Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:31][C:32]1[C:33]2[N:34]([C:38]([CH3:42])=[C:39]([CH3:41])[N:40]=2)[CH:35]=[CH:36][CH:37]=1.[I-].[Na+]>COCCOC.CO.CN(C)C=O>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH2:31][C:32]1[C:33]2[N:34]([C:38]([CH3:42])=[C:39]([CH3:41])[N:40]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc2c(CCl)cccn2c1C
Reactant: Cc1cccc(C)c1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1OCc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of potassium hydroxide (0.035 g, 0.62 mmol), 2,6-dimethylphenol (0.075 g, 0.62 mmol) and 18-crown-6 (0.035 g) in 1,2-dimethoxyethane was added 8-chloromethyl-2,3-dimethylimidazo[1,2-a]pyridine (0.1 g, 0.51 mmol) in 1,2-dimethyxyethane (3 ml). The reaction mixture was stirred for 1.5 h. at room temperature and sodium iodide (0.035 g, 0.23 mmol) was added. The mixture was stirred for 3.5 h. and N,N-dimethylformamide (1 ml) and methanol were added and the solids were isolated by filtration. The filtrate was evaporated under reduced pressure, the residue was solved in methylene chloride and washed with saturated sodium bicarbonate. The organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (100:3.5) as eluent to give 0.11 (78%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.Cl.[NH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: OC1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Temperature: 80 °C
Yield: 29.5 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (0.54 g, 2.66 mmol), azetidin-3-ol hydrochloride (0.46 g, 4.17 mmol) and tetrabutylammonium iodide (0.103 g, 0.278 mmol) in 6 mL of DMSO is added potassium carbonate (1.06 g, 7.68 mmol). The resulting mixture is heated to 80° C. for 3 h. Poured into ethyl acetate/NaHCO3 solution. Extracted with ethyl acetate (2×250 mL). The organic layer is ished with brine and dried over Na2SO4. Concentrated to give 1-(6-nitro-pyridin-3-yl)-azetidin-3-ol (153 mg, 29%). MS (ESI) m/z 240.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.[CH2:25]([N:27](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN>CN(C)C=O.C(Cl)Cl>[CH3:25][NH:27][C:19]([C@@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH2:14]1)=[O:20]
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of 0.339 g (1.03 mmol) of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid in 21 ml of N,N-dimethylformamide, cooled to 0° C., is treated consecutively with 0.15 ml (1.13 mmol) of triethylamine, 0.390 g (1.03 mmol) of HBTU, 0.085 g (1.24 mmol) of methylamine hydrochloride, and 0.15 ml (1.13 mmol) of triethylamine. The reaction is stopped after 30 min and the orange colored solution is evaporated under reduced pressure. The residue obtained is triturated in ethyl acetate, the white solid product is filtered, thereafter dissolved in dichloromethane and the solution washed three times with water. The organic phase is dried over sodium sulfate, then evaporated under reduced pressure to yield 231 mg (66% of theory) of a white solid. MS: m/e=343 (M+H)+; [α]589=−25.48° (c=0.954, CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].O.[NH2:12][NH2:13]>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: NN
Reactant: Cc1c(Cl)nnc(Cl)c1C
Solvent: O
Product: Cc1c(Cl)nnc(NN)c1C
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3,6-Dichloro-4,5-dimethylpyridazine (W4.006; 29.0 g) was admixed with 160 ml of hydrazine monohydrate solution (160 ml) and heated to 90° C. while stirring for 4 h. The reaction mixture was admixed with water and the precipitate was filtered off with suction, washed with water and dried over phosphorus pentoxide. 27.2 g of the title compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][C:5]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:10].[C:23]([NH:30][CH2:31][C:32](O)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1>C1COCC1.CCOC(C)=O>[C:23]([NH:30][CH2:31][C:32]([NH:1][CH2:2][C:3]1[S:4][C:5]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:10])=[O:33])([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CNC(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 40.1 %

