Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[O:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:14]([O:23][CH2:24][C:25]([N:35]4[CH2:36][CH:37]5[O:28][CH2:29][CH2:30][O:31][CH:32]5[CH2:33][CH2:34]4)=[O:27])[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]3=[O:22])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N3CCC4OCCOC4C3)nc2n1
Yield: 81.7 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3 g) in anhydrous dimethylformamide (65 cc), N,N'-carbonyldiimidazole (1.35 g) and 1,4-dioxa-8-azaspiro[4.5]decane (1 g). After two successive recrystallizations in carbon tetrachloride and isopropyl ether, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-[2-(4-ethylenedioxypiperidino)-2-oxoethoxy]-1-isoindolinone (2.8 g), m.p. 137° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[C:6](I)=[CH:7][O:8]2.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[C:7]1[O:8][C:9]2[C:4]([C:5](=[O:16])[CH:6]=1)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=2
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1cc(OC)c2c(=O)c(I)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3nc4ccccc4[nH]3)oc2c1
Temperature: 0 °C
Yield: 67 %

Procedure:
A mixture of 5,7-dimethoxy-3-iodochromone (166 mg) prepared in Example 16, benzimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (107.9 mg; yield =67.0%) as orange plate crystals. Melting point: 245°-246° C. Mass spectrum (M+): 332. 1H-NMR(CDCl3, δ ppm): 6.71 (s, 1H, H3), 6.62 (s, H6), 8.26 (s, H8), 6.43 (s, H3'), 7.80 (d, H4'), 7.58 (t, H5'), 7.34 (t, H6'), 8.11 (d, H7'), 3.96 (s, 3H, 5MeO), 3.97 (s, 3H, 7MeO).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[Br:20]([O-])(=O)=O.[K+]>O>[Br:20][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:14])([F:13])[F:1])[NH2:10]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1ccc(OC(F)(F)F)c(Br)c1
Temperature: 80 °C

Procedure:
4-Trifluoromethoxynitrobenzene (4.1 g) was suspended in water (16 ml) and concentrated sulfuric acid (16 ml) and warmed to 80° C. with stirring. Potassium bromate (3.7 g) was added portionwise over 3 h., and the mixture was heated at 80° C. for a further 2 h. The mixture was cooled to room temperature and poured onto ice (100 g). The mixture was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue) was dissolved in acetic acid (2.5 ml) and water (10 ml) and iron powder (2.0 g) was added. The mixture was heated under reflux for 2 h., cooled to room temperature and filtered through Celite™. The filtrate was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (3:1) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ6.57 (1H, dd), 6.9 (1H, d), 7.06 (1H, dd).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=2)[N:3]=1.[F:25][C:26]1([F:41])[O:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]3([C:38](Cl)=[O:39])[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27]1>N1C=CC=CC=1.C(Cl)Cl>[C:21]([O:20][C:18]([C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:1][C:38]([C:35]3([C:33]4[CH:32]=[CH:31][C:29]5[O:30][C:26]([F:41])([F:25])[O:27][C:28]=5[CH:34]=4)[CH2:37][CH2:36]3)=[O:39])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COC(=O)c1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 7 h
Yield: 67.9 %

