Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:32]([OH:34])=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:16]([NH:23][C@H:24]([C:32]([NH2:7])=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
Dicyclohexylcarbodiimide (348 mg, 1.69 mmol) was added to a chilled solution of Boc-L-phenylalanine (387 mg, 1.46 mmol) and the ammonium salt of 1-hydroxybenzotriazole (248 mg, 1.63 mmol) in DMF (5 ml). The solution was stirred at 0° C. for 90 min, then at room temperature for 2 h. The reaction mixture was filtered, and the filtrate poured into water (77 ml). The emulsion was extracted with diethylether (1×200 ml), the layers separated, and the organic phase washed with 5% NaHCO3, water and brine, then dried (sodium sulphate) , filtered, and the filtrate concentrated in vacuo to give Boc-L-phenylalanine amide (370 mg, 96%). Analytical HPLC in the condition of example 1a), using a linear gradient of 20% A to 80% A over 25 min, then 80% A for 10 min, showed a single peak at 14.92 min.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:24][C:22]1[CH:21]=[CH:20][C:18]2[O:19][C:14]3[CH:13]=[C:12]([NH2:9])[CH:28]=[CH:27][C:15]=3[O:16][C:17]=2[CH:23]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1O2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: Nc1ccc2c(c1)Oc1ccc(N)cc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a mixture of 1200 ml of anisole and 800 ml of THF were added 69.7 g (0.254 mole) of 2,7-dinitrodibenzodioxin and 22.2 g of 10% palladium/carbon and hydrogen gas was passed through the mixture with stirring at room temperature for 8 hours. The 10% palladium/carbon was removed by filtration, then a precipitate containing the 10% palladium/carbon was collected by filtration, and the precipitate was rinsed with THF. The rinsings were concentrated and dried under reduced pressure to give 25.0 g (0.117 mole, 46.0% yield) of 2,7-diaminodibenzodioxin. The product showed a purity of 98.1% (HPLC, 254 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:23]([O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1
Reaction time: 4 h

Procedure:
In 100 ml of tetrahydrofuran were dissolved 4.6 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and 2.5 ml of benzyl alcohol, and under cooling at 0°-5° C. 2.4 ml of pyridine and 3.6 g of dicyclohexylcarbodiimide were added to the solution in that order. The mixture was stirred at the same temperature as above for 4 hours and then at room temperature for 18 hours. The precipitated dicyclohexylurea were filtered off and the filtrate was concentrated under reduced pressure. The residue was poured into a mixture of 300 ml of 2 N hydrochloric acid and 300 ml of ethyl acetate. The ethyl acetate layer was separated, washed with 2 N hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure and the residue was dissolved in a small amount of ethyl ether. To this solution was added petroleum ether to give crystals. Yield 4.8 g.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])O.[Na+].[NH2:16][C:17]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]([CH3:26])[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:19]([CH3:32])[CH:18]=1.Cl>C(O)C.O>[ClH:2].[ClH:1].[CH2:30]([O:29][C:27]([C:20]1[C:21]([CH3:26])=[C:22]([C:17]([NH:16][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:18][C:19]=1[CH3:32])[C:23]([OH:25])=[O:24])=[O:28])[CH3:31]
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)cc(NCCN2CCCCC2)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.6 %

