Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccncc2)C1
Yield: 55.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 4-pyridineboronic acid (112 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (109 mg, 55.3%) as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)C=O.[H-].[Na+].Br[C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[N+:23]([O-:25])=[O:24]>O>[N:1]1([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[N+:23]([O-:25])=[O:24])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1oc2ccccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1oc2ccccc2c1-n1ccnc1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 0.1 g. (12 mmole) of imidazole in 20 ml. of N,N-dimethylformamide is added 0.5 g. (12 mmole) of 57.6 percent suspension of sodium hydride in mineral oil. After cooling to 20° C., 2.4 g. (10 mmole) of 3-bromo-2-nitrobenzofuran in 20 ml. of N,N-dimethylformamide is added. After stirring 45 minutes, the mixture is heated on a steam bath for 15 minutes, then 50 ml. of water are added. Cooling and filtration provide yellow needles of 3-(N-imidazolyl)-2-nitrobenzofuran, m.p. 147°-149° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.C(O)CCC.O.[NH2:21][NH2:22]>[N+](C)([O-])=O>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:21][NH2:22])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Reactant: NN
Solvent: CCCCO
Solvent: C[N+](=O)[O-]
Solvent: O
Product: NNc1ccc(-c2cccc(Cl)c2)nn1

Procedure:
A mixture of 6.85 g of 3-chloro-6-(m-chlorophenyl)pyridazine, 100 ml. of n-butanol and 3.05 g. of hydrazine hydrate is refluxed overnight. The solvent is removed under vacuum to give a semi-solid. The solid is dissolved in a minimum of hot nitromethane. Cooling gives 3.5 g. of amorphous solid.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:6]=[N:5]1)[C:2]#[CH:3].[CH2:12]=[O:13]>CN(C)C=O>[CH2:1]([N:4]1[C:9](=[O:10])[N:8]([CH2:12][OH:13])[C:7](=[O:11])[CH:6]=[N:5]1)[C:2]#[CH:3]
Reactant: C=O
Reactant: C#CCn1ncc(=O)[nH]c1=O
Solvent: CN(C)C=O
Product: C#CCn1ncc(=O)n(CO)c1=O
Yield: 67.8 %

Procedure:
A mixture of 0.76 g 2-propargyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine, 15 ml 37% aqueous formalin and 7.5 ml dimethylformamide was heated under reflux for 1.5 hours. The solvent was removed under reduced pressure to obtain a white semi-solid. This semi-solid was purified by chromatography on silica gel using a chloroform/methyl alcohol (75:1) mixed solvent to obtain 0.61 g of a white semi-crystalline product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[C:35](O)=[O:36])[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:34]=4[NH:26][CH:27]=[CH:28]5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cc[nH]c45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-7-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C=O.C(O)(=O)C.[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([CH3:21])[CH2:19][C:18]3[C:14]4[C:15](=[N:24][CH:25]=[CH:26][C:13]=4[C:12]=2[CH:27]=1)[N:16](CO)[CH:17]=3>O>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:20]([CH3:21])[CH2:19][C:18]3[C:14]4[C:15](=[N:24][CH:25]=[CH:26][C:13]=4[C:12]=2[CH:27]=1)[NH:16][CH:17]=3
Reactant: CN1Cc2cn(CO)c3nccc(c23)-c2cc(F)ccc21
Agent: C=O
Solvent: CC(=O)O
Solvent: O
Product: CN1Cc2c[nH]c3nccc(c23)-c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of paraformaldehyde (12.76 g, 425 mmol), Example 41A (20.5 g, 85 mmol) and acetic acid (243 mL) was stirred at room temperature overnight. The mixture was poured into water and the solid was collected by filtration to provide a mixture of the title compound and (7-fluoro-4-methyl-3,4-dihydro-1H-1,4,11-triazadibenzo[cd,f]azulen-1-yl)methanol. To a solution of this mixture in acetonitrile (506 mL) at room temperature was added 5N aqueous sodium hydroxide (122 mL, 608 mmol) and the mixture was heated at 60° C. for 1 hour. The mixture was cooled to room temperature and poured into water. The solid was collected by filtration to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 7.75 (dd, J=10.6, 3.0 Hz, 1H), 7.35 (d, J=5.3 Hz, 1H), 7.32-7.13 (m, 3H), 4.12 (s, 2H), 2.87 (s, 3H). MS (ESI+) m/z 254.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.BrC1C=CC(CBr)=CC=1[Cl:48]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:22][C:23]=1[Cl:48]
Reactant: Clc1cc(CBr)ccc1Br
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)c(Cl)c1

Procedure:
1-(4-(4-Bromo-3-chlorobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 4-bromo-3-chlorobenzyl bromide. MS(ES+):403/405.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)C.O.[NH2:39][NH2:40]>CCO>[NH:39]([C:4](=[O:3])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[C:13]3[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)=[CH:19][CH:18]=2)=[CH:35][CH:36]=1)[NH2:40]
Reactant: CCOC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Yield: 100 %

