was filtered and the solid washed with water and dried in vacuo to afford 0.26 g (65%) of the title compound as an off-white solid. LRMS (ESI): 319.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:9]2=[N:10][CH:11]=[CH:12][N:13]=[C:8]2[C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:5])C.[OH-].[Na+].Cl.[Na+].[Cl-]>C1COCC1.C(O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][N:13]=3)[C:14](=[O:17])[N:15]([CH3:16])[C:6]=2[C:4]([OH:5])=[O:3])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c2nccnc2c(=O)n1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(C(=O)O)c(-c2ccc(F)cc2)c2nccnc2c1=O
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of the compound (1.10 g) obtained in Step 3, ethanol (25 ml), THF (25 ml) and 1N-NaOH (13 ml) was stirred for one hour under reflux. The reaction mixture was cooled, to which was added dilute HCl to adjust the pH to 3-4. The mixture was saturated with NaCl, followed by extraction with ethyl acetate. The extract solution was dried, then the solvent was distilled off to leave the above-titled compound as colorless crystals (0.93 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[S:8][CH:9]=1)=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 117.2 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (prepared as in Example 26, 60.0 mg, 0.14 mmol) in ethyl acetate (25 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 4.5 h. The catalyst was then filtered off through a pad of celite, which was washed well with ethyl acetate. The resulting filtrate was concentrated in vacuo to give 2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (61.3 mg, 100%) as a pale yellow oil: EI-HRMS m/e calcd for C19H23N3O3S (M+) 373.1460, found 373.1454.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]=1[O:10]C)([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)C)C=1OC)C=O)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC>C(OCC)C.CCCCCC>[CH3:20][O:19][C:17](/[CH:16]=[CH:15]/[C:6]1[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)=[O:18]
Reactant: COC(=O)C=Cc1cc(C(C)C)c(OC)c(C(C)C)c1
Agent: COc1c(C(C)C)cc(C=O)cc1C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)/C=C/c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 50 °C

Procedure:
Methyl 3-(3,5-diisopropyl-4-methoxyphenyl)acrylate. 3,5-diisopropyl-4-methoxybenzaldehyde (881 mg) free powder. Ph3P═CHCOOCH3 (1.7 g) was added, followed by 10 mL of hexane. The reaction mixture was heated at 50° C. for 24 hours, and the resulting mixture was loaded on a silica-gel column. Chromatography, with diethyl ether:hexane (10:90) as the eluent, provided the ester (944 mg).