Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:9]1[C:20](=[O:41])[CH2:21][NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([O:30]CC[Si](C)(C)C)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:9]1[C:20](=[O:41])[CH2:21][NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([OH:30])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccc(O)c2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccc(O)c2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 19.5 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 4.0 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-hydroxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate and 11.8 cm3 of 1M tetrabutylammonium fluoride solution. The crude product is purified by chromatography on silica [eluent: ethyl acetate]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. The solid residue is dissolved in 8.0 cm3 of a 0.5N aqueous sodium hydroxide solution. The solution is filtered and acidified with 4.1 cm3 of a 1N aqueous hydrochloric acid solution. The insoluble product is separated by filtration, washed with 2 times 5 cm3 of water and dried in air. 0.65 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-hydroxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}-benzoic acid, melting at 150° C., is thus obtained. ([α]D20 =+62°±2° (C=0.28%; DMF)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 6.8 (bd, 1H, O--C6H4 --C in position 4; 7.0 to 7.6 (m, 6H, aromatic); 8.0 (bs, 1H, N--C6H4 -- in position 2). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2975, 2930, 2625, 1700, 1650, 1590, 1560, 1490, 1370, 1235, 1150, 785, 760, 690, 680].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3(=[O:33])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)S(=O)CC3)cc(C(C)(C)C)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(-c2cn3c(n2)S(=O)(=O)CC3)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
In 10 ml of chloroform was dissolved 0.6 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole 1-oxide and then 0.4 g of m-chloroperbenzoic acid was added to the solution. After 30 minutes, 0.4 g of m-chloroperbenzoic acid was further added to the mixture and the resultant mixture was allowed to stand for one hour. The reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent thereof was distilled off. The residue was purified by silica gel chromatography using chloroform as the eluent and further recrystallized from aqueous ethanol to provide 0.2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole 1,1-dioxide.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C(N(CC)CC)C>O1CCCC1>[C:1]([O:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 15 h
Yield: 70.1 %

Procedure:
A solution of decanoyl chloride (5.0 g) in tetrahydrofuran (20 ml) was dropwise added to a mixture of N-hydroxysuccinimide (3.06 g) and triethylamine (3.7 ml) in tetrahydrofuran (30 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for one hour and then at ambient temperature for 15 hours. A precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give N-decanoyloxysuccinimide as a crystal (4.95 g).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:13](Cl)=[CH:12][C:11]([CH3:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.[CH2:19]([OH:24])[C:20]([F:23])([F:22])[F:21]>>[Cl:7][C:8]1[C:13]([O:24][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]([CH3:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1
Reactant: OCC(F)(F)F
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cc(OCC(F)(F)F)c(Cl)cc1[N+](=O)[O-]

Procedure:
40.4 g (360 mmol) of potassium tert-butylate were added in portions to 60 ml of trifluoroethanol, while stirring and cooling, and the mixture was heated to 80°-90° C. After cooling, 14.4 g (70 mmol) of 4,5-dichloro-2-nitrotoluene were added and the mixture was stirred at 105° C. for 1 hour. It was concentrated in vacuo and the residue was treated with 300 ml of water to give, after filtration with suction, 12 g of crude product, which were purified over silica gel with n-heptane/ethyl acetate, 10 g of product, melting point 76°-79° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([S:24][CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:15])=[O:14])=[CH:9][CH:8]=1.I[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1.[Cl-].[NH4+]>O.C(OCC)C.CN(C)C=O.O1CCCC1.CCCCCC>[C:37]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:16]([S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)(=[O:15])=[O:14])([S:24][CH3:25])[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:33][C:32]=1[N+:34]([O-:36])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Reactant: CCCCCCCC(SC)S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CSC(Cc1ccc(C(C)(C)C)c([N+](=O)[O-])c1)(CC1CCCCC1)S(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3.45 ml (5.52 mmol) of a 1.6M hexane solution of butyllithium was added dropwise over a period of 5 minutes to 10 ml of a tetrahydrofuran solution containing 1.73 g (5.52 mmol) of 1-[2-(4-methylphenyl)sulfonyl-2-methylthioethyl]hexane (prepared as described in Preparation 8), maintained at -78° C. After 15 minutes, 12 ml of a dimethylformamide solution containing 1.68 g (5.26 mmol) of 5-iodomethyl-2-t-butyl-1-nitrobenzene (prepared as described in Preparation 51) was added dropwise. The reaction mixture was allowed to return to room temperature, after which it was stirred for 1 hour and 20 minutes. At the end of this time, a dilute aqueous solution of ammonium chloride was added, to stop the reaction. Water and diethyl ether were added, and the product was distributed between the organic solvent and water. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, to obtain the title compound. Since this compound was unstable, however, it was used for the next step without purification.
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])CC1.CN>>[CH3:1][N:4]1[CH2:16][CH:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:17]
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Agent: CN
Product: COC(=O)C1NCCN2C(=O)N(C)CC12