Procedure:
To a solution of N-(2-aminomethyl-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.20 g, 0.63 mmol) and N-carbo-tert-butoxyglycine (0.11 g, 0.63 mmol, 1.0 equiv) in THF (2 mL) at room temp. were added dicyclohexylcarbodiimide (0.13 g, 0.63 mmol, 1.0 equiv) and 1-hydroxybenzotriazole monohydrate (0.008 g, 0.06 mmol, 10 mol %). The resulting mixture was allowed to stir 18 h, diluted with EtOAc (5 mL), and washed with a saturated NaCl solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient from 30% EtOAc/hexane to 50% EtOAc/hexane) to afford N-(2-(N-(N-carbo-tert-butoxyglycyl)aminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.12 g, 40%, Example 52): mp 174-176° C.; 1H NMR (CDCl3) δ1.38 (s, 9H), 2.27 (m, 3H), 4.38 (m, 2H), 6.67 (bs, 1H), 6.89 (m, 1H), 7.27 (m, 1H), 7.33 (m, 2H), 8.58 (bs, 1H); FAB-LRMS m/z 475 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12]C(N(C)C)=O)[CH:3]=1.[OH-].[Na+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([SH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1SC(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Br)cc1S
Temperature: 100 °C
Reaction time: 14 h
Yield: 98.7 %

Procedure:
A mixture of methyl 4-bromo-2-[[(dimethylamino)carbonyl]thio]benzoate (3.2 g, 10 mmol) and 10% aqueous sodium hydroxide solution (20 g, 50 mmol) was stirred at 100° C. for 14 hrs. The reaction mixture was acidified (pH 3) by the addition of 6 N hydrochloric acid. The precipitates were collected by filtration, dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (2.3 g, 100%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41].C(Cl)CCl>C(#N)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[N:20]=[C:32]([C:30]3[CH:29]=[CH:28][C:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=3)[O:22][N:21]=2)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1Cl
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Solvent: ClCCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 75 (0.270 g, 0.83 mmol) and Intermediate 3 (0.192 g, 0.75 mmol) in ACN (2 mL) was added EDC (0.201 g, 1.05 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. under microwave irradiations for 45 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.43 (1H, d, J=1.8 Hz), 8.21 (1H, d, J=1.7 Hz), 8.17 (1H, dd, J=7.9, 1.9 Hz), 8.08 (1H, dd, J=8.0, 1.7 Hz), 7.72 (1H, d, J=8.0 Hz), 7.35-7.21 (4H, m), 7.13 (1H, d, J=7.4 Hz), 4.29-4.17 (2H, m), 3.90 (2H, s), 3.33 (3H, s), 3.29 (2H, s), 2.46 (3H, s), 2.08 (3H, s), 1.50 (9H, s).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:14]>CO.O=[Pt]=O>[ClH:14].[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: c1ccc(CC2CCCNC2)cc1
Reaction time: 24 h
Yield: 68 %

Procedure:
To a solution of 3-benzylpyridine (10 g, 59.8 mmol) in methanol (150 mL) were added PtO2(350 mg) and HCl conc. (5 mL). This heterogeneous solution was hydrogenated in a Parr hydrogenator at 20-25 psi at 25° C. and for 24 hrs then filtered through a celite pad and concentrated in vacuum. The crude compound was purified by crystallization from acetone/diethyl ether to give a white solid (8.5 g, 68%). 1H-NMR (DMSO): 1.05-1.2 (m, 1H); 1.5-1.75 (m, 3H); 1.87-2.05 (m, 1H); 2.4-2.55 (m, 3H); 2.57-2.75 (m, 1H); 2.982 (d, J=11.7, 1H); 3.97 (d, J=12.0, 1H); 7.136 (d, J=7.0, 2H); 7.184 (d, J=7.0, 1H), 7.296 (t, J=7.2, 2H); 8.89 (bs, 1H); 9.15 (bs, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[O:13])=[C:10]([F:23])[CH:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>O.C1(C)C=CC=CC=1.C(O)C.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>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[O:13])=[C:10]([F:23])[CH:9]=2)=[CH:33][N:34]=1
Reactant: COC(=O)C(C)NC(=O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(NC(=O)c1ccc(-c2cnc(N)nc2)cc1F)C(=O)O
Temperature: 120 °C
Yield: 101.1 %

