Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:32](=[O:35])[CH2:33][CH3:34])([CH2:11]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC3CC3(CNc3ccccc3)C2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N(CC12CC1CCN(Cc1ccccc1)C2)c1ccccc1
Reaction time: 2 h

Procedure:
To the a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]hept-1-ylmethyl)-phenyl-amine (175) (250 mg, 0.86 mmol) in CH2Cl2 (2 ml) at 0° C. was added i-Pr2NEt (0.30 ml, 1.72 mmol)) and propionyl chloride (0.11 ml, 1.29 mmol). The mixture was stirred for 2 hrs. The mixture was diluted with CH2Cl2 (5 ml), washed with sat. NaHCO3 (2×5 ml), brine (5 ml) and water (5 ml) and dried with Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0.5% to 2% MeOH in CH2Cl2) to give 176 as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.41-7.20 (m, 10H), 4.20 (d, 1H), 3.42 (AB, 2H), 3.21 (d, 1H), 2.65 (q, 2H), 2.20-2.00 (m, 4H), 1.80-1.60 (m, 2H), 1.30 (m, 1H), 1.05 (t, 3H), 0.80-0.20 (m, 2H) ppm; LRMS (calculated for C23H28N2O) 348, found 348; IR (film) 3308, 3105, 3064, 2978, 2937, 2874, 2811, 1689m 1666, 1598, 1540, 1499, 1445, 1314, 1246, 1196, 1074, 757 cm−1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[C:8]([CH:14]=1)[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])(=[O:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[C:1]([C:4]1[C:5]([N+:24]([O-:26])=[O:25])=[CH:6][C:7]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[C:8]([CH:14]=1)[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Sc2ccc(F)cc2F)c(NS(C)(=O)=O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)c1cc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 5'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1 g) and nitric acid (248 mg) in acetic acid (5 ml) was stirred at 80° C. for 1 hour. The reaction mixture was evaporated to dryness. The residue was washed with ethanol to give yellow crystals of 5'-acetyl-2'-(2,4-difluorophenylthio)-4'-nitromethanesulfonanilide (0.96 g).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[CH:25]1[O:27][CH2:26]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[CH:17]=2)[CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Product: OC(COc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1)C(F)(F)F
Temperature: 95 °C
Yield: 74.4 %

Procedure:
The N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine (400 mg, 1.35 mmol) product from EX-655A and 1,1,1-trifluoro-2,3-epoxypropane (348 mg, 3 mmol) were placed in a sealed vial, then stirred and heated to 95° C. for 15 h under an atmosphere of nitrogen. The vial was cooled, and more 1,1,1-trifluoro-2,3-epoxypropane (112 mg, 1 mmol) was added. The vial was sealed, then stirred and heated to 95° C. for a further 20 h under an atmosphere of nitrogen. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:6) to give 518 mg (77%) of the desired 3-[(3-phenoxyphenyl)[[3-(2-hydroxy-3,3,3-trifluoro-n-propoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ7.20-7.32 (m, 3H), 7.14 (t, 1H), 7.07 (t, 1H), 6.95 (d, 2H), 6.80 (m, 2H), 6.74 (s, 1H), 6.48 (dd, 1H), 6.38 (m, 2H), 4.59 (ABq, 2H), 4.31 (m, 1H), 4.18 (dd, 1H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.54 (dd, 1H), 2.92 (d, 1H), 2.61 (d, 1H). 19F NMR (CDCl3) δ−78.0 (d, 3F). −79.2 (d, 3F). HRMS calcd. for C25H23F6 NO4: 516.1611 [M+H]+, found: 516.1618.
Reaction SMILES: C[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C@@H:11]1[CH2:13][C@H:12]1[C:14]([OH:16])=O)=[O:10].B(OC)(OC)O[CH3:19].C1COCC1.Cl>>[CH3:19][C@H:6]1[CH2:7][CH2:2][C@H:3]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][OH:16])=[O:10])[CH2:4][CH2:5]1
Reactant: C[C@@H]1CCCC[C@H]1NC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CO)CC1
Reaction time: 2 h

