Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[OH:9][CH2:8][C:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH:4]=1
Reactant: CCOC(=O)C1=CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC=C(CO)CC1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate (10.0 ml, 0.061 mole) in THF (200 ml) was added, maintaining temperature below 25° C., lithium aluminium hydride (2.76 g, 0.073 mole). After stirring for a further 15 min, water (2.75 ml), 10% NaOH (4 ml) and water (4 ml) were successively added, and the mixture was filtered. The filtrate was dried (Na2SO4) and evaporated in vacuo to give the title compound as an amber oil (6.30 g, 81%), which solidified on standing.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[O:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[C@@H:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nc2ccccc2o1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nc3ccccc3o2)cc1Cl
Temperature: 0 °C
Yield: 75.6 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 19, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (121 mg, 0.91 mmol) and pyridine (0.15 mL, 1.8 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzoxazol-2-yl-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (206 mg, 76%) as a light orange foam: [α]23589=−24.4° (c=0.119, chloroform); EI-HRMS m/e calcd for C22H23ClN2O4S (M+) 446.1067, found 446.1083.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])(=O)=O.O[C@H:17]([C:21]([CH3:38])=[CH:22][C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])[S:26][CH:27]=1)[CH2:18][CH:19]=[CH2:20].N1C(C)=CC=CC=1C.Cl>C(Cl)Cl>[CH2:12]([Si:7]([CH2:8][CH3:9])([CH2:10][CH3:11])[O:6][C@H:17]([C:21]([CH3:38])=[CH:22][C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:36])([Cl:37])[Cl:35])=[O:31])[S:26][CH:27]=1)[CH2:18][CH:19]=[CH2:20])[CH3:13]
Reactant: C=CC[C@H](O)C(C)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC[C@H](O[Si](CC)(CC)CC)C(C)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylsilyl trifluromethanesulfonate (15 mL) is added dropwise to a −78° C. solution of (4S)-4-hydroxy-5-methyl-6-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazol-4-yl)-1,5-hexadiene (7.65 g) and 2,6-lutidine (10 mL) in 50 mL of CH2Cl2. After the addition, the reaction mixture is allowed to warm to ambient temperature and is stirred for 5 hours. The reaction mixture is poured into 2 N HCl and extracted with ether. The combined organic layers were washed with 10% aq NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. Flash chromatography on SiO2 (hexanes/ethyl acetate, 20:1) provides the product as a colorless oil.
Reaction SMILES: [C:1](OC)([CH3:4])([CH3:3])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C:14]1[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[O:8][CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(O)c1
Reactant: COC(C)(C)C
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(O)ccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a suspension of zirconium tetrachloride (2.3 g, 10 mmol) in methylene dichloride (30 ml) was added methyl tert-butyl ether (0.88 g, 10 mmol) at 0° C. After stirring at 0° C. for 30 minutes, 3-methoxyphenol (1.24 g, 10 mmol) in methylene dichloride was added and the mixture was stirred for 2 hours at ambient temperature. The reaction was quenched with saturated aqueous sodium bicarbonate, followed by the addition of methylene dichloride. Then, the organic layer was separated, dried over magnesium sulfate, filtered off, evaporated under reduced pressure to give a residue, which was applied to a silica gel chromatography column eluted with a volume mixture of hexane and ethylacetate (20/1 to 4/1) to furnish 360 mg (20% yield) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>C(OCC)(=O)C.CCCCCC>[F:30][C:31]1[CH:32]=[C:33]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])[CH:34]=[CH:35][CH:36]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(F)c1)OCC2c1ccc(C(C)C)cc1
Yield: 67 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-fluorophenyl)boronic acid, the title compound was synthesized in the same manner as in Example 107. Yield: 67%. Melting point: 182-183° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)C1C=CC=CC=1.[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)CC)C.C(O)(C)C>C(Cl)Cl.CO.[Pd]>[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][S:2](=[O:3])(=[O:4])[NH2:5])=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: OCc1ccccc1
Product: NS(=O)(=O)Oc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a chilled solution of chlorosulfonyl isocyanate (8.7 ml, 0.10 mole) in 50 ml of methylene chloride was added a solution of 10.8 g (0.10 mole) of benzyl alcohol in 200 ml of methylene chloride over a period of 6 minutes at 3°-15° C. The reaction was then stirred at ambient temperature for 2 hours and then chilled in an ice-water bath. To this solution was added 4-(imidazol-1-yl)phenol (12 g, 0.075 mole) as a solid, and the mixture was stirred at room temperature for 45 minutes. Triethylamine (14 ml, 0.1 mole) was then added to the suspension, and the reaction became a dark brown solution. The mixture was stirred for two days, and the solid was collected by filtration, stirred in water for half an hour, and filtered again, rinsed with isopropyl alcohol and isopropyl ether. This solid intermediate weighed 18.24 g (65%) and 1H NMR showed it exists as zwitterion. The zwitterion (18 g) was added to a solution of isopropyl alcohol containing 0.05 mole hydrogen chloride and diluted with 100 ml methanol. The resultant solution was mixed with 1.8 g Pd-C (5%) and hydrogenated until there was no further absorption of hydrogen. The catalyst was removed, and the solution was concentrated to give 10 g solid. Part of the solid was recrystallized by dissolving in excess amount of methanol, filtering, and concentrating to crystallize out about 5 g solid. The solid was dried in vacuum oven at 80° C. overnight, mp 198°-200° C.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.[OH-].[NH4+].Cl[CH2:14][C:15]([NH:17][C:18]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)=[O:16].N>C(O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[NH:17][C:15](=[O:16])[CH2:14][N:2]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH:28]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 167 %