Procedure:
Compound 91-C was prepared in analogy to compound 82-C by using methyl amine instead of cyclopropylamine.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C1COCC1.[CH3:12][C:13]1([CH3:25])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)[O:14]1.CI>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:22]1[CH:23]=[CH:24][C:20]([B:15]2[O:16][C:17]([CH3:18])([CH3:19])[C:13]([CH3:25])([CH3:12])[O:14]2)=[N:21]1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide in THF (1.0 M, 0.309 mL, 0.309 mmol) was added to a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30.0 mg, 0.155 mmol, Alfa Aesar, Cat. No. H27619) in DMF (0.5 mL) and stirred at r.t. for 10 min, and then methyl iodide (28.9 uL, 0.464 mmol) was added and the stirred at r.t. for 1 h. LCMS showed the reaction was complete. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude product which was directly used in the next reaction without further purification. LCMS (M+H−82)+: m/z=127.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([C:11]2[O:12][C:13](I)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19]([O-:21])=[O:20].[Na+].COC(=O)CCS([O-])=O.[Na+]>[Cu]I>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([C:11]2[O:12][C:13]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)o2)CC1
Agent: [Cu]I
Agent: COC(=O)CCS(=O)[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1(c2ccc(S(C)(=O)=O)o2)CC1

Procedure:
[1-(5-Methanesulfonyl-furan-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester is prepared from [1-(5-iodo-furan-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.500 g, 1.43 mmol) according to the copper (I) iodide-mediated coupling procedure described in Example 19; however, sodium methanesulfinate is used as coupling partner instead of sodium 3-methoxy-3-oxopropane-1-sulfinate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14]([N:36]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)cc3N21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)cc3N21
Temperature: 80 °C