Procedure:
Stir a solution, under argon, at 0° C., of trans-2-(trans-2-methylcyclohexylcarbamoyl)-cyclopropanecarboxylic acid (Example 11b) (3.69 g, 16.4 mmol), trimethyl borate (5.6 mL, 50 mmol), and add slowly 2N borane dimethylsulfide complex in THF (16.4 mL, 32.8 mmol). Continue to stir the reaction at 0° C. for 1 h, and then at ambient temperature for 2 h. Carefully pour the reaction mixture into ice-H2O and acidify with 2N HCl. Extract the mixture with EtOAc (3 times), wash with brine, dry over MgSO4 and concentrate to obtain 2.85 g (83%) of product as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[N:9]([CH3:15])[C:10](=[O:14])[C:11]=1[O:12][CH3:13])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[O:23]=[S:17]1(=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21][N:16]1[C:8]1[N:9]([CH3:15])[C:10](=[O:14])[C:11]([O:12][CH3:13])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C(=O)O)nc(N2CCCCS2(=O)=O)n(C)c1=O
Yield: 80.6 %

Procedure:
A solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.180 g, 0.52 mmol) in 90% ethanol (10 ml) was treated at 22° C. 1 N with sodium hydroxide (1 ml) and the resulting mixture was stirred for 30 min. Then 1 N hydrochloric acid (2 ml) was added and the ethanol was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and recrystallization of the solid residue from ethyl acetate gave 0.133 g (81% yield) of the title acid as a white crystals; mp 180–181° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.55–1.6 (1H, m, CH), 2.0–2.25 (3H, m, CH2 and CH), 3.43 (2H, m, CH2), 3.44 (3H, s, NCH3), 3.75 (2H, m, CH2), 3.83 (3H, s, OCH3). Anal. Calcd for C11H15N3O6S: C, 41.64; H, 4.76; N, 13.24. Found: C, 41.84; H, 4.96; N, 12.88.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:4][C:3]=1[CH3:21].[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH2:19][C:17]1[S:18][C:14]([C:12]2[O:11][N:10]=[C:9]([C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[C:3]([CH3:21])[CH:4]=3)[N:13]=2)=[CH:15][CH:16]=1)[CH3:24]
Reactant: Cc1cc(-c2noc(-c3ccc(C=O)s3)n2)cc(C)c1O
Reactant: CNC
Product: Cc1cc(-c2noc(-c3ccc(CN(C)C)s3)n2)cc(C)c1O

