Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:23])[CH2:10][C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:7].Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=O>O.C(O)C>[CH2:6]([O:8][C:9]([C:10]1[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:26][NH:25][C:11]=1[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])[CH3:7]
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c[nH]c1CCNC(=O)OC(C)(C)C
Yield: 91.4 %

Procedure:
A stirred solution of anhydrous sodium acetate (2.05 g, 25 mmol) in water (12.5 ml) was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (3.23 g, 12.5 mmol) in anhydrous ethanol (2 ml), then the mixture was added with 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (2.37 g, 12.5 mmol), heated to reflux for 3 hours. The resulting mixture was extracted with ethyl acetate (50 ml×3) and the combined extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (4.3 g, 91.7%) as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[NH2:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:32]>CN(C=O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([C:31](=[O:32])[CH2:30][NH:29][C:10]([CH:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]2)=[O:12])=[CH:38][CH:37]=1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: NCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a 22-L flask is added 526.4 g (3.07 mol) of 1-acetylpiperidine-4-carboxylic acid, 8 L of methylene chloride, and 55 mL of DMF. To the resultant heterogeneous suspension is added 508.9 g (3.13 mol) of carbonyl diimidazole in two portions at room temperature. After two hours, 583.5 g (3.07 mol) of 2-Amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (J. Heterocylcic Chem (1987), 24, 297. ) is added and the resultant mixture is allowed to stir overnight. The reaction mixture is extracted with 2 N HCl (3×1 L), saturated sodium bicarbonate solution (3×1 L), brine (1×1 L), dried over sodium sulfate, and filtered. To the filtrate is added toluene and the solution is concentrated in-vacuo to ca. 100 mL and the resultant precipitate is filtered. The solid is dried in-vacuo at 60° C. for 18 h to give 800 g of 1-Acetyl-piperidine-4-carboxylic acid[2-(4-fluoro-phenyl)-2-oxo-ethyl]-amide as an off-white solid.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C(N(CC)CC)C.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N>ClCCl>[Si:22]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(CO)c1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
To 1,3-benzenedimethanol (5.10 g, 36.91 mmol) in dichloromethane (70 ml) was added at 0° C. triethylamine (7.47 g, 73.82 mmol), 4-dimethyl-aminopyridine (451 mg, 3.61 mmol) and t-butyldimethylchlorosilane (5.56 g, 36.91 mmol) successively, and the mixture was stirred for 20 hours at room temperature. Thereto was added a saturated ammonia solution and the mixture was extracted with ethyl acetate and separated by a separating funnel. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (4.23 g, 45%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[C:20]2[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)SC)#[N:5]>CN(C=O)C>[NH2:5][C:4]1[N:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[C:20]3[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CSC(=NCCCOc1cccc2c(N3CCCCC3)nccc12)NC#N
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc2c(N3CCCCC3)nccc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Methyl hydrazine (5.7 ml) is added to a stirred suspension of 1-cyano-3-[3-(1-piperidino-5-isoquinolyloxy)propyl]-2-methylpseudothiourea (7.77 g) in 62 ml of DMF under nitrogen. The reaction mixture is stirred at 40° C. under nitrogen for 24 hours, cooled to RT, evaporated under vacuo and the residue dissolved in warm absolute ethanol. The resulting precipitate is collected, washed with absolute ethanol and dried in air. The filtrate is evaporated in vacuo and the residue crystallized from acetonitrile and dried overnight, yielding 5.3 g of the crude product as an off-white solid, M.P. 173°-175° C. The crude product is placed on a silica gel column and eluted with methylene chloride/methanol. The combined pure fractions are evaporated and recrystallized from acetonitrile, yielding the desired product, M.P. 181°-182° C.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])#[N:12].CCN(C(C)C)C(C)C.Cl>C1COCC1>[C:11]([CH:13]([CH2:1][C:2](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:12]
Reactant: COC(=O)CC#N
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
A solution (1 M) of phenacyl bromide in THF was added dropwise to a solution (5.5 M) of methyl cyanoacetate (1.1 eq.) and DIEA (2.4 eq.) in THF at RT. The resulting solution was stirred at RT for 20 h then the mixture was filtered and the filtrate was concentrated in vacuo to obtain an oil that was treated with little portions of aqueous HCl (1 N). The organic phase was washed with brine, dried and concentrated affording the title compound (97%) as an oil that solidified when stored in the fridge.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.OC1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOC(C)=O>[C:9](=[O:10])([O:8][C:1]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1)[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: Oc1ccc2cccnc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Oc1ccc2cccnc2c1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Di-tert-butyl dicarbonate (7.40 g, 33.92 mmol) and 4-(dimethylamino)pyridine (222 mg, 1.81 mmol) were added in sequence to 7-hydroxyquinoline (2.00 g, 13.75 mmol) in anhydrous N,N-dimethylformamide (20.0 mL) at room temperature. After 18 hours, the reaction was diluted with EtOAc (250 mL). The organic layer was washed with 1.0 M NaOH (250 mL), water (3×250 mL), saturated aqueous NaCl solution (250 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 1:1 Hexanes:EtOAc) to give 28 as a colorless amorphous solid (3.26 g, 97%): 1H NMR (CDCl3, 500 MHz) δ 8.93 (dd, J=4.2, 1.7 Hz, 1H), 8.17 (bd, J=8.4 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.43 (dd, J=8.8, 2.3 Hz, 1H), 7.40 (dd, J=8.3, 4.3 Hz, 1H), 1.60 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 151.7, 151.7, 148.9, 135.9, 129.0, 126.3, 122.0, 121.0, 120.2, 84.2, 27.8 (3C); IR (film) νmax 1759, 1277, 1240, 1142, 768, 750 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H15NO3, 246.1130. found, 246.1113.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([Cl:22])=[O:13])[CH:5]=[CH:6][CH:7]=2)[O:2]1
Reactant: CCCCC[C@H](CC(=O)O)c1cccc2c1OCO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC[C@H](CC(=O)Cl)c1cccc2c1OCO2
Reaction time: 2 h