Procedure:
A mixture of (4R,10aR)-7-bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (3.0 g, 8 mmol), benzophenone imine (1.52 g, 8 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (85 mg, 0.08 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtalene (153 mg, 0.24 mmol) and sodium tert-butylate (1.1 g, 11.4 mmol) in toluene (30 mL) was heated to 80° C. for 3 h. After cooling the mixture was diluted with diethyl ether (300 mL) and filtered through Celite®. The solvents were evaporated and the residue was purified by chromatography on silica gel with ethylacetate/n-hexane (1:4). The title product was isolated as yellowish foam (3.4 g, 89%); ISP-MS: m/e=468.3 (M+H+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:40]2[N:45]=[C:44]([O:46][CH3:47])[C:43]([CH2:48][CH3:49])=[CH:42][CH:41]=2)=[CH:34]\[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:29][C:28]=1[Cl:50])(C(C)(C)C)(C)C.O.Cl>O1CCCC1>[Cl:50][C:28]1[CH:29]=[C:30](/[C:33](/[C:40]2[CH:41]=[CH:42][C:43]([CH2:48][CH3:49])=[C:44]([O:46][CH3:47])[N:45]=2)=[CH:34]\[CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)[CH:31]=[CH:32][C:27]=1[OH:26]
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c2)nc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(O)c(Cl)c2)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.73 mL) was added to a solution of 6-[(E)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-cyclopentylethenyl]-3-ethyl-2-methoxypyridine (409 mg) in tetrahydrofuran (3 mL) under ice-boiling, and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water and made acidic with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→1:1) to give 2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenol as a yellow oil (306 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2C(C)=CC=C2C)[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:3]=1.[OH-].[K+].Cl.NO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.CO.O>[NH2:8][C:6]1[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)CCCCc1cc(C)cc(-n2c(C)ccc2C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Solvent: O
Product: COC(=O)CCCCc1cc(C)cc(N)n1
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Methyl 5-(4-methyl-6-(2,5-dimethylpyrrol-1-yl)-2-pyridinyl)pentanoate (330 mg, 1.10 mmol) was dissolved in 6.0 mL of 95% ethanol, and 1.0 mL of water was added followed by 199 mg (3.08 mmol) of 87% potassium hydroxide. After 2 h, an additional 1 mL of water was added along with 351 mg (5.06 mmol) of hydroxylamine hydrochloride. The solution was heated to reflux for 20 h, then cooled and concentrated. The residue was dissolved in 15 mL of 2 N aqueous hydrochloric acid and washed with 2×10 mL of ethyl ether. The aqueous layer was evaporated and triturated with 3×5 mL of methanol. The methanol extracts were evaporated to give 619 mg of partially crystalline material. A portion (495 mg) of this material was dissolved in 6.0 mL of methanol along with 510 mg (2.68 mmol) of p-toluenesulfonic acid and heated to reflux for 20 h. The reaction was cooled and concentrated and the residue was partitioned between 25 mL of saturated aqueous sodium bicarbonate and 50 mL of ethyl acetate. The aqueous layer was extracted with 2×25 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated aqueous sodium chloride, dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 20 g of silica gel, eluting with 500 mL of 50% ethyl acetate in dichloromethane to give 119 mg (61% yield) of methyl 5-(6-amino-4-methyl-2-pyridinyl)pentanoate as an amber oil.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:15]>>[OH:15][N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCc1ccccc1
Reactant: CC(C)=O
Product: CC(C)(C)N(O)Cc1ccccc1
Yield: 99.6 %

Procedure:
A solution of 0.057 M DMD in acetone (47.4 ml, 2.7 mmol) was added to a cold stirred solution of N-tert-butyl-N-benzylamine (Aldrich, 0.4417 g, 2.7 mmol) in acetone (5 ml). The reaction mixture was stirred for fifteen minutes in an ice bath. Solvent was removed on a rotary evaporator to give a white, microcrystalline solid (0.4803 g, 99.6% yield), mp 58-60. Flash chromatography of the solid over silica gel and elution with a 90:10 mixture of petroleum ether (bp 35-60) and ethyl acetate gave the hydroxylamine as a white crystalline solid, mp 60-61.5 (reported mp 71-73, Emmons 1957). Distillation of this material gave a solid with the same mp.
Reaction SMILES: CC([O-])(C)C.[Na+].Cl[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:15]([NH:22][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(NCc2ccccc2)cc1
Temperature: 100 °C
Yield: 89.7 %

Procedure:
An oven dried Schlenk tube was purged with argon and charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 1.0 mol % Pd), Cy-BINAP (9.6 mg, 0.015 mmol, 1.5 mol %), and NaOtBu (135 mg, 1.4 mmol). The tube was purged with argon and charged with toluene (2 mL), 4-chlorotoluene (0.12 mL, 1.0 mmol), and benzylamine (0.165 mL, 1.5 mmol). The mixture was heated to 100° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was cooled to room temperature, diluted with ether (20 mL), filtered through celite, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 177 mg (90%) of a pale yellow oil.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:31])[N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:20][CH2:19]1)(=O)C>Cl>[ClH:30].[ClH:30].[NH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:31])[N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:22][CH2:23]1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)N2CCCN1CCN(c2cccc(Cl)c2)CC1
Agent: Cl
Product: Nc1cccc2c1CCC(=O)N2CCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 168.2 %

