Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([OH:7])[C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:25][C:19]([O:7][C:4]1[C:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[NH:6][N:5]=1)([CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1[nH]nc(O)c1-c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1n[nH]c(C)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-ol (200 mg, 0.89 mmol), ethyl bromoisobutyrate (0.14 mL, 0.89 mmol) and potassium carbonate (136 mg, 0.98 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded compound ethyl 2-methyl-2-(5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-yloxy)propanoate as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C[O:37][CH2:36]C1.CO.[OH-].[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH2:31][CH2:32][O:37][CH3:36])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCS(=O)(=O)N1CCN(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1M aqueous NaOH solution (1.46 ml) was added thereto, followed by stirring at room temperature for 3 hours. CHCl3 was added to the reaction mixture, which was washed with water and saturated brine, and dried over Na2SO4. Then, the organic layer was concentrated under reduced pressure to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-{4-[(2-methoxyethyl)sulfonyl]piperazin-1-yl}pyrimidine (353 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][N:27]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: CNCC(=O)OC
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30.0 μL, 0.176 mmol). Following 4 hours of stirring at room temperature, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 (MHz, DMSO-d6) δ ppm 0.98-1.20 (m, 2 H), 1.38-1.55 (m, 2 H), 1.70-1.93 (m, 5 H), 2.20-2.33 (m, 2 H), 2.78-2.88 (m, 1 H), 3.01-3.10 (m, 3 H), 3.64 (s, 3 H), 4.08 (s, 2 H), 7.03-7.19 (m, 1 H), 7.28-7.41 (m, 2 H), 7.66-7.76 (m, 2 H), 13.80-14.09 (m, 1 H); MS (ESI) m/z 438 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
4-((6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (32 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 22 mg (yield 30%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16](=[O:25])[C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[C:14]=2[CH:15]=1)=[CH:10][C:9]([F:27])=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:26])[N:13]([C:16]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)=[O:25])[C:14]=2[CH:15]=1)=[CH:10][C:9]([F:27])=[CH:8][CH:7]=3
Reactant: COc1ccc(C(=O)N2c3cc(F)ccc3-c3ccc(F)cc3C2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2cc(F)ccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
4-[(3,8-Difluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol—A stirred suspension of 3,8-difluoro-5-(4-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine (0.20 g, 0.55 mmol) and cyclohexene (1.64 g, 20.0 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (4.0 mL, 4.0 mmol). After stirring for approximately two hours at room temperature, the reaction was cooled to −20° C. and quenched with methanol (5 mL). The solvent was evaporated in vacuo to a dark oil. The dark oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min to afford, after evaporation of the solvent in vacuo and trituration with diethyl ether-hexane, the title compound (0.19 g, 0.54 mmol, 99%) as a homogeneous, colorless, racemic solid, m.p. 193-195° C.; MS [(+ESI), m/z]: 352 [M+H]+; MS [(−ESI), m/z]: 350 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ: 1.21 (d, J=7.0 Hz, 3H), 5.71 (q, J=6.8 Hz, 1H), 6.55 (dd, J=10.5, 2.5 Hz, 1H), 6.70 (d, J=8.6 Hz, 2H), 7.06 (td, J=8.6, 2.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 7.27 (td, J=8.8, 2.7 Hz, 1 H), 7.38 (dd, J=9.2, 2.7 Hz, 1H), 7.97 (dd, J=9.0, 6.4 Hz, 1H), 8.01 (dd, J=9.1, 6.0 Hz, 1H), 10.04 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)C2CCCC2)cc1Br
Product: Cc1ccc(S(=O)(=O)N(C)C2CCCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-cyclopentyl-4,N-dimethyl-benzenesulfonamide (Intermediate 153), the title compound was obtained as a orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:6][CH:7]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CS(O)(=O)=O.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2nnc[nH]2)ccc1Br
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Temperature: 68 °C