Procedure:
A solution of potassium carbonate (0.35 g, 2.5 mmol) in water (2 mL) was added to a mixture of methyl 2-[(4-bromo-2-fluorobenzoyl)amino]propanoate (0.5 g, 1.6 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.28 g, 1.3 mmol), and tetrakis(triphenylphosphine)palladium (0.07 g, 0.06 mmol) in toluene (4 mL) and ethanol (2 mL). The resulting mixture was heated at 120° C. for 15 min. The reaction mixture was extracted with ether (3×10 mL) to remove impurity. The aqueous layer was adjusted to pH 7 with aqueous HCl and purified by RP-HPLC (pH 10) to afford the desired product (0.40 g, 100%). LCMS: (M+H)=305.0.
Reaction SMILES: [CH2:1]([C:5](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[CH:6]=[O:7])[CH2:2][CH2:3][CH3:4].Cl.[CH3:19]O>>[CH2:1]([C:5]1[CH2:8][C:9]2[C:14]([C:6]=1[O:7][CH3:19])=[CH:13][C:12]1[O:15][CH2:16][O:17][C:11]=1[CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCC(C=O)=Cc1ccc2c(c1)OCO2
Agent: Cl
Product: CCCCC1=C(OC)c2cc3c(cc2C1)OCO3
Yield: 90 %

Procedure:
Dissolved in 80 ml of methanol was 12 g of 2-n-butyl-3-(3,4-methylenedioxyphenyl)acrylaldehyde, into which hydrogen chloride gas was blown under ice-salt cooling. Upon confirmation of full consumption of the raw material by thin-layer chromatography (eluent: a 5:1 mixture of n-hexane and ether), the bubbling of hydrogen chloride gas was stopped. Water was added to the reaction mixture, followed by extraction of the resultant mixture, followed by extraction of the resultant mixture with ether. After the resultant ether solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water successively, the ether solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of n-hexane and ether) to give 11.4 g of 2-n-butyl-3-methoxy-5,6-methylenedioxyindene as an oily substance (yield: 90%).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.Cl[C:7]([O:9][CH3:10])=[O:8]>C(OCC)C>[CH3:10][O:9][C:7](=[O:8])[C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: C#CC1CC1
Solvent: CCOCC
Product: COC(=O)C#CC1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of cyclopropyl acetylene (10.0 g, 148 mmol) in 50 mL of ethyl ether at −78° C. under argon was added methyllithiium (1.4 M in ethyl ether, 107 mL, 150 mmol). This solution was stirred at −78° C. for 1 h. Methyl chloroformate (12.0 mL, 154 mmol) was added. The reaction mixture was warmed to room temperature in 2 h and was quenched with water. The organic layer was separated. The aqueous layer was extracted with ethyl ether (50 mL×3). The combined organic layer was dried over sodium sulfate and evaporated to give cyclopropyl-propynoic acid methyl ester as a yellow oil (13.25 g, 72%).
Reaction SMILES: [NH3:1].CO[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:21]=2[CH2:20]1)=[O:5]>CN(C)C=O>[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[O:27][C:21]=2[CH2:20]1)(=[O:5])[NH2:1]
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reactant: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 1 h

Procedure:
0.02 mol of concentrated ammonia (D=0.9) is added dropwise to a solution of 4.02 g of 2-[4-(5-methoxycarbonyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine in 30 ml of dimethylformamide at 20°. The mixture is stirred at 20° for 1 hour, the usual working up is carried out and 2-[4-(5-carbamoyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [Li]CCCC.[B:6](OC(C)C)([O:11]C(C)C)[O:7]C(C)C.O.[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:22]1([B:6]([OH:11])[OH:7])[CH:21]=[CH:20][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: O
Product: OB(O)c1ccccc1
Reaction time: 8 h

Procedure:
In an Ar atmosphere, the crystals of 2-(4-bromophenyl)-naphthalene obtained in Synthesis Step C1-3, 10 g, and 500 mL of anhydrous tetrahydrofuran were put into a 1-L flask, and then 22 mL of a 1.6 mol/L n-BuLi solution in hexane was added dropwise at −60° C. over 30 minutes. Thirty minutes later, 7 g of triisopropyl borate was added dropwise, and then the reaction was allowed to proceed overnight with no temperature control. After the completion of the reaction, 100 mL of water was added dropwise, and the obtained solution was subjected to extraction with 2 L of toluene and separated. The isolated organic layer was concentrated, the residue was recrystallized, and the crystals were collected by filtration and dried. In this way, a phenylboronic acid derivative was obtained as a white solid weighing 5 g.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH-].[K+:37]>C(#N)C.O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O-:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1.[K+:37]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)[O-])C(C)(C)C3)s2)c1
Temperature: 35 °C