Procedure:
A mixture of 3-[4-(2-ethoxy-2-oxoethoxy)benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (400 mg), hydrazine hydrate (2 mL), and EtOH (50 mL was refluxed for 3.5 hours, cooled, and evaporated in vacuo to give the title compound as an amorphous solid (0.4 g, 100%).
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[O:8])=[O:5])#[N:2].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:2][C:1]1[N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[N:6]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:4](=[O:5])[CH:3]=1
Reactant: CCCNC(=O)N(CC1CCCCC1)C(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCn1c(N)cc(=O)n(CC2CCCCC2)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of 1-(2-cyanoacetyl)-1-cyclohexylmethyl-3-propylurea from above (7.10 g, 26.8 mmol) in water (45 mL)-ethanol (15 mL) was heated to 100° C. (oil bath), with adjustment of the pH to 10 by the addition of solid sodium carbonate. The resulting yellow solution was stirred for 1 h, during which time white crystalline solids formed. After 1 h 40 min, the mixture was cooled to 0° C. (icebath), and the white crystals were filtered off, washed with water (3×15 mL), and air-dried to provide 6-amino-3-(cyclohexylmethyl)-1-propyluracil as a slightly moist crystalline solid (8.85 g, quantitative yield). A small portion of this material was dried at 0.1 Torr to provide an analytically pure sample, m.p. 121°-122° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:8]=3[CH:7]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:26].[CH2:27]([O:29][C:30]([C:32]1[O:33][C:34]([CH2:37]Br)=[CH:35][CH:36]=1)=[O:31])[CH3:28]>>[CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:8]=3[CH:7]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:37][C:34]4[O:33][C:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])=[CH:36][CH:35]=4)[CH:23]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:26]
Reactant: CCOC(=O)c1ccc(CBr)o1
Reactant: Cc1ccc2c(c1)C=Cc1c(ccc(C)c1C)C2c1c[nH]c(=O)[nH]c1=O
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4c3ccc(C)c4C)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of step (v) (0.95 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807)(0.64 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 20% ethyl acetate in toluene. Yield 1.02 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCC(F)(F)F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCC(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2,2,2-trifluoro-ethyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:42])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:12]([CH3:13])[NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:42])[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 98 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl-].[OH:18][NH3+:19].[OH-].[K+].Cl>CO>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1/[C:4](=[N:19]/[OH:18])/[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: [NH3+]O
Reactant: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: O/N=C(\Cn1ccnc1)c1ccc(Cl)cc1Cl

Procedure:
1240 g (4.9 moles) of the thus prepared 2,4-dichlorophenacyl-1H-imidazol is dissolved in 6.2 l methanol. 506.6 g (7.3 moles) hydroxylammonium chloride and 818.2 g KOH (14.6 moles) are added to this solution, which then is heated for one hour under reflux while stirring. After cooling the reaction mixture is poured into 5330 ml aqueous HCl having a concentration of 5% by weight, whereby the oxime product is precipitated. About one hour later the solid product is filtered off and well washed with water. Then after well drying the thus obtained raw product is recrystallized from ethylene glycol monomethyl ether. The pure oxime product, i.e. the (Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanone oxime thus is obtained in the form of colourless crystals having a melting point of 227°-229° C. The yield is 89%. The purity and the identity of the obtained product were confirmed by chemical analysis, TLC, NMR and IR absorption spectra.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]=1[CH:7]=[O:8].Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[Na+].Cl>C(O)(C)(C)C.CC(=CC)C>[Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]=1[C:7]([OH:22])=[O:8]
Reactant: [O-][Cl+][O-]
Reactant: COCCCCn1c(-c2ccccc2)nc(Cl)c1C=O
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Product: COCCCCn1c(-c2ccccc2)nc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
To a solution of 4-chloro-1-(4-methoxybutyl)-2-phenyl-1H-imidazole-5-carbaldehyde (790 mg) in tert-butanol (15 ml) and 2-methyl-2-butene (1.5 ml) was added aqueous solution (4 ml) of sodium chlorite (300 mg) and sodium dihydrogen phosphate (400 mg), and the mixture was stirred at room temperature for 12 hr. 1M Hydrochloric acid was added, and the mixture was adjusted to pH 3, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (730 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=2[CH:4]=1)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][CH2:1][C:3]2[CH:23]=[CH:22][C:6]3[NH:7][C:8]([C@@H:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=3[CH:4]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C=O)ccc2[nH]1
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Reaction time: 17 h
Yield: 99.6 %