Procedure:
The title compound is prepared from 5-[3-(4-hydroxy-3,5-dimethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-thiophene-2-carbaldehyde and dimethylamine according to Method B; LC-MS: tR=0.75 min; [M+1]+=330.05.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH:16]3[CH2:25][CH2:24][C:19]4([CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:18][CH2:17]3)[CH:11]=2)[CH:6]=1)=O.O1CCCC1>[AlH4-].[Li+]>[CH2:20]1[C:19]2([CH2:24][CH2:25][CH:16]([O:15][C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13]4)[CH2:17][CH2:18]2)[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
6-(Spiro[4.5]dec-8-yloxy)-naphthalene-2-carboxylic acid methyl ester (0.312 g, 0.000922 mol) in tetrahydrofuran (9 mL, 0.1 mol) and 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (2.76 mL, 0.00276 mol) was added at 0° C. After stirring at rt for 2 h, quench with EtOAc, then Rochele's salt was added and stirred at rt for 1 h. Extraction with EtOAc, c/c give the product as a white solid (257.2 mg, 90%). LCMS Rt=2.21 min m/z=293.30 ([M−17], 100%).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.CON(C)[C:23]([C:25]1[CH:26]=[N:27][CH:28]=[N:29][CH:30]=1)=[O:24]>C1COCC1>[CH3:6][N:7]1[C:11]([C:23]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)=[O:24])=[CH:10][N:9]=[CH:8]1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cncnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1cncnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexane, 3.71 mL, 5.94 mmol) was added to a solution of 1-methylimidazole (0.452 mL, 5.7 mmol) in THF (10 mL) at −78° C. The mixture was stirred at −78° C. for 30 min. Chlorotriethylsilane (0.957 mL, 5.7 mmol) was added slowly. The mixture was stirred at −78° C. for 30 min. A second portion of n-BuLi (1.6 M in hexane, 3.71 mL, 5.94 mmol) was added. The mixture was stirred at −78° C. for 30 min. Crude N-methoxy-N-methylpyrimidine-5-carboxamide (794 mg, 4.75 mmol, Intermediate 28, step a) was added via cannula as a solution in THF (5 mL). The mixture was stirred at −78° C. for 5 min and was removed from the cold bath and stirred at room temperature overnight. Saturated aqueous NH4Cl was added and the phases were separated. The aqueous phase was extracted twice with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 10-100% EtOAc-heptanes, then 0-10% MeOH-EtOAc) to afford impure title compound, which was further purified by flash column chromatography (silica gel, 4-5% MeOH-DCM).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH:1]=[O:3])=[CH:30][CH:31]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NC=O)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Formic acid (0.13 ml) was added to acetic anhydride (0.27 ml), and the admixture was stirred at 60° C. for 2 hours. A solution of 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (303 mg) in tetrahydrofuran (8 ml) was added to the reaction mixture, and the admixture was stirred at room temperature for 45 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 327 mg of 6,7-dimethoxy-4-(4-formylaminophenoxy)quinoline.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[CH2:34](I)[CH3:35].Cl>C(O)C>[CH2:34]([S:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:12][CH:13]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)[CH3:35]
Reactant: CCI
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(SCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of ethyl 2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing 1H-NaOH (4 ml) was added ethyl iodide (0.34 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate gave colorless prisms (0.55 g, 57%), m.p. 153-154° C. (decomp.).
Reaction SMILES: C([O:3][C:4](=[O:43])[C@@H:5]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH2:6][NH:7][C:8](=[O:32])[CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:37]1([S:34]([NH:33][C@@H:5]([CH2:6][NH:7][C:8](=[O:32])[CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:17][CH2:16]2)[C:4]([OH:43])=[O:3])(=[O:36])=[O:35])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)[C@H](CNC(=O)CCNC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1)NS(=O)(=O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CCNC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1)NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Reaction time: 1.5 h

Procedure:
The compound (144 mg) obtained in the above (2) is dissolved in DMF (3 ml), and thereto is added 1N aqueous sodium hydroxide solution (698 μl) under ice-cooling, and the mixture is stirred for 1.5 hour. The pH value thereof is adjusted to pH 2 with 10% aqueous citric acid solution, and extracted three times with ethyl acetate. The extract is washed twice with a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (92 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][CH:7]=1.[Cl:24]N1C(=O)CCC1=O.O.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[N:6][C:7]=1[Cl:24]
Reactant: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2nc(Cl)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (50 mg), N-chlorosuccinimide (23.9 mg) in DMF (1.5 ml) was stirred at 60° C. for 2 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of CHCl3 and MeOH. The fractions were concentrated in vacuo to obtain 6-(5-amino-6-chloro-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (30 mg) as white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH3:28])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: CNC1CCCCC1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN(C)C3CCCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (400 mg, 1.03 mmol, Example 56, Step D) in dioxane (10 mL) was added N-methylcyclohexylamine (1.3 mL, 10.3 mmol). The mixture was stirred at 80° C. overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was purified by chromatography (5%-15% methanol in methylene chloride) to give 250 mg (60%) of the desired product as a white solid: mp 122-124° C.; MS(APCI+): m/z 405.2 (MH+); Anal. Calcd for C26H32N2O2.0.5H2O: C, 75.51; H, 8.04; N, 6.77. Found: C, 75.25; H, 8.04; N, 6.78.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][O:19][CH2:20][C:21]1([C:26]#[N:27])[CH2:24][C:23](=O)[CH2:22]1>O1CCCC1>[C:7]([CH:9]=[C:23]1[CH2:24][C:21]([CH2:20][O:19][CH3:18])([C:26]#[N:27])[CH2:22]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COCC1(C#N)CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1(C#N)CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (2.25 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (0.381 mL, 0.00236 mol) in tetrahydrofuran (4 mL, 0.05 mol). The reaction was warmed to rt and then cooled to 0° C. again. To the reaction mixture was added a solution of 1-(methoxymethyl)-3-oxocyclobutanecarbonitrile (0.298 g, 0.00214 mol) in tetrahydrofuran (2 mL, 0.02 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was used directly in next step. LCMS calculated for C9H11N2O(M+H)+:163.1; Found: 163.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17](OCC)=[O:18])[CH2:11][CH2:10]1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:13][CH2:14]1
Reactant: CCOC(=O)CCN1CCN(c2ccccc2OC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1N1CCN(CCCO)CC1

