Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:39]([N:16]1[CH2:15][C:14]([CH3:28])([CH3:27])[C:13]2[N:12]=[C:11]([CH:29]([CH3:31])[CH3:30])[C:10]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:18]=2[CH2:17]1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)c1ccccc1)CC2(C)C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a stirred turbid mixture of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (0.0105 g, 0.025 mmol) and Et3N (0.017 ml, 0.123 mmol) in CH2Cl2 (2 mL) was added benzoyl chloride (8.53 μl, 0.074 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-(6-benzoyl-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (0.0102 g, 77% yield) as a white powder. 1H NMR (500 MHz, CD3OD) δ ppm 6.94-7.58 (9H, m), 4.79 (1H, br. s.), 4.59 (0.5H, d, J=17.4 Hz), 4.40 (0.5H, d, J=17.7 Hz), 4.30 (0.5H, d, J=16.5Hz), 4.00 (0.5H, d, J=12.5 Hz), 3.92 (0.5H, d, J=16.5Hz), 3.77 (0.5H, d, J=12.8 Hz), 3.54-3.64 (2H, m), 1.43 (3H, d, J=19.2 Hz), 1.12-1.35 (9H, m), 0.98 (4H, br. s.), 0.94 (5H, br. s.). LCMS (M+H) calcd for C32H38FN2O4: 533.28. found: 533.4.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[OH-].[NH4+:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH2:29])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Example 5, Step F) (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (36 mg), with a melting point above 255° C.
Reaction SMILES: Cl.N=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](OCC)=O.[NH2:15][CH:16]([C:20]([NH2:22])=[O:21])[C:17]([NH2:19])=[O:18]>CO>[CH2:3]([C:4]1[NH:19][C:17]([OH:18])=[C:16]([C:20]([NH2:22])=[O:21])[N:15]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)C(=N)c1ccccc1
Agent: Cl
Solvent: CO
Product: NC(=O)c1nc(Cc2ccccc2)[nH]c1O
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a chilled solution of ethyl iminophenylacetate hydrochloride (5.99 g) in anhydrous methanol (80 ml) was added aminomalonamide (3.51 g). The mixture was stirred for 1 hour at 0°-5° C. and then 3 hours under reflux. After cooling the mixture to 0°-5° C., the precipitated product was filtered and washed with ethanol, isopropylether to give 2-benzyl-5-hydroxy-1H-imidazole-4-carboxamide (4.52 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[S:27][C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1.O>N1C=CC=CC=1>[CH3:25][C:26]1[S:27][C:28]([S:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=2[CH3:24])[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(C)c(S(=O)(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in pyridine (4.0 mL) was added 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (157 mg, 0.74 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) and washed with hexane/ethyl acetate to give the title compound (196 mg, 64%) as a white powder.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1.O.[H][H]>[OH-].[Na+].[Pd]>[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccc2c(c1)OCO2
Yield: 97 %

Procedure:
To a solution of 10.0 g of 3,4-methylenedioxycinnamic acid dissolved in 130 ml of 10% NaOH and 80 ml of distilled water was added 1.0 g of 5% Pd-C. This mixture was reacted at 40 psi until the consumption of hydrogen gas was ceased and then filtered through a Celite layer. The filtrate was acidified with concentrated hydrochloric acid, allowed to be cooled and filtered to give solids. The obtained solids were washed twice with 100 ml of cold water and dried to provide 9.8 g(yield 97%) of 3-(3,4-methylenedioxyphenyl) propanoic acid, having the characteristics of: NMR(CDCl3, 200 MHz) δ2.62(t, J=7 Hz, 2H, CH2), 2.88(t, J=7 Hz, 2H, CH2N), 5.93(s, 2H, CH2O2), 6.63-6.76(s, 3H, ArH).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:18])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:41]S(C2C=CC=CC=2)(=O)=O)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:29]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:28]=1)#[N:26]>O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH2:41][C:13]2[C:14](=[O:17])[CH2:15][CH2:16][C:12]=2[NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]([F:18])[F:3])[CH:6]=2)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[C:29]([S:51]([CH3:54])(=[O:52])=[O:53])[CH:28]=1)#[N:26]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Reactant: O=C1C=C(Nc2cccc(C(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)F)c2)CCC1=O)c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 106 mg, 2.67 mmol) is added in portions to a mixture of 3-(3-(difluoromethyl)phenylamino)cyclopent-2-enone (intermediate 5, 595 mg, 2.66 mmol) and 2-methyltetrahydrofuran (20 mL). After 2 h tert-butyl (4-cyano-2-(methyl-sulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (intermediate 15, 1.00 g, 2.20 mmol) is added, and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with 2-methyltetrahydrofuran. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 665 mg; ESI mass spectrum [M+H]+=532; Retention time HPLC: 1.13 min (Z018_S04).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6]CC)=O.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18].[Na]>CO>[C:17]([CH:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[CH3:13])[C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:10][CH2:11][CH3:12])=[O:9])#[N:18]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccccc1CC#N
Agent: [Na]
Solvent: CO
Product: CCOC(=O)CCC(=O)C(C#N)c1ccccc1C
Reaction time: 16 h