Procedure:
The product from Example 99A (0.50 g, 1.59 mmol), 4-fluoroaniline (0.15 g, 1.59 mmol), and acetic acid (0.09 mL, 1.59 mmol) were combined at ambient temperature in methanol (15 mL) and treated with sodium cyanoborohydride (0.10 g, 1.59 mmol) and stirred 17 hours. The mixture was poured into water, extracted into ethyl acetate, dried over sodium sulfate, filtered, and concentrated to give 0.65 g (100%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C@@H:13]2[CH2:15][O:14]2)[C:5]=1[NH2:6])([O-])=O.[O:16]1CCC[CH2:17]1>[Ni]>[O:14]1[CH2:15][C@H:13]1[CH2:12][O:11][C:7]1[C:5]2[NH:6][C:17](=[O:16])[NH:1][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: Nc1c(OC[C@@H]2CO2)cccc1[N+](=O)[O-]
Agent: [Ni]
Product: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Reaction time: 8 h

Procedure:
2-Nitro-6-[(2S)oxiranylmethoxy]aniline (0.20 g, 0.96 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Excess Raney Ni was added and the mixture hydrogenated under an atmosphere of hydrogen overnight. The mixture was filtered through a Celite pad. To the anhydrous tetrahydrofuran solution was added with cooling anhydrous N,N-diisopropylethylamine (0.365 mL) followed by phosgene in toluene (0.525 mL). The solvent was partially removed and the title compound collected by filtration (0.10 g, 0.49 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][C:25]3([C:31]([O:33]CC)=[O:32])[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.O1CCCC1.CO.[OH-].[Li+]>C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][C:25]3([C:31]([OH:33])=[O:32])[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)C1(Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCNC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CC3(C(=O)O)CCNC3=O)s2)c1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.032 g, 0.063 mmol) was added tetrahydrofuran (0.3 mL), methanol (0.16 mL) and water (0.16 mL). Lithium hydroxide (0.003 g, 0.13 mmol) was added and the reaction was stirred at room temperature. Once complete, the reaction was diluted with ethyl acetate, washed with hydrochloric acid (1N in water), dried over magnesium sulfate, filtered and concentrated to yield 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylic acid (0.02 g, 66%) without further purification. MS ESI: [M+H]+ m/z 477.7. 1H NMR (500 MHz, CD3OD) δ 8.71 (d, J=5.2, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.45 (s, 1H), 7.16-6.98 (m, 2H), 3.67 (m, 1H), 3.54-3.39 (m, 2H), 3.24-3.13 (m, 1H), 2.70-2.52 (m, 1H), 2.36 (s, 3H), 2.00 (d, J=10.4, 1H). rhSYK activity=+++
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](Br)(Br)[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>CN1CCCC1=O.O>[C:1]([NH:4][CH:5]([CH:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: Fc1ccc(C(Br)(Br)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CC(=O)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of diethyl acetamidomalonate (1.09 g, 5 mmol) in N-methyl-2-pyrrolidone (4 mL) was added 55% sodium hydride (219 mg, 5 mmol), and the mixture was stirred at room temperature for 1 hr. Bis(4-fluorophenyl)methylene bromide (990 mg, 4 mmol) was added, and the mixture was stirred at 50° C. for 4 hrs. After completion of the reaction, toluene (20 mL) and water (10 mL) were added to the reaction mixture and the mixture was partitioned. The obtained organic layer was washed twice with water (10 mL) and concentrated. Ethanol (4.5 mL) and 2M aqueous sodium hydroxide solution (5 mL) were added to the concentrated solution, and the mixture was stirred at 90° C. for 16 hrs. The reaction mixture was allowed to cool to 25° C., toluene (8 mL) and water (5 mL) were added, and the mixture was partitioned. The aqueous layer was concentrated to a half volume, and isopropyl acetate (8 mL) and water (10 mL) were added. The mixture was adjusted to pH 1.1 with concentrated hydrochloric acid and partitioned. The organic layer was washed with water (10 mL), concentrated and dried under vacuum to give the title compound (973 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1-n1cccn1
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1-n1cccn1
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (154 mg, brown solid) from 4-chloro-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.62 mmol, Intermediate-85, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.Cl.[NH2:19][C:20]1[CH:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[C:22]([OH:28])[C:21]=1[OH:29].CCN(CC)CC.O>CN(C)C=O>[NH2:19][C:20]1[CH:25]=[C:24]([CH:23]=[C:22]([OH:28])[C:21]=1[OH:29])[CH2:26][NH:27]/[CH:14]=[C:5]1\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]2[C:4]\1=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: NCc1cc(N)c(O)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc(O)c1O
Yield: 28.7 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (124 mg, 0.44 mmol), 3-amino-5-aminomethyl-benzene-1,2-diol dihydrochloride salt (100 mg, 0.44 mmol) and Et3N (0.15 mL, 1.1 mmol) in N,N-dimethylformamide (DMF) (5 mL) is stirred at 25° C. for 24 hours. Water (10 mL) is added to the reaction mixture. The resulting solid is filtered and washed with water. The crude solid is purified by HPLC, eluting with 20% CH3CN/H2O to 100% CH3CN over 30 minutes to give 51 mg (22%) of the title compound as a brown solid. HRMS (ESI) m/z calcd for C17H14BrN3O4 (M+H)+ 404.02405. found: 404.02336.