Procedure:
1-(2-Chloroethyl)piperidine hydrochloride (0.85 g) and sodium hydrogen carbonate (1.5 g) were added to a solution of 6-amino-3-ethoxycarbonyl-2,4-dimethylbenzoic acid (1.0 g) in ethanol (10 ml) and water (10 ml). The mixture was stirred at room temperature for 24 hours and then its pH was adjusted to 4-5 by addition of 10% hydrochloric acid. The solution was concentrated under reduced pressure, and the resulting residue was extracted with CHCl3. The CHCl3 extracts were combined, washed with water, and dried over anhydrous MgSO4. The solvent was evaporated, and the residue was recrystallized from ethanol/diethyl ether to give 3-ethoxycarbonyl-2,4-dimethyl-6-(2-piperidinoethylamino)benzoic acid dihydrochloride (1.2 g, 68%). MS: m/e, 348(M+), 304, 303, 259. NMR: δ (ppm CDCl3), 1.37 (3H, t), 1.75 (6H, b), 2.25 (3H, s), 2.41 (3H, s), 3.00 (6H, b), 3.65 (2H, b), 4.36 (2H, q), 6.33 (1H, s), 8.20 (2H, b).
Reaction SMILES: [CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15]([O:17]C)=[O:16])[C:6]1=[O:19])[CH3:2].Cl>O1CCOCC1>[CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]1=[O:19])[CH3:2]
Reactant: CCSCn1c(=O)c(C(=O)OC)cc2cccnc21
Agent: Cl
Solvent: C1COCCO1
Product: CCSCn1c(=O)c(C(=O)O)cc2cccnc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
2.81 g (10.1 mmol) of methyl 1-(ethylthiomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (70 mL), and 6 N hydrochloric acid (20 mL) was added thereto at room temperature. The resulting mixture was stirred for 3 hours at 50° C. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue thus obtained was washed sequentially with water and diisopropyl ether. Thus, 2.20 g of the title compound was obtained as pale yellow crystals (yield: 82%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[F:57][C:58]1[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:59]=1[CH2:60][CH:61]1[CH2:66][N:65]([CH3:67])[CH2:64][CH:63]([NH2:68])[CH2:62]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:68][CH:63]3[CH2:62][CH:61]([CH2:60][C:59]4[C:69]([F:73])=[CH:70][CH:71]=[CH:72][C:58]=4[F:57])[CH2:66][N:65]([CH3:67])[CH2:64]3)=[O:36])[CH:33]=2)[N:28]([C:38]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1CC(N)CC(Cc2c(F)cccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(Cc2c(F)cccc2F)CC(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.1 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (1 g, 2.07 mmol) in DMF (5 mL) and was stirred at room temperature for 15 minutes. A solution of 5-(2,6-difluorobenzyl)-1-methylpiperidin-3-amine (511 mg, 2.13 mmol) in DMF (5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.72 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude product was progressed to the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:22][CH2:19][CH2:20][N:21]2[C:15](=[O:17])[C:11]2[N:10]([CH:14]=[CH:13][CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(Cn1cccc1C(=O)O)c1ccc(Br)cc1
Product: O=C1c2cccn2CC2(c3ccc(Br)cc3)NCCN12
Yield: 91.1 %

Procedure:
To a suspension of crude 1-[2-(4-bromophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (1.1 g, 0.714 mmol) suspended in xylenes (50 mL) was added ethane-1,2-diamine (0.5 mL, 7.5 mmol). The orange reaction mixture was heated at reflux for 1 h. The reaction mixture was concentrated in vacuo to give a dark orange oil that was purified using flash chromatography (Biotage SP4, 40 g cartridge, 0-10% MeOH gradient in EtOAc) to give 10a-(4-bromophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a pale yellow solid (216 mg, 90% yield). 1H NMR (400 MHz, d6-acetone): δ 2.71-2.84 (m, 1H), 3.30-3.38 (m, 1H), 3.42 (ddd, 1H, J 11.0, 7.7, 3.2 Hz), 3.70 (dt, 1H, J 10.8, 7.8 Hz), 4.36 (d, 1H, J 12.3 Hz), 4.65 (d, 1H, J 12.3 Hz), 6.03 (dd, 1H, J 3.7, 2.6 Hz), 6.66 (m, 2H), 7.29-7.33 (m, 2H), 7.45-7.49 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C:10]1([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.[ClH:21]>O1CCOCC1.CCOCC>[ClH:21].[CH3:1][NH:2][C:10]1([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1(COc2cccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNC1(COc2cccnc2)CC1
Temperature: 25 °C