Procedure:
Diethyl succinate (510 g.) and 2-methylbenzyl cyanide [prepared according to the method of Meisenheimer et al, Ann. 468, 217 (1929); 155 g.] were added to a solution of sodium (42 g.) in dry methanol (585 ml.) at ambient temperature. The mixture was heated under reflux, with stirring, for 16 hours and excess methanol was then removed by distillation under reduced pressure. The residue was dissolved in a mixture of toluene (500 ml.) and water (2000 ml.). The aqueous layer was separated, acidified with concentrated sulphuric acid (50 ml.) and extracted with diethyl ether (3 × 800 ml.). The ethereal extract was washed with water, dried over sodium sulphate and evaporated to dryness to give ethyl 5-cyano-4-oxo-5-(2-methylphenyl)pentanoate (305 g.) in the form of a dark coloured oil.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>O>[CH3:6][N:7]([CH2:14][CH2:15][O:16][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
In a 2l three necked, round bottom flask, 500 ml dimethylformamide is added, followed by addition of 100 g of 2-(N-methyl-N-(2-pyridyl)amino)ethanol (II) and 100 g of 4-fluorobenzaldehyde (III) was added to the reaction mixture and it was stirred for 10 minutes at room temperature and 80 g of potassium tertiary butoxide was added to the reaction mixture. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 5-10° C. and under the cold conditions, 1.5 l of water was added and stirred for 15 min. The mixture was extracted with 4×500 ml of ethyl acetate. The combined organic layer was washed with 3×1 l water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 148 g (88%) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzaldehyde (IV).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][CH3:27])=[CH:22][CH:23]=1>>[CH2:24]([C:21]1[S:20][C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:23][CH:22]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1ccc(Br)s1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: CCCCc1ccc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)s1

Procedure:
rac-3,4-Dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2,3 g (10 mmol) was reacted with 2.4 g (11 mmol) of 2-bromo-5-butylthiophene under the conditions described in Example 15. Chromatography of the crude product over 100 g of silica gel and crystallization from petroleum ether yielded colorless crystals with m.p. 80°-82°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)=[CH:11][C:10]=1[CH2:21][C:22](OC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:20])[O:16][CH2:17][CH2:18][O:19]2)=[CH:11][C:10]=1[CH2:21][CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cc(C2(C)OCCO2)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(c2ccc(OCc3ccccc3)c(CCO)c2)OCCO1
Yield: 108.9 %