Procedure:
A mixture of ethyl 3-(4-(methoxyphenyl)piperazin-1-yl)propanoate (17a) (0.0048 mol) and sodium borohydride (5.4 g, 0.14 mol) in 100 mL anhydrous ethanol was refluxed for overnight (12 h). The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was concentrated on rotavapor. The residue was diluted with DCM, washed with saturated aqueous NaHCO3 solution (25 mL×2) and water (25 mL), dried over sodium sulphate (Na2SO4) and evaporated under reduced pressure to give 3-(4-(methoxyphenyl)piperazin-1-yl)propan-1-ol (21a) which was purified by silica gel column chromatography using 0-5% gradient of ethyl acetate and methanol. White solid, 0.6 g (50%). 1H NMR (400 MHz, CDCl3): δ 1.75 (quintet, J=5.2 Hz, 2H); 2.69 (t, J=6.0 Hz, 2H), 2.74 (broad s, 4H); 3.08 (broad s, 4H); 3.82 (t, J=5.2 Hz, 2H); 3.85 (s, 3H); 5.35 (broad s, 1H); 6.84-6.86 (m, 1H); 6.90-6.93 (m, 2H); 6.97-7.02 (m, 1H). MS (ESI): m/z=251.40 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][N:22]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:10][CH:9]=2)[CH:7]=1.[N:30]1(C(OC(C)(C)C)=O)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[N:26]=[C:25]([C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:24]=[CH:23][N:22]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:16])([F:17])[F:15])=[N:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Nc2nccc(C(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(=O)N3CCNCC3)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)-pyrimidine-4-carboxylic acid (Example 68, 68.9 mg, 0.162 mmol) in a scintillation vial was added DMF (812 μL), tert-butyl piperazine-1-carboxylate (33.4 mg, 0.179 mmol), DIPEA (85 μL, 0.487 mmol) and BOP (108 mg, 0.244 mmol). The reaction was stirred at room temperature for 1 hour before being diluted with water and dichloromethane. The organic was dried over sodium sulfate, filtered and concentrated to dryness. The resultant residue was purified by normal phase chromatography (10% MeOH in DCM: hexanes, 10-100%, linear gradient). Boc deprotection was carried out on the isolated material with 1:1 TFA:dichloromethane (1 mL) at room temperature. Upon completion the reaction was concentrated to dryness and was directly purified by reverse phase chromatography (10-80% MeCN in water, linear gradient) to yield [2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)-pyrimidin-4-yl](piperazin-1-yl)methanone as a TEA salt. MS ESI: [M+H]+ m/z 493.1. 1H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.87 (s, 2H), 8.67 (d, J=4.8, 1H), 8.08 (s, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 7.00 (s, 1H), 3.82 (s, 2H), 3.67 (s, 2H), 3.21 (s, 2H), 3.08 (s, 2H), 233 (s, 3H), 1.76 (s, 3H). rhSYK activity=+++
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]2[NH:11][C:12](=[O:20])[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[CH:8]=1.[CH3:31]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]2[N:11]([CH3:31])[C:12](=[O:20])[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[CH:8]=1
Reactant: CCOC(=O)C1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
60% Sodium hydride (1.0 g) was suspended in dimethylformamide (hereinafter abbreviated as DMF) (5 ml) and under ice-cooling, a DMF solution (5 ml) of ethyl 7-(2-chloro-4-trifluoromethylphenoxy)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylate (Compound 1) (0.8 g) was dropwise added thereto, followed by stirring for 10 minutes. Methyl iodide (0.4 g) was then added, the mixture was further stirred for 10 minutes, and to the reaction mixture was added water (20 ml) and the mixture was extracted twice with ethyl acetate (50 ml). The extract was washed with water and then saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was then evaporated under a reduced pressure and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.4 g of the title compound (colorless oil).