Procedure:
To a solution of 1.3 g (4.9 mmol) of (R)-3-(2, 3-methylenedioxyphenyl) octanoic acid in 20 ml of methylene chloride were added 1.1 ml of thionyl chloride and 0.1 ml of N, N-dimethylformamide, and the resultant mixture was refluxed under stirring for 2 hours. The reaction mixture was concentrated in vacuo to give (R)-3-(2, 3-methylenedioxyphenyl) octanoyl chloride as an oil. This oil was dissolved in methylene chloride to give a solution, which was dropwise added to a solution of 1.08 g (4.9 mmol) of 2, 6-diisopropyl-3-dimethylaniline and 1.0 ml of triethylamine in 20 ml of methylene chloride (5°-10° C.). The reaction mixture was allowed to react at room temperature overnight and chromatographed on a silica gel column, eluting with ethyl acetate/hexane to give 1.16 g of gelatinous material. This was dissolved in acetone and mixed with 22% solution of hydrogen chloride in 2 ml of ethyl acetate. The resultant mixture (hydrochloride) was concentrated and crystallized from hexane to give 1.23 g of (R)-N-(2, 6-diisopropyl-3-dimethylaminophenyl)-3-(2, 3-methylenedioxyphenyl) octanamide hydrochloride. Yield, 50%.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13](Br)[CH:14]=1.[C-]#N.[Na+].CN([CH:23]=[O:24])C>O>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13]([O:24][CH3:23])[CH:14]=1
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1cc(OC[C@@H]2CCCN2C)c[n+]([O-])c1

Procedure:
A sample of 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5bromo-pyridine-N-oxide, from Example 98a above, is reacted with sodium cyanide in DMF and water according to standard procedures. The solvents are removed, and the product is extracted, then purified by chromatography on silica gel.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:8]1[CH2:13][NH:12][CH:11]=[N:10][CH2:9]1)[C:5]([NH2:7])=[O:6].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[C:36](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[NH2:3][CH:4]([CH:8]1[CH2:13][N:12]([C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:11]=[N:10][CH2:9]1)[C:5]([NH2:7])=[O:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)C(N)C1CN=CNC1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)C(N)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 71 %