Procedure:
Methyl 2-[2-benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]acetate (9.0 g) was dissolved in 130 ml of diethyl ether, 1.0 g of lithium aluminum hydride in small portions was added to the solution with stirring under ice-cooling, and the mixture was subjected to 1 hour of reaction. Water was added in small portions to the reaction solution with stirring under ice-cooling, and the formed precipitates were removed by filtration. By concentrating the resulting filtrate under reduced pressure, 9.0 g of 2-[2-benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethanol was obtained in an oily form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:20][CH2:19][O:18][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Amine preparation: To 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.5 g) in dry DMF (15 mL) was added sodium hydride (447 mg). After stirring for 2 hrs at room temperature, 2-bromoethyl methyl ether (0.7 mL) was added. The reaction mixture was heated to 40° C. overnight, and then diluted with ethyl acetate, washed with water and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(2-methoxy-ethoxy)-piperidine-1-carboxylic acid tert-butyl ester (447 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([O:30][CH3:31])=[CH:21][C:22]([O:28][CH3:29])=[C:23]([N:25]=[C:26]=[O:27])[CH:24]=1>C(#N)C>[Cl:18][C:19]1[C:20]([O:30][CH3:31])=[CH:21][C:22]([O:28][CH3:29])=[C:23]([NH:25][C:26](=[O:27])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[CH:6][CH:7]=2)[CH:24]=1
Reactant: Nc1ccc(NC(=O)c2ccccc2F)cc1
Reactant: COc1cc(OC)c(N=C=O)cc1Cl
Solvent: CC#N
Product: COc1cc(OC)c(NC(=O)Nc2ccc(NC(=O)c3ccccc3F)cc2)cc1Cl
Reaction time: 12 h

Procedure:
A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) in acetonitrile (4 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes a solution and is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.79 g). [M+H]444.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:7]1=[O:21])=[O:4].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CC(O)=O.[Pd]>[C:24]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:23])([F:22])[F:1])[C:7]2=[O:21])=[CH:13][CH:14]=1)(=[O:26])[CH3:25]
Reactant: O=C1[C@@H](NC(=O)C(F)(F)F)CCN1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CN2CC[C@H](NC(=O)C(F)(F)F)C2=O)cc1
Reaction time: 4.5 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-acetamide (0.75 g, 2.27 mmol) in AcOH (12 mL) is added acetic anhydride (1 mL) and a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is hydrogenated at room temperature on a Parr apparatus under 70 p.s.i. of H2. After 4.5 h, the reaction mixture is filtered through a pad of Celite, washed with CH2Cl2 and then MeOH. The crude product is concentrated in vacuo to yield 1.2 g of crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide as a residue (wet with HOAc). A solution of the crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide (1.2 g, wet with AcOH) in AcOH (12 mL) is cooled at 0° C. and acetic anhydride (1 mL) is added. The resulting mixture is treated with a catalytic amount of NaNO2, followed by the dropwise addition of fuming HNO3(3.8 mL). The reaction mixture is stirred at 0° C. for 1.5 hours, then at room temperature for 1.5 hours. Upon re-cooling to 0° C., a mixture of ice/ice water is added slowly with stirring. The mixture is diluted further with water and extracted with EtOAc (3×50 mL). The combined organic layers are washed twice with water. The organic phase is dried over anhydrous MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to provide the title compound (0.65 g, 1.67 mmol) as a beige solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]([NH2:8])=S)=[O:5].[CH:9]([NH:11][NH2:12])=[O:10]>>[CH2:2]([O:3][C:4](=[O:5])[C:6]([N:11]([CH:9]=[O:10])[NH2:12])=[NH:8])[CH3:1]
Reactant: CCOC(=O)C(N)=S
Reactant: NNC=O
Product: CCOC(=O)C(=N)N(N)C=O
Temperature: 65 °C
Yield: 76.3 %

Procedure:
A mixture of ethyl thioxamate (10.55 g, 79.2 mmol) and formylhydrazine (5.00 g, 83.2 mmol) was heated at 65° C. for 30 minutes and stirred in accordance with a method described in Collect. Czech Chem. Commun., 1984, 49, p 2492. After cooling, the precipitated crystal was collected by filteration and washed with ethanol to give (N-formylhydrazino)-imino acetic acid ethyl ester (9.62 g). Yield: 76%.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([O:20][CH2:21][CH:22]=[CH2:23])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7](Cl)[CH:6]=1)(=[O:3])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(#N)C>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([O:20][CH2:21][CH:22]=[CH2:23])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CCNC1
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(Cl)cc(NC(C)=O)c(c23)C1=O
Solvent: CC#N
Product: C=CCON1C(=O)c2ccc(Cl)c3c(N4CCCC4)cc(NC(C)=O)c(c23)C1=O
Yield: 78.5 %