Procedure:
A solution containing 0.32 g of the compound obtained in Step 1 in 3 ml of dioxane and 3 ml of 4N hydrochloric acid in dioxane is stirred at ambient temperature and under an inert atmosphere, and is then diluted with ether. The liquid phase is then separated off and the residue is taken up in 25 ml of ethanol. The solution is concentrated to 2 ml and is then diluted with 20 ml of ether and stirred; the precipitate formed is filtered off, rinsed and dried, allowing the expected product to be isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:16]([OH:18])=[O:17])[CH2:11][C:10]([O:14]C)(OC)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:16]([O:18][CH3:20])=[O:17])[CH2:9][C:10](=[O:14])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: COC1(OC)CC(C(=O)O)(c2ccc(F)cc2)C1
Agent: Cl
Product: COC(=O)C1(c2ccc(F)cc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a stirred solution of Intermediate 308B (1.0 g, 3.93 mmol) in MeOH (15 mL) was added a concentrated aq. solution of HCl (5 mL) and the solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography (24 g REDISEP® column, eluting with 20% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 308C as a colorless oil (700 mg, 80%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.45 (dd, J=8.94, 5.05 Hz, 2H), 7.09 (t, J=8.66 Hz, 2H), 3.89 (m, 2H), 3.71 (s, 3H), 3.57-3.72 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.C(Cl)CCl>>[Br:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Reactant: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Br)c2F)c1
Yield: 63.2 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethylbenzonitrile (0.053 g, 0.174 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.036 g, 0.174 mmol) and DIEA (0.061 mL, 0.348 mmol) were combined and treated with EDC (0.067 g, 0.348 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 4-bromo-N-({4-chloro-3-[(3-cyano-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.054 g, 0.110 mmol, 63.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6+1 drop D2O) δ ppm 7.40-7.51 (m, 2H), 7.32 (t, J=7.83 Hz, 1H), 7.14 (d, J=6.73 Hz, 2H), 4.47 (s, 2H), 2.62 (q, J=7.51 Hz, 2H), 2.24 (s, 3H), 1.12 (t, J=7.49 Hz, 3H). LC-MS (ES−) m/z 488.97, 490.93, 492.87 [M−1]. LC-MS (ES+) m/z 491.10, 493.10, 495.07 [M+H].
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:13])([CH:10]([F:12])[F:11])[CH2:8][OH:9].Cl>N1C=CC=CC=1>[C:2](=[O:3])([O:9][CH2:8][C:7]([F:13])([F:6])[CH:10]([F:12])[F:11])[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: OCC(F)(F)C(F)F
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)OCC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Methyl chloroformate (130 mL, 159 g, 1.68 mol) was added slowly over a period of 3 h to a solution of 2,2,3,3-tetrafluoropropanol (132 g, 1.00 mol) in pyridine (300 mL, anhydrous) at −10° C. to 0° C. with magnetic stirring. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was mixed with 5% HCl (500 mL) and approximately 50 g of ice, and the resulting mixture was extracted three times with 300 mL portions of ether. The combined organic layer was washed three times with 100 mL portions of 5% HCl, followed by two washes with 100 mL portions of 5% sodium carbonate. The organic phase was then dried over anhydrous sodium sulfate. Ether was removed by rotary evaporation. The crude product (approximately 200 g) was distilled, yielding 166 g (87% yield) of pure methyl 2,2,3,3-tetrafluoropropyl carbonate, also referred to herein as “FS-C”. NMR analysis data were consistent with the literature values (U.S. Pat. No. 5,659,062).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:8][C:9]1[O:10][C:11]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])=[CH:12][CH:13]=1)[CH3:2]>C(O)C.[Pd]>[C:27]([O:26][C:24]([CH:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:31])[CH2:8][C:9]1[O:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)CCC(=Cc1ccc(C(=O)OCc2ccccc2)o1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(Cc1ccc(C(=O)O)o1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-[5-(Benzyloxycarbonyl)furan-2-yl]-4-tert-butoxycarbonyl-4-pentenoic acid ethyl ester obtained in step 2 was dissolved in ethanol (5 mL), a catalytic amount of 10% palladium/carbon was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (82 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.S(=O)(=O)(O)[O-].[Na+]>C(#N)C>[Br:12][C:8]1[C:7]([CH3:11])=[C:3]([C:2]([OH:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(O)c1C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(Br)ccc(O)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
Step 2 A suspension of 2-hydroxy-6-methylbenzoic acid (1.32 g, 8.68 mmol) in acetonitrile (20 mL) at −20° C. was treated with tetrafluoroboric acid dimethyl ether complex (1.109 mL, 9.11 mmol), followed by portionwise addition of N-bromosuccinimide (1.699 g, 9.54 mmol) over 30 min. The mixture was warmed to 0° C. and stirred for 1 h, then was treated with 40% aqueous sodium bisulfate (10 mL). The acetonitrile was removed under vacuum and the aqueous residue was extracted with EtOAc (3×40 mL). The combined organic layers were washed with water and brine, dried and concentrated to give 3-bromo-6-hydroxy-2-methylbenzoic acid as a white solid (1.60 g, 80%). 1H NMR (400 MHz, methanol-d4) δ 7.47 (1 H, d, J=8.80 Hz), 6.67 (1 H, d, J=8.80 Hz), 2.50 (3 H, s). Mass spectrum m/z 231, 233 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]12([CH2:18][S:19](O)(=O)=O)C(C)(C)[CH:12]([CH2:13][CH2:14]1)[CH2:11][C:9]2=O>C1(C)C=CC=CC=1>[S:19]1[CH:18]=[CH:8][CH:9]=[C:11]1[C:12]1[N:3]2[N:4]=[C:5]([NH2:7])[N:6]=[C:2]2[N:1]=[CH:14][CH:13]=1
Reactant: Nc1n[nH]c(N)n1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Nc1nc2nccc(-c3cccs3)n2n1
Temperature: 100 °C
Yield: 66.2 %

