Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH3:33])=[C:13]([C:26]#[N:27])[C:14](=[C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:18]=1[Cl:19])[C:15]#[N:16]>C(O)CC>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH3:33])=[C:13]2[C:14](=[C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[C:18]=1[Cl:19])[C:15](=[NH:2])[NH:16][C:26]2=[NH:27]
Reactant: CCOCCOc1c(Cl)c(Sc2ccccc2N)c(OCCOCC)c(C#N)c1C#N
Reactant: N
Agent: [Na]
Solvent: CCCO
Product: CCOCCOc1c(Cl)c(Sc2ccccc2N)c(OCCOCC)c2c1C(=N)NC2=N
Reaction time: 20 h
Yield: 96.2 %

Procedure:
To a solution of sodium metal (0.8 g) in n-propyl alcohol (250 mL) was fed gaseous ammonia at a flow rate of 120 mL/min. at room temperature for 1 hour. Then, 27.6 g of 4-(2-aminophenylthio)-5-chloro-3,6-di-(2-ethoxyethoxy) phthalonitrile was added and the mixture was stirred at 50~60° C. for 20 hours. After cooling, the reaction mixture was worked up in the same manner as in Example 1 to provide 27.6 g (yield 96.2%) of 5-(2-aminophenylthio)-6-chloro-1,3-diimino-4,7-di-(2-ethoxyethoxy) isoindoline of the following chemical formula. ##STR11##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:22][CH2:21][C:11]3([O:16][CH2:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br.Br[CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH3:33]>>[CH:18]([N:13]1[CH2:12][C:11]2([CH2:21][CH2:22][N:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[CH3:33])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[O:16][CH2:15][C:14]1=[O:17])([CH3:20])[CH3:19]
Reactant: CC(C)N1CC2(CCN(c3ccc(O)cc3)CC2)OCC1=O
Reactant: C[C@@H]1CCCN1CCCBr
Agent: Br
Product: CC(C)N1CC2(CCN(c3ccc(OCCCN4CCC[C@H]4C)cc3)CC2)OCC1=O

Procedure:
The entitled compound was obtained as a white solid according to the same method as in Example 4-(c) or according to a method similar to it but using 9-(4-hydroxyphenyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecan-3-one obtained in Example 4-10-(b) and (2R)-1-(3-bromopropyl)-2-methylpyrrolidine hydrobromide produced in Reference Example 4-2.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=O)=O>>[F:25][C:24]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OCc1ccccc1C(F)(F)F
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1ccccc1C(F)(F)F

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2-trifluoromethylbenzyl methanesulfonate in place of the benzyl bromide used in Example 1 to give 1.44 g of 1-(2 -trifluoromethylbenzyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 95%.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][CH:34]=2)[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O.O>[CH2:14]([O:21][C:22]1[CH:31]=[C:30]([CH:29]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([OH:3])=[O:40])=[CH:35][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C=O)cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)O)cc2)c1

Procedure:
Jones reagent (˜60 mL) was added dropwise to a stirring solution of Methyl 3-(benzyloxy)-5-(4-formylphenoxy)benzoate (Intermediate 12) (30 g, 82.9 mmol, 1 equiv.) in acetone (200 mL) at room temperature until a brown color persists. The reaction mixture was diluted with water and extracted several times with dichloromethane. The combined organic extracts was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated to furnish acid as white solid (30 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:5]=2[N:6]=1.[CH3:15][N:16]=[C:17]=[O:18].[N-]=C=O>C(OCC)(=O)C>[CH3:13][C:8]1([CH3:14])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:17]([NH:16][CH3:15])=[O:18])[S:3][C:4]=2[C:10]([CH3:12])([CH3:11])[CH2:9]1
Reactant: CN=C=O
Reactant: CC1(C)Cc2nc(N)sc2C(C)(C)C1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1nc2c(s1)C(C)(C)CC(C)(C)C2
Reaction time: 2 h