Procedure:
Amino(1,4,5,6-tetrahydropyrimidine-5-yl)acetamide dihydrochloride (1.33 g, 5.8 mmol), diazabicycloundecene (DBU, 2.6 ml, 17.4 mmol), and tritylchloride (1.61 g, 5.8 mmol) are dissolved in anhydrous DMF (20 ml) with stirring under nitrogen at room temperature. After 18 hours stirring the suspension is evaporated in vacuo, and the residue chromatographed (silica, chloroform/methanol, 9:1) to yield 1.64 g (71%) white crystalline solid, identified by 300 MHz nmr and ms m/z=398.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1.CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:26])[C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
3-(4-Bromo-5-ethoxy-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (2.38 g), methyl iodide (1.06 g) and potassium carbonate (1.04 g) were suspended in DMF (12 ml), and the mixture was stirred at room temperature for about 8 hours. After the reaction, DMF was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:5 v/v) to obtain the objective 3-(4-bromo-5-ethoxy-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4( 1H,3H)-pyrimidinedione (2.08 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:21][CH:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=[O:23]>O1CCCC1.O>[CH2:14]([O:13][CH2:12][CH:11]([OH:23])[CH:10]([OH:21])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(COCC2OC2COCc2ccccc2)cc1
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)C(O)COCc1ccccc1
Temperature: 0 °C

Procedure:
4.2 g of the 1,4-bis(benzyloxy)-2,3-epoxybutane thus obtained was dissolved in a mixture comprising 120 ml of tetrahydrofuran and 30 ml of water. Then 30 ml of an aqueous solution containing 6 ml of 60% perchloric acid was added dropwise thereto under ice-cooling and stirring. After stirring at the same temperature for additional 4 hours, the reaction mixture was poured into ice/water and extracted with ether. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to thereby give 2.7 g of 1,4-bis(benzyloxy)-2,3-butanediol as a colorless liquid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C1(C=CC(O)=CC=1)O.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:16][CH2:15]1.[OH-].[Na+]>O.C(#N)C>[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][NH:23][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:16][CH2:15]1
Reactant: NCCCN1CCOCC1
Reactant: C=CC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C=CC(=O)NCCCN1CCOCC1
Reaction time: 3.5 h

Procedure:
In a 1 liter capacity round bottom flask equipped with a stirrer were put 90.5 g (1.0 mole) of acrylic acid chloride and 300 cc of acetonitrile and, as a polymerization inhibitor, 0.5 g of hydroquinone, and then, after the contents were cooled to 5°-10°C, 143 g (1.0 mole) of 3-morpholinopropylamine was added dropwise thereto over the course of 3.5 hours while stirring. Afterwards, the reaction mixture was stirred additionally for 2 hours at 40°-50°C. Next, a solution of 40 g of sodium hydroxide in 100 cc of water was added thereto and then the mixture was stirred for 30 minutes. After removal of the sodium chloride which separated, 152 g (77.0%) of a fraction of 144°-146°C/0.1 mmHg were obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][C:28]2([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][C:28]2([F:34])[CH2:33][CH2:32][N:31]([CH3:37])[CH2:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC2(F)CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCc1nnc(OCC2(F)CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-piperidin-4-ylmethoxy)-pyridazine dihydrochloride (0.058 mmol, 30 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1 mL), and stirred for 5 min. Sodium triacetoxyborohydride (0.35 mmol, 75 mg) was added stirred at room temperature for 2 h. Reaction was diluted with DCM (5 mL), DCM layer was separated and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 2% (NH3 in MeOH, 2M) in DCM—6% (NH3 in MeOH, 2M) in DCM gave 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-1-methyl-piperidin-4-yl methoxy)-pyridazine, which was converted to the title compound by treating with 4 N HCl in dioxane (0.5 mL) in DCM (2 mL). The volatiles were removed under reduced pressure, salt was washed with anhydrous ether and solid was dried under high vacuum (24 mg). LCMS: m/z 457 [M+1]. 1H NMR (300 MHz, CD3OD): δ 7.86 (1H, s), 7.45 (2H, d), 7.12 (2H, d), 4.68 (2H, d), 4.44-4.50 (1H, m), 3.50-3.62 (2H, m), 3.24-3.39 (2H, m), 3.13 (2H, t), 2.94 (3H, s), 1.74-2.50 (8H, m), 1.20-1.68 (10H, m), 0.82 (3H, t).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 80.8 %