Procedure:
The obtained 3-dimethylamino-1-thiophen-2-ylpropenone (10.78 g) was dissolved in toluene (160 ml). Thereafter, 3,5-diamino-1,2,4-triazole (14.15 g) was added to the solution, and the obtained mixture was stirred at 100° C. After 10-camphorsulfonic acid (13.82 g) was added thereto, the mixture was heated to reflux for 1.5 hours. The reaction solution was cooled to a room temperature, and the supernatant was then eliminated (decant). The residue was washed by successive suspension in an aqueous 5% sodium carbonate-10% ethanol solution, a 10% ethanol solution, ethanol, and methylene chloride. The resultant was then dried under a reduced pressure to obtain the captioned compound (8.55 g).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]1.C1COCC1>[Pd].CO>[F:30][C:2]([F:1])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:23]1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1N
Reaction time: 2 h

Procedure:
A mixture of N-(3,3,3-trifluoro-propyl)-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-nitro-benzoic acid amide (2.5 g, 5.7 mmol), Pd/C (200 mg), THF (10 mL) and MeOH (100 mL) is stirred for 2 h under 3 bar H2-atmosphere. The mixture is filtered, and the filtrate is concentrated. Yield: 2.3 g. HPLC Rt=1.25 min (method A). MS m/z: 413 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O>[OH:1][C:2]([C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(O)c3ccc(C(=O)O)cn3)s2)c1
Temperature: 100 °C
Yield: 93.8 %

Procedure:
The product of Step 2 (366 mg, 0.710 mmol) was taken up in MeOH (8.0 ml) in a microwave vial, and sodium hydroxide (1.0 M in H2O, 1.42 ml, 1.42 mmol) was added. The reaction was heated to 100° C. for 10 min in the microwave. The colorless solution was adjusted to a pH of 3-4 with 1 N HCl, diluted with water, and extracted with 15% IPA/CHCl3 (2×). The combined organic layers were dried (MgSO4), filtered and evaporated to a yellow solid that was triturated with CH2Cl2/hexanes, filtered, and dried to provide the title compound (334 mg, 0.666 mmol, 94% yield) as a pale yellow powder. MS ESI: [M+H]+ m/z 502.1. 1H NMR (500 MHz, DMSO-d6) δ 13.53-13.21 (s, 1H), δ 10.24 (s, 1H), 8.99 (d, J=2.0, 1H), 8.82 (d, J=4.9, 1H), 8.29 (dd, J=2.2, 8.3, 1H), 7.98-7.90 (m, 2H), 7.85 (d, J=8.3, 1H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.29 (s, 3H), 1.98 (s, 3H). rhSYK activity=+++
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][C:11]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)#[N:9]>C(Cl)Cl>[NH:33]1[C:29]2=[N:30][CH:31]=[CH:32][C:27]([C:25]3[CH:24]=[N:23][N:22]([C:11]4([CH2:10][C:8]#[N:9])[CH2:12][NH:13][CH2:14]4)[CH:26]=3)=[C:28]2[CH:35]=[CH:34]1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4[nH]ccc34)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CNC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (7.0 mL) was added to tert-butyl 3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.90 g, 2.4 mmol) in methylene chloride (7.0 mL). The reaction mixture was stirred at 30° C. for 2 h. The volatiles were removed under reduced pressure to afford the desired product (quantitative) as TFA salt which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=279.1.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: COc1ccc(NCCN)nc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)nc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(50 ml) and triethylamine(1.95 ml), and then diphenylphosphinic chloride(1.34 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylamino)-5-methoxypyridine(1.17 g) added thereto, was stirred for 8 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.22 g of the aimed compound.