Procedure:
2-Amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole (21 grams; 0.1 mole) was dissolved in ethyl acetate (100 ml) and the solution charged into a glass reaction vessel fitted with a mechanical stirrer and themometer. Methyl isocyanate (6.2 grams 0.11 mole) was added dropwise to this solution over a period of 30 minutes. The temperature of the reactants was at about 20°-25° C. during the addition. At the conclusion of the isocyanate addition, stirring was continued at room temperature for a period of about 2 hours. The desired product, 2-amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole, a solid, was then filtered from the reaction mixture and air dried. Its melting point was greater than 250° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[NH:19][CH:20]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].N1([C:30](N2C=CN=C2)=[O:31])C=CN=C1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[CH:17]=[C:18]3[C:21](=[O:22])[NH:23][C:30](=[O:31])[N:19]3[CH:20]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(-c3c[nH]c(C(N)=O)c3)c2nc1NC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4n(c3)C(=O)NC4=O)c2nc1NC(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-2-carboxamide (Example 420; 21.8 mg, 0.067 mmol), di(1H-imidazol-1-yl)methanone (CDI; Aldrich; 12.02 mg, 0.074 mmol), and NaH (60% w/w in mineral oil; 3.24 mg, 0.081 mmol) in a mixture of THF (1.0 mL) and DMF (0.10 mL) was stirred under argon at 23° C. for 1 h. Additional di(1H-imidazol-1-yl)methanone (12 mg, 0.074 mmol) was added, and the resulting mixture was stirred at 23° C. for 5 min. Additional di(1H-imidazol-1-yl)methanone (72 mg, 0.444 mmol) was added, and the resulting mixture was stirred at 23° C. for 5 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes) to provide 6-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (11.9 mg, 0.034 mmol, 51% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (1H, s), 7.82 (1H, d, J=7.6 Hz), 7.66 (1H, dd, J=7.3, 1.3 Hz), 7.40 (1H, d, J=7.6 Hz), 7.32 (1H, d, J=0.7 Hz), 7.30 (0.5; H, br. s), 4.76 (1H, s), 4.05 (0.5; H, s), 2.56 (3H, s), 1.57 (9H, s). m/z (ESI, +ve) 350.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13](OC)=[O:14])[CH2:5]2.[BH4-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([CH2:13][OH:14])[CH2:5]2
Reactant: COC(=O)C1Cc2cc(Br)cnc2NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ncc(Br)cc2CC1CO
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (285 mg, 1 mmol) in THF (10 mL) under Argon at room temperature was added sodium borohydride (151 mg, 4 mmol). The reaction mixture was stirred at 60° C. for 4 h, then diluted in EtOAc and washed four times with a NH4Cl solution (pH=6.5). The white organic phase was filtered to give the title compound contaminated by impurities as a white solid (59 mg). The filtrate was dried over sodium sulphate, filtered and concentrated in vacuo to give a yellow solid (143 mg). The crude was purified by preparative TLC (eluent: dichloromethane/MeOH 93/7) to give the title compound (10 mg, 4%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:31])=[C:6]([C@@H:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[C:7]([O:12]C)=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2].B(Br)(Br)Br>ClCCl>[C:1]([C:4]1[C:5]([CH3:31])=[C:6]([C@@H:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:7]([OH:12])=[C:8]([CH3:11])[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)=O)c(C)c(C)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1c(C)c(C)c(O)c([C@H](CCCCCC(=O)O)c2ccc(F)cc2)c1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 82.9 %

Procedure:
A solution of methyl (R)-7-(3-acetyl-6-methoxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoate (2.0 g, 4.7 mmol) in dichloromethane (10 ml) was added dropwise to boron tribromide (2.0 ml, 5.3 g, 21.0 mmol) in dichloromethane (30 ml) at -78° C. The temperature of the reaction solution was elevated gradually to room temperature, and the reaction solution was stirred for 6 hours at the same temperature. To the reaction solution was was added ice-water at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium chloride in the order mentioned, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography to give (R)-7-(3-acetyl-6-hydroxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoic acid (1.56 g). Physico-chemical properties and spectral data are shown in [Table 5].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.C(O)(=[O:16])C.C(C(C)=O)C(C)C>O.[Cl-].[Na+]>[O:16]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: CC(=O)O
Reactant: CC(=O)NC1CCCc2sccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(=O)NC1CCC(=O)c2sccc21
Reaction time: 0.42 h