Procedure:
A solution of methyl 6-amino-2-(3-(tert-butoxycarbonyl)phenyl)nicotinate (400 mg, 1.2 mmol) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (630 mg, 2.4 mmol) in pyridine (12 mL) was stirred at room temperature for 3 days and then at 90° C. for 7 hours. Additional 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (320 mg, 1.2 mmol) was added and the reaction was heated at 90° C. for 12 hours until the amine was completely consumed. The reaction mixture was concentrated and the residue was purified by column chromatography (0-40% ethyl acetate—hexanes). The material obtained was dissolved in CH2Cl2 and was washed with 1N HCl (×3) and saturated aq. NaHCO3 (×3), dried (MgSO4) and concentrated to yield methyl 2-(3-(tert-butoxycarbonyl)phenyl)-6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate as a cream colored solid (450 mg, 67%). ESI-MS m/z calc. 552.2. found 553.3 (M+1)+. Retention time 2.49 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.95-7.91 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.57-7.51 (m, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.6, 8.3 Hz, 1H), 3.63 (s, 3H), 1.54 (m, 11H), 1.22-1.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:33])[CH2:31][CH3:32].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:33]=[C:30]([CH2:31][CH3:32])[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 4 g, 19.21 mmol) was dissolved in DMF (30 mL) to which 1,1′-Carbonyldiimidazole (CDI) (4.04 g, 24.97 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-propionamidine (2.03 g, 23.05 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, additional CDI (4.04 g, 24.97 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 8 h to effect cyclodehydration. After evaporation of DMF, the residue obtained was cooled to room temperature followed by addition of water (25 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:17])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])O)[CH:2]=1.[BH4-].[Na+].Cl.C(O)C[OH:23]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])([OH:23])[CH2:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:2]=1
Reactant: OCCO
Reactant: O=C(c1cccnc1)C(O)c1ccccc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(O)(Cc1ccccc1Br)c1cccnc1

Procedure:
20 g (0.068 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-2-hydroxyethanone in 300 ml of methanol were reduced with 3 g (0.079 mol) of sodium borohydride at 0° C. Stirring was carried out for a few hours at room temperature (21° C.), the pH was brought to 2 with 4N hydrochloric acid and 4 ml of ethylene glycol were added. The solution was evaporated down, after which the residue was covered with a layer of ethyl acetate and neutralized with NaHCO3 solution. The ethyl acetate phase was washed twice with water and dried over Na2SO4. After the ethyl acetate had been distilled off, the product was obtained as a white powder of melting point 115° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:31]=[C:32]([NH2:37])[CH:33]=[CH:34][C:35]=1[F:36].Cl>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:17]=[C:18]3[C:26]4[C:25]([NH:37][C:32]5[CH:33]=[CH:34][C:35]([F:36])=[C:30]([Cl:29])[CH:31]=5)=[N:24][CH:23]=[N:22][C:21]=4[NH:20][C:19]3=[O:28])=[CH:15][CH:16]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)NCCN2CCOCC2)[nH]1
Yield: 16 %

Procedure:
The title compound (16% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 3-chloro-4-fluoro-phenylamine according to the procedure described for Example 12 without the conversion to HCl salt. MS 512.3 [M+1].
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
A stirred solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90° C. under N2. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold H2O. The reaction mixture was then extracted with Et2O (3×300 mL). The combined organic extracts were washed with H2O (4×100 mL) and brine (2×100 mL). The organic portion was dried over MgSO4 and concentrated to give 52.0 g of tert-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[N:15]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:14]=2)=[N:5][C:6](S(C)(=O)=O)=[N:7][CH:8]=1)#[N:2].[CH:43]([NH2:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:3]1[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[N:15]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:14]=2)=[N:5][C:6]([NH:46][CH:43]([CH3:45])[CH3:44])=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Yield: 81.6 %

Procedure:
Benzyl 3-(5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (0.826 g, 1.372 mmol) in THF (30 mL) was treated with isopropylamine (0.234 mL, 2.744 mmol, 2.0 Eq) and DIPEA (0.478 mL, 2.744mmol, 2.0 Eq) and allowed to heat at reflux for I hour. The mixture was concentrated in vacuo and purified by column chromatography (ISCO Companion™, 40 g column, 0-100% EtOAc/Petroleum ether) to give 0.651 g (82%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][O:16][CH2:17]Cl.[Cl-].[Na+]>C1COCC1>[Cl:3][C:4]1[C:5]([C:11]([F:12])([F:13])[F:14])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:15][O:16][CH3:17]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cccc(C(F)(F)F)c1Cl
Temperature: 12 °C
Reaction time: 16 h
Yield: 110.7 %