Procedure:
3-Bromo-2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridine (1 equiv), 3,4-dihydro-2H-pyran (2 equiv) and methanesulfonic acid (0.1 equiv) were combined in tetrahydrofuran. The reaction was heated to 68° C. for 3.5 h, cooled to room temperature, and treated with triethylamine (0.4 equiv). The reaction mixture was concentrated under reduced pressure, treated with acetonitrile and concentrated under reduced pressure at 35° C. The residue was dissolved in acetonitrile (1 volume) and water (2.25 volumes), and the solids were collected by filtration, washed with a solution of 20% acetonitrile in water and dried. The crude product was triturated with hexanes, filtered, washed with hexanes and dried to provide the desired product, as a solid. MS (ESI) m/z 324.9 [M+2]+.
Reaction SMILES: [CH3:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[C:9]([C:27](=O)[C:28]([OH:30])=[O:29])=[CH:8]2)=[CH:4][CH:3]=1.O.NN.C[O-].[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=4)=[CH:13][CH:14]=3)[C:9]([CH2:27][C:28]([OH:30])=[O:29])=[CH:8]2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(Cn2cc(C(=O)C(=O)O)c3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Agent: C[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cn2cc(CC(=O)O)c3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from {1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid, hydrazine monohydrate and sodium methoxide according to the procedure described in Example 64. The product was obtained as a brown solid, mp: 62-63° C. Mass spectrum (−ESI, [M−H]−) m/z 438. 1HNMR (400 MHz, DMSO-d6): δ 7.79 (s, 1H), 7.75 (d, 2H, J=8.70 Hz), 7.50 (d, 1H, J=8.56 Hz), 7.42-7.39 (m, 4H), 7.12 (d, 2H, J=8.55 Hz), 7.11 (d, 2H, J=8.55 Hz), 5.34 (s, 2H), and 2.23 ppm (s, 3H).
Reaction SMILES: [C:1]12([Li])[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3].[Cl-].[Zn+2:13].[Cl-]>CCCCC.C(OCC)C>[C:1]12([Zn:13][C:1]34[CH2:10][CH:7]([CH2:8][CH2:9]3)[C:5](=[CH2:6])[C:2]4([CH3:4])[CH3:3])[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3]
Reactant: [Zn+2]
Reactant: [Li]C12CCC(C1)C(=C)C2(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCC
Product: C=C1C2CCC([Zn]C34CCC(C3)C(=C)C4(C)C)(C2)C1(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Thiele et al. Anorg. Allg. Chem. Chem. 1988, 561, 73. To a stirred suspension of 18.4 g 1-camphenyllithium in 250 mL n-pentane is added dropwise a solution of 9 g zincchloride in 300 mL diethylether at room temperature (keep the speed of addition in such a way that the solution is boiling smoothly). This reaction mixture is stirred for 3 h and is subsequently allowed to stand overnight. The precipitated LiCl is filtered off and the solvent of the filtrate is completely removed. The residue is solved in n-pentane and remaining LiCl is separated. The solution is the cooled to -78° C. The precipitated crystalls are filtered at low temperature and dried in vacuo. Yield: 12.5 g (60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([CH2:15][OH:16])[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:18]=[O:19]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([CH2:15][O:16][C:18]([NH:17][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1C2CCC1N(Cc1ccccc1)C2
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)OCC2C3CCC2N(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.6 %

Procedure:
200.00 mg (0.920 mmol) of (2-benzyl-2-aza-bicyclo[2.2.1]hept-7yl)methanol were dissolved in 3 ml of dry THF and then 176.00 mg (0.920 mmol) of ethyl 3-isocyanatobenzoate in 1 ml of dry THF were added at room temperature. After stirring for 6 hours at room temperature, 125 mg (0.30 mmol) of tris-(2-aminoethyl)amine-polystyrene and 250 mg (0.30 mmol) of methyl isocyanate-polystyrene (each from NovaBiochem) were added and stirred at 50° C. overnight. After the resins had been filtered off, the solvent was removed and the required product was purified by chromatography with ethyl acetate as mobile phase. In this way, 220.00 mg (0.539 mmol) of ethyl 3-(2-benzyl-2-azabicyclo[2.2.1]hept-7-ylmethoxycarbonylamino)benzoate were obtained in the form of a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[O:14]=[C:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[C:16]([C:15](=[O:14])[CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC(=O)CCCCCCC(=O)O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)CCCCCC(=O)O

Procedure:
The procedure described in Example 9 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.72 g of 8-ketononanoic acid. Yield1.85 g (55%), yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH3:30])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH3:30])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1