Procedure:
A mixture of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-acetamide (2.0 g; 10.25 m mole), cobaltous acetate (0.49 g; 2.77 m mole), cobaltous bromide tetrahydrate (0.635 g; 2.18 m mole), water (0.4 ml), acetic acid (5.0 ml) and methyl isobutyl ketone (35.0 ml) in suitable flask fitted with a reflux condenser, a gas dispersion tube and a thermometer is stirred vigorously. Air is introduced through the dispersion tube into the turbid blue solution at room temperature for 45 minutes, and then the mixture is heated. After 25 minutes, the solution turns greenish blue (temperature: 45° C.) and in 15 minutes green (temperature: 55° C.). The reaction is run overnight with periodic additions of methyl isobutyl ketone. The greyish green reaction mixture containing some suspended dark gray solid is then diluted with water (40.0 ml) and saturated with sodium chloride. The upper organic phase is separated and the aqueous phase extracted with chloroform (2×100 ml). The organic phase and the chloroform extracts are combined, washed with brine (50 ml) and water (25 ml), respectively. The water wash is counter-extracted with chloroform (50 ml) and the chloroform extract added to the above organic phase. The combined organic phase is evaporated in vacuo to afford a gum, which contains the desired compound. The latter is hydrolyzed without further purification and the resultant amine hydrochloride is converted to 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:26])[O:25][CH2:2][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=2)=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1F
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(Br)cc3)C(=O)OC2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 32 using 2-bromo-1-[3-fluoro-4-(methylsulfonyl)phenyl]ethanone (Lalezari, Iradj et al., J. Chem. Eng. Data, 11, 619 (1966)) instead of 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone, 4-bromophenylacetic acid instead of 4-(3-thienyl)phenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([NH2:15])=[CH:4][CH:3]=1.[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]=[CH:16][N:8]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Br)cc1NC1CCOCC1
Solvent: COC(OC)OC
Product: Brc1ccc2ncn(C3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of compound 5-bromo-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (500 mg, 1.852 mmol) in HC(OMe)3 (2 mL) was added TsOH (15 mg, 0.0789 mmol). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was extracted with DCM washed with water and the organic layer dried over sodium sulfate which was removed by filtration. After concentration of the filtrate, the crude product was purified by column (201 mg, 38.53%). LCMS (m/z): 281.0, 283.0 (M+1).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10]O.O=S(Cl)[Cl:14]>ClCCl>[Cl:14][CH2:10][C:2]1[S:1][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2ncccc2s1
Solvent: ClCCl
Product: ClCc1cc2ncccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of thieno[3,2-b]pyridin-2-ylmethanol (C-4) (17 mg, 0.1 mmol) in anhydrous dichloromethane (10 mL) was added SOCl2 (120 mg). After the mixture was stirred at room temperature for 2 hours, it was concentrated and used for the next step without further purification. MS (m/z): 184 (M+1)+.
Reaction SMILES: C([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[CH2:26](N)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:26]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using phenethylamine instead of benzylamine and obtained in 25% (HPLC: 90%, RT: 6.36 min). 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.38 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.32 (t, J=5.5 Hz, 1H), 7.75 (d, J=5.1 Hz, 1H), 7.36 (dd, J=3.7, 2.6 Hz, 1H), 7.33-7.18 (m, 5H), 6.46 (dd, J=3.7, 1.8 Hz, 1H), 3.54-3.47 (m, 2H), 2.87 (dd, J=8.1, 7.0 Hz, 2H); MS (m/z) 364 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][N:4]=[C:5]([C:13](=NC1C=CC=CC=1)[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[O:24]1CCCC1>>[F:1][CH:2]([F:22])[O:3][N:4]=[C:5]([C:13](=[O:24])[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(=Nc1ccccc1)C(=NOC(F)F)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)C(=NOC(F)F)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 2-difluoromethoxyimino-3-phenyliminobutyrate (0.76 g) in tetrahydrofuran (3.8 ml) was added 1N hydrochloric acid (3.64 ml) under ice-cooling. After being stirred at 20° C. for 1.5 hours, the mixture was extracted with ethyl acetate. The separated organic layer was washed with water three times, dried over magnesium sulfate and concentrated under reduced pressure to give tert-butyl 2-difluoromethoxyimino-3-oxobutyrate (0.55 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1C=NC=CC=1C>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:25])=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccncc1Br
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cnccc2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-4-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a light brown solid, MS (ISP): m/e=323.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:11][C:12](=[O:22])[CH2:13][NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>O1CCOCC1>[ClH:31].[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:11][C:12](=[O:22])[CH2:13][NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
13.4 Parts N-t-butoxycarbonylglycyl-L-phenylalanine benzyl ester is dissolved in 200 parts dioxane and treated with a 10 fold excess of 2 N hydrochloric acid in dioxane for 10 minutes. Removal of the solvent under reduced pressure affords pure glycyl-L-phenylalanine benzyl ester hydrochloride.
Reaction SMILES: [C:1]([CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([OH:3])=O.[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:37]1([CH2:36][CH2:35][CH2:34][NH:33][C:1]([CH:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:3])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)O
Reactant: NCCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)NCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 107.1 %