Procedure:
To a suspension of sodium hydride (3.78 g) in THF (150 mL) were added dropwise 2-chloro-3-hydroxybenzotrifluoride (12.4 g) and chloromethyl methyl ether (6.10 g) under ice-cooling, and the mixture was stirred at 12° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (16.8 g) as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[C:22]([O-])([O-])=O.[K+].[K+].C=O>CO.C(Cl)Cl>[CH2:10]([C:9](=[CH2:22])[C:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:2]([F:1])[CH:7]=1)=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C=C(CCCC)C(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: 55 °C
Yield: 105.2 %

Procedure:
A solution of N-(2-fluoro-4-hexanoylphenyl)-2,2-dimethylpropanamide (17.8 g, 60.7 mmol) in methanol (75 mL) was treated successively with K2CO3 (8.4 g, 60.7 mmol) and formaldehyde (37 wt. % solution in water, 5.0 mL, 67 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 55° C. for 4 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 (300 mL), dried over MgSO4, and filtered through a pad of silica gel, using more CH2Cl2 (200 mL) to wash the pad. The filtrate and washings were concentrated under vacuum to provide a mixture (19.5 g) of N-[4-(2-butylacryloyl)-2-fluorophenyl]-2,2-dimethylpropanamide, N-{2-fluoro-4-[2-(hydroxymethyl)hexanoyl]phenyl]-2,2-dimethylpropanamide, and N-{2-fluoro-4-[2-(methoxymethyl)hexanoyl]phenyl]-2,2-dimethylpropanamide.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3Cc3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of Example 1 (0.20 g, 0.66 mmol) in DMF (5 mL) was added 2-picolyl chloride hydrochloride (0.10 g, 0.61 mmol) and triethylamine (0.24 mL, 1.72 mmol). The subsequent mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was extracted into ethyl acetate (25 mL) and washed with water (25 mL) followed by brine (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.07 g, 36%); 1H NMR (400 MHz, CDCl3); δ 1.73-1.80 (m, 3H), 2.05 (m, 1H), 2.40 (m, 1H), 3.02-3.08 (m, 2H), 3.71 (d, J=13.6 Hz, 1H), 3.83 (m, 1H), 3.91 (s, 2H), 3.95 (m, 1H), 4.25 (d, J=13.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 4H), 7.25-7.27 (m, 2H), 7.41 (m, 1H), 7.61 (m, 1H), 8.53 (m, 1H); MS (m/z) 359.2 (M+1); LC (100.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:21]2[S:25][C:24]([C:26]([S:29]([NH2:32])(=[O:31])=[O:30])([CH3:28])[CH3:27])=[N:23][CH:22]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:21]2[S:25][C:24]([C:26]([S:29]([NH2:32])(=[O:31])=[O:30])([CH3:28])[CH3:27])=[N:23][CH:22]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: CC(C)(c1ncc(-c2cc(Nc3nccc(C(F)(F)F)n3)cc([N+](=O)[O-])c2)s1)S(N)(=O)=O
Solvent: CO
Product: CC(C)(c1ncc(-c2cc(N)cc(Nc3nccc(C(F)(F)F)n3)c2)s1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a suspension of 2-[5-(3-nitro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propane-2-sulfonamide (Example 70, 200 mg, 0.409 mmol) in MeOH (10 mL) was added 3% Pt/0.6% V/C (53 mg, 0.008 mmol). The reaction was sealed, purged with hydrogen, and stirred under a hydrogen balloon at room temperature overnight. A small amount of starting material remained, so additional catalyst (50 mg) was added, and a fresh hydrogen balloon was placed on the reaction. After another 24 h at room temperature, the starting material had been consumed. The reaction was diluted with MeOH, gently heated to dissolve any precipitated product, and filtered through Celite. The filtrate was evaporated, and flash chromatography of the residue (dry load, 20-100% ethyl acetate in hexanes) afforded 2-[5-(3-amino-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propane-2-sulfonamide (116 mg, 62%) as an off-white solid. MS ESI: [M+H]+ m/z 459.0. 1H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.78 (d, J=4.9, 1H), 7.87 (s, 1H), 7.37 (s, 1H), 7.22 (d, J=4.9, 1H), 7.03 (s, 2H), 6.89 (s, 1H), 6.53 (t, J=1.7, 1H), 5.28 (s, 2H), 1.78 (s, 6H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7]([N:10]2[CH2:20][CH2:19][C:13]3([C:17](=[O:18])[NH:16][CH2:15][CH2:14]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[C:5]([CH3:21])[O:4][N:3]=1.I[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([S:7]([N:10]2[CH2:11][CH2:12][C:13]3([C:17](=[O:18])[N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)[CH2:19][CH2:20]2)(=[O:9])=[O:8])=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1S(=O)(=O)N1CCC2(CCNC2=O)CC1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: Cc1noc(C)c1S(=O)(=O)N1CCC2(CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared according to example 162 step B) from 8-(3,5-dimethyl-isoxazole-4-sulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-iodo-4-trifluoromethyl-benzene. Off white solid. MS (ESI): 458.13 MH+).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Product: CC(C)c1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4isopropylaniline using the same procedure described in example 5.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])([O-:12])=[O:11]>ClCCCl>[NH2:17][C:16](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1
Reactant: COC(=O)CC(=O)OC
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCCl
Product: COC(=O)C(C(=O)OC)=C(N)c1cccc([N+](=O)[O-])c1
Yield: 65.8 %