Procedure:
A mixture of methyl 2-[(4-{3-[(2,4-difluorobenzyl)(propyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (0.184 g, 0.382 mmol) and lithium hydroxide (0.018 g, 0.76 mmol) in THF (2 ml) and water (2 ml) was heated at 150 degrees for 7 minutes. The mixture was diluted with water, acidified with hydrochloric acid and extracted with methylene chloride. The combined extracts were dried with magnesium sulfate and evaporated to give 2-[(4-{3-[(2,4-difluorobenzyl)(propyl)amino]-3-oxopropyl}phenoxy)methyl]benzoic acid.
Reaction SMILES: C(O)C.FC(F)(F)S(O[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccccc2F)CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethanol (100 mL) was added to a solution of ethyl 2-trifluoromethanesulfonyloxycyclohex-1-enecarboxylate obtained in Preparation Example 1-(1) (17.0 g) in toluene (200 mL). 2-Fluorophenylboronic acid (7.74 g) and tetrakis(triphenylphosphine)palladium (1.60 g) were added. A 1 N sodium carbonate solution (55.3 mL) was added, followed by replacement of the reaction atmosphere with nitrogen. The reaction solution was heated to 80° C. and stirred for eight hours. After returning to room temperature, the excess of ethanol was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=[O:17].CO.[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([F:21])[C:5]2=[O:17]
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Product: O=C1c2cc(Br)ccc2OC2(CCCOC2)C1F
Yield: 10 %

Procedure:
To a solution of 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (2 g, 6.8 mmol) in MeOH Selectfluor™ (2.5 g, 7.1 mmol) was added. The suspension was refluxed overnight. Then the solvent was removed in vacuo. CH2Cl2 was added to the resulting residue and insoluble material filtered off. The filtrate was washed with H2O, dried and concentrate in vacuo. The crude product was purified by column chromatography to give 6-bromo-3-fluoro-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (220 mg, 10%). 1H-NMR (CDCl3): 1.72-2.21 (m, 4H), 3.44 (m, 1H), 3.63 (m, 1H), 3.73 (m, 1H), 3.92 (m, 1H), 4.91 (m, 1H), 6.94 (m, 1H), 7.56 (m, 1H), 7.90 (m, 1H).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][CH:25]([NH2:34])[CH:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:34][C@H:25]([CH3:24])[C@@H:26]([OH:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:18])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CC(N)C(O)c1ccccc1
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)[C@@H](O)c1ccccc1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with (1S,2R)-(+)-norephedrine as in EXAMPLE 1, Part C. HPLC: RT=10.13 min. MS (ESI−): mass calcd. for C22H19ClN4O4S2, 502.05; m/z found, 501 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.69 (s, 1H), 8.37 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.73 (d, J=2.0, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.41-7.29 (m, 5H), 7.24 (d, J=8.4, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.28 (br d, J=8.3, 1H), 4.98 (d, J=3.0, 1H), 4.45 (dd q, J=8.3, 6.9, 3.0, 1H), 2.60 (br s, 1H), 1.05 (d, J=6.9, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:34])[CH2:33][CH2:32][C:27]4(OCC[O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[N-:35]=[N+]=[N-].[Na+].CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[OH:34][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:33][CH2:32][NH:35][C:27](=[O:28])[CH2:26][CH2:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC4(CC3)OCCO4)s2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Yield: 63.9 %

Procedure:
A mixture of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (60 mg, 0.122 mmol), sodium azide (23.76 mg, 0.365 mmol) and methanesulfonic acid (95 μL, 1.462 mmol) in CHCl3 (1.2 mL) was heated at 65° C. for 1 h and cooled to room temperature. The mixture was treated with water, and extracted with ethyl acetate. The combined organics were dried, filtered, concentrated and purified by flash chromatography to afford 5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (36 mg, 0.078 mmol). APCI: [M+H]+ m/z 464.2. 1H NMR (600 MHz, CDCl3): δ 8.63 (d, J=4.9, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 7.03 (d, J=4.9, 1H), 6.21 (s, 1H), 3.81 (s, 1H), 3.46 (s, 1H), 3.21-3.03 (m, 2H), 2.41 (dd, J=7.5, 14.4, 1H), 2.37 (s, 3H), 2.24 (t, J=13.3, 1H), 2.18-2.04 (m, 3H). rhSYK activity=+++
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][CH:35]([C:37]#[N:38])[CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH:35]([C:37]#[N:38])[CH2:36]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(C#N)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CC(C#N)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 68.9 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 0.5 mL, 6.49 mmol, Eq: 94.1), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane (added few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, light yellow flakes separated by decantation and dried under high vacuum to give N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 63.2 μmol, 91.6%). MS (M+H)+=523; 1H NMR (DMSO-d6) δ: 12.80 (br. s., 1H), 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.81-7.96 (m, 2H), 7.39 (dd, J=9.1, 2.3 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.53 (t, J=6.6 Hz, 2H), 3.35-3.57 (m, 3H), 3.16-3.25 (m, 2H), 2.38 (t, J=6.8 Hz, 2H), 1.78-2.02 (m, 2H), 1.49 (s, 9H).