Procedure:
To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially 1-amino-3-(piperidin-1-yl)propane (345 mg, 1.1 eq), 1-hydroxybenzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.35 grams of an orange foam.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29]C(C)(C)C)=[O:28])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][C:26]([CH3:35])([CH3:34])[C:27]([OH:29])=[O:28])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc(Nc2nccc(OC(C)(C)C(=O)OC(C)(C)C)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(OC(C)(C)C(=O)O)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To tert-butyl 2-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)-pyrimidin-4-yl]oxy}-2-methylpropanoate (Example 94A-25, 140 mg, 0.28 mmol) in DCM (1 mL) was added of trifluoroacetic acid (220 μL, 2.8 mmol). The mixture was aged for 2 hours and additional trifluoroacetic acid (500 μL, 6.4 mmol) was added. The reaction was stirred overnight. The reaction was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and solvent removed under reduced pressure to afford 2-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)pyrimidin-4-yl]oxy}-2-methylpropanoic acid (110 mg, 0.25 mmol, 88%) as pale yellow oil. MS ESI: [M+H]+ m/z 441.2. 1H NMR (600 MHz, DMSO-d6): δ 9.50 (s, 1H); 8.18 (d, J=6 Hz, 1H); 7.96 (s, 1H); 7.66 (s, 1H); 7.44 (s, 1H); 7.05 (s, 1H); 6.27 (d, J=6 Hz, 1H); 2.52-2.27 (m, 4H); 2.46 (s, 3H); 1.86 (s, 2H); 1.66 (s, 6H). rhSYK activity=++
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:33])[CH:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)[CH:11]=1)[C:7]([OH:33])=[O:6])[CH3:32]
Reactant: CCOC(=O)C(Cc1cccc(OCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1cccc(OCCc2ccc(OS(C)(=O)=O)cc2)c1)C(=O)O
Yield: 96.6 %

Procedure:
Lithium hydroxide hydrate (0.175 g; 4.18 mmole) in water (5 ml) was slowly added to a solution of 2-ethoxy-3-{3-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 22) (1.66 g; 3.80 mmole) in tetrahydrofuran (17 ml) at 0° C. After stirring at room temperature for 2 hours tetrahydrofuran was removed by evaporation in vacuo. The residue was extracted with diethyl ether. The water phase was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 1.5 g (96.5% yield) of 2-ethoxy-3-{3-[2-(4-methanesulfonyloxyphenyl)ethoxy]-phenyl}propanoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH2:23])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[O:36])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25]
Reactant: COc1cc2c(Sc3ccc(N)s3)ccnc2cc1OCCCN(C)C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Sc3ccc(NC(=O)Nc4ccc(F)cc4)s3)ccnc2cc1OCCCN(C)C
Yield: 6.2 %

Procedure:
5-({7-[3-(Dimethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiophenylamine (190 mg), para-fluorophenyl isocyanate (69 mg) and tetrahydrofuran (30 ml) were stirred together at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=10:1) using NH type silica gel. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for solidification to obtain 16 mg of a yellowish-brown solid.