Procedure:
To a mixture of dimethyl malonate (100 g) and 3-nitrobenzonitrile (112 g) in 1,2-dichloroethane (500 ml) was added stannic chloride (177 g) at once with a syringe and refluxed for 1 hour with stirring. The white precipitates were collected by filtration, dissolved in a mixture of acetone (2 l) and water (2 l) and adjusted to pH 9.0 with 20% aqueous sodium hydroxide. The resulting white solid was filtered off, and the filtrate was extracted with methylene chloride (2 l). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting precipitates were recrystallized from a mixture of diethyl ether and methylene chloride to give dimethyl (α-amino-3-nitrobenzylidene)malonate (139.5 g).
Reaction SMILES: Cl.N[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([OH:7])=[O:6].Cl.N([O-])=O.[Na+].[S-:18][S-].[Na+].[Na+]>O>[SH:18][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: [S-][S-]
Reactant: Cc1cccc(N)c1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(S)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
5.0 g of 2-amino-6-methylbenzoic acid hydrochloride was converted to a diazonium salt with concentrated hydrochloric acid and 2.3 g of sodium nitrite. Then, this diazonium salt was gradually dropwise added to a previously prepared sodium disulfide solution (which was prepared from 8.7 g of sodium sulfide nonahydrate, 1.1 g of sulfur, 1.5 g of sodium hydroxide and 15 ml of water) at from 0° to 5° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours to complete the reaction. The reaction solution was poured into a large amount of water, and concentrated hydrochloric acid was added thereto. Then, the mixture was extracted with ethyl acetate. A sodium hydrogen carbonate aqueous solution was added to the ethyl acetate layer, and sodium hydrogencarbonate-soluble components were extracted. 5.8 g of sodium pyrosulfate was added to the aqueous solution, and the mixture was refluxed for 30 minutes to complete the reaction. Concentrated hydrochloric acid was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The extract was dried, and then the solvent was distilled off under reduced pressure to obtain 3.6 g (yield: 65%) of 2-mercapto-6-methylbenzoic acid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: COc1cccc(/C=C/C(=O)O)c1
Agent: Cl
Product: COc1cccc(/C=C/C(=O)N[C@H]2CN3CCC2CC3)c1

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-methoxyphenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 287 (MH+).