Procedure:
A mixture of tert-butyl 3-aminoazetidine-1-carboxylate (10.0 g, 58 mmol), ethyl 2-bromoacetate (10.7 g, 64 mmol) and potassium carbonate (24.0 g, 174 mmol) in MeCN (200 mL) was stirred at rt for 13 hrs. The reaction mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography (gradient elution 0˜66% EtOAc/petroleum ether) to afford tert-butyl 3-(2-ethoxy-2-oxoethylamino)azetidine-1-carboxylate (12.1 g, 81%) as a white solid. ESI-MS (EI+, m/z): 259.0 [M+H]+.
Reaction SMILES: N[CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4].C(O)(=[O:17])C.N([O-])=O.[Na+]>O>[OH:17][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(=O)O
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1ccc2c(c1)CCO2
Temperature: 65 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
α-Amino(2,3-dihydro-5-benzofuranyl)acetic acid (200 mg, 1.04 mmole) is dissolved in 250 mg (4.14 mmole) of glacial acetic acid and 145 mg (2.08 mmole) of sodium nitrite in about 5 ml of water is added dropwise. An additional 1 ml of glacial acetic acid is added and the mixture is heated to 65° C. and held at 65° C. for 4 hours. After cooling the reaction mixture is diluted with water and extracted with ethyl acetate for several hours. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give about 65% of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[C:23](#[N:25])[CH3:24].ClCCl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[CH2:11][NH:12][C:23](=[NH:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: ClNCc1cc(Br)ccc1OCc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=N)NCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-benzyloxy-5-bromobenzylamino hydrochloride (10 g) in toluene (75 ml) at 4° C. was added a solution of trimethylaluminium in toluene (2M, 15.2 ml). The mixture was stirred at ambient temperature for 2 hours, acetonitrile (6.5 ml) added and the mixture heated at 80° C. for 18 hours. The mixture was cooled and poured onto a slurry of silica gel (300 g), and dichloromethane. The solvent was filtered off and the product eluted from the silica gel with methanol to give N1 -[2-benzyloxy-5-bromobenzyl]acetamidine (5.51 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH2:18][O:19][CH:20]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(#N)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:19][CH2:18][CH2:17][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:22][CH:23]=1
Reactant: OCCN1CCNCC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: OCCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a refluxing mixture of 1.05 g (0.0081 mol) N-(2-hydroxy-ethyl)piperazine, 0.75 g (0.0054 mol) dry potassium carbonate and 5 ml toluene, a solution of 0.76 g (0.0027 mol) 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene in 3 ml toluene was added dropwise. The reaction mixture was refluxed for 11 h and then cooled to room temperature. It was diluted with toluene (100 ml) and extracted with 2N hydrochloric acid (100 ml). The acidic extract was washed with one portion of toluene, then rendered basic by addition of 4N sodium hydroxide solution (75 ml) and extracted with toluene (100 ml). The toluene solution was washed successively with two portions of water and once with brine. Evaporation in vacuo gave a yellowish oil, which was redissolved in acetonitrile (20 ml). The title compound was precipitated as the dimaleate salt with an excess of a maleic acid solution in acetonitrile. By recrystallization from hot acetonitrile/methanol 1.29 g (78% of the theoretical yield) of the title compound was obtained as white crystals, m.p. 163° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5]1.Br[CH2:15][C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]([NH:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=3)[CH:24]=[C:25]([CH3:27])[CH:26]=2)=[CH:19][N:20]=1>O1CCCC1.C(OCC)(=O)C>[CH3:27][C:25]1[CH:26]=[C:21]([C:18]2[S:17][C:16]([CH2:15][C:8]3([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5][C:4]3=[O:3])=[N:20][CH:19]=2)[CH:22]=[C:23]([NH:28][C:29]2[N:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:32]=[CH:31][N:30]=2)[CH:24]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CBr)s2)c1
Reactant: CCOC(=O)C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCNC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (in 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++