Procedure:
A near solution of 4-acetylamino-2-allyloxy-6,7-dichlorobenzo[de]isoquinoline-1,3-dione (0.3 g, 0.8 mmol, from Example G4), pyrrolidine (0.16 g, 2.2 mmol), and 15 mL of acetonitrile was heated from room temperature to reflux over 0.5 hour. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with water, dried, and evaporated in vacuo to give 0.26 g of the title compound.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[O:15])=[O:7])[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[O:15])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CCCNC(N)=O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
To a room temperature solution of Fmoc-Val-Cit (2.18 g, 4.4 mmol, U.S. Pat. No. 6,214,345 to Firestone et al.) in anhydrous DMF (10 mL) was added DEA (10 mL). The reaction mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated in vacuo to thick oil, and then was added drop wise to a flask containing diethyl ether (˜500 mL) to precipitate the crude product. The white precipitate was collected by filtration and washed with ethyl acetate (2×250 mL). After drying material in vacuo, it was dissolved in DMSO (30 mL), and maleimidocaproic acid-N-hydroxysuccinimide ester (1.42 g, 1.05 eq, Molecular Biosciences, Inc., Boulder Colo.) was added, followed by the addition or DIEA (0.843 mL, 1.1 eq). The reaction mixture was stirred ˜6 h, the DMSO solution was concentrated in vacuo to a volume of ˜2 mL. Product was purified on a semi-preparative HPLC system (stationary phase: C12, mobile phase: 0.1% TFA/H2O/MeCN) to give 1.19 g (2.55 mmol, 58% yield). ES-MS m/z 468.23 [M+H]+. 1H NMR (d6-DMSO) □: 8.15 (d, J=7.2 Hz, 1H), 7.75 (d, J=9.2 Hz, 1 H), 7.00 (s, 1 H), 5.93 (br s, 1 H), 5.38 (br s, 1 H), 4.21 (dd, J1=6.8 Hz, J2=2.148, 1 H), 4.1 (m, 1 H), 2.94 (br s, 2 H), 2.22-2.05 (m, 2 H), 1.93 (q, J=6.8, 1 H), 1.68 (m, 1 H), 1.6-1.2 (m, 7 H), 1.17 (t, J=7.6, 2 H), 0.86-0.80 (dd, J1=6.8 Hz, J2=9.0, 6 H).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: OB(O)c1ccccc1F
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccccc3F)c2s1
Temperature: 80 °C
Yield: 23 %

Procedure:
A stirred mixture of 1-(7-Bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (50 mg, 0.133 mmol), 2-fluorobenzeneboronic acid (19 mg, 0.139 mmol), powdered potassium phosphate tribasic (34 mg, 0.160 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride complex (16 mg, 0.01995 mmol) in anhydrous 1,4-dioxane (1 ml) and anhydrous methanol (2 ml) was purged with nitrogen for 5 min and heated in a sealed vessel for 16 h at 80° C. After cooling to ambient temperature, the mixture was filtered through kieselguhr. The kieselguhr was thoroughly washed with methanol and the combined filtrates evaporated to dryness in vacuo to give the crude 1-Ethyl-3-[7-(2-fluoro-phenyl)-5-pyridin-3-yl-benzothiazol-2-yl]-urea which was purified by “flash” silica chromatography eluting with 0 to 30% methanol in ethyl acetate. 12 mg of a pale-brown solid was obtained.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cc[nH]n1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that of Example 2 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 7.1) and (1H-pyrazol-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 1) tR=1.89 min, m/z=448.0 [M+H]+, m/z=446.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.64 (m, 1H) 1.77-1.90 (m, 1H) 2.15-2.28 (m, 1H) 3.03 (dd, J=11.25, 6.85 Hz, 1H) 3.22 (br. s, 2H) 3.25-3.31 (m, 2H) 3.34-3.39 (m, 1H) 4.62 (br. s, 1H) 6.39 (br. s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.51-7.84 (m, 1H) 7.83-7.90 (m, 2H) 8.03 (s, 1H) 8.68-8.79 (m, 1H) 10.19 (s, 1H) 12.87-13.12 (m, 1H).