Procedure:
(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 μL) and water (20 μL). Potassium hydroxide (19 μL, 0.019 mmol) was added, and the mixture was heated to 35° C. for 10 min. The mixture was allowed to cool to room temperature, diluted with water, froze to a solid, and lyophilized to dryness to afford potassium (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M+H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.27 (d, J=4.9, 1H), 7.12 (s, 1H), 5.97 (s, 2H), 2.31 (s, 3H), 1.92-1.82 (m, 211), 1.81-1.65 (m, J=13.8, 5H), 1.54-1.48 (m, 1H), 1.47-1.39 (m, 1H), 1.05 (s, 3H), 0.95 (s, 31-1). rhSYK activity=+++
Reaction SMILES: C([BH3-])#[N:2].[Na+].[NH2:5][C:6]1[C:38]([Br:39])=[CH:37][C:9]([CH2:10][C@H:11]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[O:23])[NH:12][C:13]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[O:14])=[CH:8][C:7]=1[Br:40].C([O-])(=O)C.[NH4+].Cl>CO>[NH2:5][C:6]1[C:38]([Br:39])=[CH:37][C:9]([CH2:10][C@H:11]([C:22]([N:24]2[CH2:29][CH2:28][CH:27]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[O:23])[NH:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([NH2:2])[CH2:17][CH2:16]2)=[O:14])=[CH:8][C:7]=1[Br:40]
Reactant: CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(N)c(Br)c3)NC(=O)N3CCC(=O)CC3)CC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(N)c(Br)c3)NC(=O)N3CCC(N)CC3)CC2)CC1

Procedure:
653 mg (10.4 mMol) 95% sodium cyanoborohydride (Aldrich 15.615-9) was stirred into the mixture of 930 mg (1.48 mMol) 1-[4-amino-3,5-dibromo-N-[(4-oxo-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, 1143 mg (14.8 mMol) ammonium acetate (Merck No. 1115) and 30 ml anhydrous methanol at room temperature, and was stirred overnight. The deposit was adjusted to pH ≦2 with conc. hydrochloric acid and was evaporated in a vacuum. The residue is taken up in water and made alkaline with 40% soda lye. Exhaustive extraction with dichloromethane followed, then the combined extracts were dried over sodium sulphate and evaporated in a vacuum. The residue was purified over 100 g silica gel (Amicon, 35-70 μm) by column chromatography using dichloromethane/methanol/conc. ammonia(60/40/5 v/v/v) for elution. From the suitable fractions, 250 mg (27% of theory) of the sought substance was isolated as a colourless, amorphous product of Rf 0.15 (dichloromethane/methanol/conc. ammonia 50/50/0.5 v/v/v).
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:63][N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:63][N:64]1[CH2:69][CH2:68][N:67]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH2:66][CH2:65]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 73.7 %

Procedure:
To an N2 degassed solution of 1,4-dioxane (20 mL), was added 4-bromo-1-(methyloxy)-2-nitrobenzene (0.5 g, 2.16 mmol), XANTPHOS (0.37 g, 0.65 mmol, Aldrich), Pd2(dba)3(0.39 g, 0.43 mmol, Aldrich), Cs2CO3 (1.4 g, 4.3 mmol, Aldrich), and 1-methylpiperazine (0.43 g, 4.3 mmol, Aldrich). After heating overnight at 90° C., the reaction was diluted with ethyl acetate (50 mL), washed with water (50 mL), the organic layer adsorbed to silica gel and purified by column chromatography (dichloromethane to 5% methanol/dichloromethane) to afford 1-methyl-4-[4-(methyloxy)-3-nitrophenyl]piperazine (0.4 g, 74%) as a tan solid. ESIMS (M+H)+=252.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH2:20]([N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and benzaldehyde (0.10 mL). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (163 mg).