Procedure:
5-Acetylamino-1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril (800 mg) was dissolved in 20 ml of 6 N hydrochloric acid, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 480 mg of 5-amino-1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril dihydrochloride as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:9]=1[C:10]([N:12]=[S:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:11].[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.O>C1(C)C=CC=CC=1>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=3[Cl:22])=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:40])[F:41])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
To a suspension of potassium carbonate (7.78 g, 56.3 mmol, 1.10 equiv) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)benzamide (15.00 g, 51.16 mmol) in toluene (50 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)-pyrazole-3-carbonyl chloride (17.62 g, 51.15 mmol, 1.000 equiv.) in toluene (55 mL) at 60° C. After 1.5 h at this temperature, the mixture was cooled and water was added. The resulting precipitate was collected by filtration, washed with water and petrol ether and dried to obtain the title compound (18.73 g, 65%).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.C[N:28](C1C=CC=CN=1)C.[OH-].[NH4+]>O>[C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8]([NH2:28])=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12
Reactant: CN(C)c1ccccn1
Reactant: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
To a stirred solution of 3-phthalimido-3(4-propoxyphenyl)propionic acid (1.41 g, 4.0 mmol) in 25 mL of under nitrogen was added carbonyldlimidazole (0.68 g, 4.2 mmol) followed by a catalytic amount of dimethylaminopyridine. The mixture was stirred for 45 minutes at room temperature. To the reaction mixture was then added concentrated ammonium hydroxide (0.29 mL, 4.4 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was then diluted with 10 mL of water and the tetrahydrofuiran was removed in vacuo. The resulting slurry was filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford 1.2 g of crude product. The crude product was purified by dissolving in 200 mL of ethyl acetate, stirring for 3h and then concentrating to an 80 mL volume. The resulting slurry was filtered and the solid was washed with ethyl acetate (2×20 mL). The solid was air-dried to afford 0.513 g (36%) of 3-phthalimido-3-(4-propoxyphenyl)propionamide as a white powder: mp 109.5-110.4° C.; 1H NMR (DMSO-d6, 250 MHz) δ7.85 (br s, 4H), 7.55 (br s, 1H), 7.33 (d, 2H, J=8 Hz), 6.75-7.00 (m, 3H), 5.69 (t, 2H, J=8 Hz), 3.88 (t, 2H J=6 Hz), 3.10-3.30 (m, 2H), 1.60-1.80 (m, 2H), 0.95 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ171.2, 167.7, 158.0, 134.5, 131.23, 131.19, 128.4, 123.1, 114.3, 68.9, 49.9, 36.9, 22.0, 20.4, 10.4; Anal. Calcd. for C20N2O40.37 H2O. Theoretical: C, 66.90; H, 5.61; N, 7.80. Found: C, 66.90; H, 5.52; N, 7.75.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)=[N:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:20][C:16]1([C:14]2[S:15][C:11]([C:9]3[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[C:7]([NH:21][C:22]4[N:27]=[C:26]([O:28][CH:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)[CH:25]=[CH:24][N:23]=4)[CH:8]=3)=[CH:12][N:13]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCNCC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91176.5 %

Procedure:
To the product of Step 4 (20 mg, 0.034 mmol) in DCM (1 mL) was added TFA (133 μL, 1.722 mmol). The mixture was stirred at ambient temperature for 1 hr. LCMS indicated complete reaction. To the reaction was added saturated aqueous NaHCO3 to adjust pH>8 and the product was extracted with ethyl acetate. The combined organic layer was dried, filtered and solvent removed in vacuo to afford 15 mg (0.031 mol, 91%) of N-(3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-{[4-(piperidin-4-yloxy)pyrimidin-2-yl]amino}phenyl)acetamide as pale yellow oil. MS ESI: [M+H]+ m/z 481.2. 1H NMR (600 MHz, CD3OD): δ 8.16 (m, 2H); 7.90 (s, 1H); 7.55 (s, 1H); 7.30 (s, 1H); 6.26 (d, J=5.4 Hz, 1H); 5.58 (m, 1H); 3.34 (m, 2H); 3.21 (m, 2H); 2.65 (m, 2H); 2.40 (m, 2H); 2.22 (m, al); 2.14 (s, 3H); 2.01 (m, 4H). rhSYK activity=+++