Procedure:
A mixture of ethanol (1100 ml), hexamethylenetetramine (70.0 g., 0.5 mol), 26% ammonium hydroxide (58 ml) and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) was stirred and slowly heated to reflux with ammonia bubbling into the mixture. Reflux was continued for 5 hours, the flow of ammonia was interrupted, and the reaction mixture distilled to dryness in vacuo. The residue was heated to reflux for 30 minutes in a mixture of toluene (500 mls) and water (500 mls) and then allowed to cool slowly to room temperature. The crystalline material was filtered, washed with toluene (100 mls) and hot water (2 × 250 mls) and dried to constant weight. The product, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (226 g) obtained corresponded to a yield of 83.5%, melting point 210° C.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:9]1[N:10]=[CH:11][C:12]([C:22]([OH:24])=[O:23])=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.Cl>CN(C=O)C.O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[N:13]=[C:12]([C:22]([OH:24])=[O:23])[CH:11]=[N:10][C:9]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:20][CH:19]=1
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
Cyclopropylmethanol (1.54 g, 1.73 ml, 21.3 mmol) was diluted in dried DMF (15 mL); sodium hydride (512 mg, 21.3 mmol) was added in portions and the reaction mixture was stirred at room temperature for 15 minutes. The resulting solution was added slowly at <5° C. to a solution of 5-bromo-6-(4-chlorophenyl)pyrazine-2-carboxylic acid (CAN 960247-80-7; 3.040 g, 9.7 mmol) in dried DMF (15 mL). The reaction mixture was stirred at room temperature for 30 minutes; water was added and the mixture was acidified with 1M HCl solution to pH=2. The mixture was extracted with ethyl acetate; organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude did still contain starting material and was dissolved again in 15 mL DMF; a solution of cyclopropylmethanol (1.05 g, 1.18 ml, 14.5 mmol) and sodium hydride (582 mg, 14.5 mmol) in 15 mL DMF was added and the mixture was stirred at room temperature for 3 hours. Water was added and the reaction mixture was acidified with 1M HCl solution to pH 2; the product precipitated to give 2.55 g (86%) of the title compound as light yellow solid; MS (ESI) 303.2 (M−H)−.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.Cl>ClCCl>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([C:18]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22](=[O:23])[C:11]3[CH:12]=[CH:13][C:8]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)[CH:20]=2)=[O:28])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1cccc(C(=O)c2ccc(Oc3ccccc3)cc2)c1
Temperature: -60 °C
Reaction time: 72 h
Yield: 60.8 %

Procedure:
Diphenyl oxide (51 g), 100 ml of dichloromethane and 13.3 g of aluminum trichloride are placed in a flask equipped with a mechanical stirrer, a reflux condenser and an addition funnel. After cooling the flask to -60° C., 10.15 g of isophthaloyl chloride is added over a 30-minute period. The reaction is stirred at 25° C. for 72 hours and refluxed for 4 hours. The reaction mixture is poured into 100 ml of 1M hydrochloric acid and the organic layer is washed once with ammonium hydroxide and twice with water. The organic layer is dried with sodium bisulfate and the solvent is evaporated. The product is recrystallized from methylethyl ketone, yielding 14.3 g (61 percent yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1.[CH2:17]([Sn](CC)(CC)CC)[CH3:18]>CN(C)C=O.CO.C(OCC)(=O)C.[Pd].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1)[CH3:18]
Reactant: CC[Sn](CC)(CC)CC
Reactant: COC(=O)c1nc2c(cc1Br)SCC(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1cc2c(nc1C(=O)OC)NC(=O)CS2
Yield: 16.8 %

Procedure:
Methyl 7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (Example 304b) (2.00 g, 6.6 mmol), tetraethyltin (3.17 mL, 16 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.12 g, 1.6 mmol) in dimethylformamide (40 mL) were heated at 120° C. for 24 h. The mixture was filtered through Kieselguhr, washed through with ethyl acetate and evaporated. Chromatography on silica gel (20-50% ethyl acetate/petroleum ether) gave a mixture of the 7-ethyl and 7-vinyl compounds (0.29 g). This mixture was hydrogenated in methanol/ethyl acetate (2:1, 60 mL) over 10% palladium on carbon (60 mg) (1 atmosphere, room temperature) for 24 h. Filtration and evaporation of solvent gave the product (0.28 g).
Reaction SMILES: [CH3:1]N(C)CCN.C[Al](C)C.C(O[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[CH:20]=1)=[O:15])C>C1(C)C=CC=CC=1>[Br:27][C:23]1[CH:22]=[C:21]([N:19]2[CH:20]=[C:16]([C:14](=[O:15])[CH3:1])[CH:17]=[N:18]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1cnn(-c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A solution of N,N-dimethylethylenediamine (1.8 ml, 16.76 mmol) in toluene (30 ml) was treated dropwise at 0° C. under an argon atmosphere with trimethylaluminum (2M in toluene, 22.86 ml, 45.7 mmol). The reaction mixture was stirred at 25° C. for 1 hour before adding 1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (3.8 g, 12.8 mmol) (CAS 784142-89-8; WO2004092140). The resulting mixture was heated to reflux for 12 hours. For the workup, the mixture was cooled to 25° C., quenched with hydrochloric acid (1N) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulphate and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a 9:1-mixture of hexane and ethyl acetate as the eluent to give the 1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]ethanone (2.4 g, 83.5%) as an off-white solid. MS (ISP): m/z=310 [M+CH3CN]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[S:22][C:21]([C:23]3([OH:27])[CH2:26][CH2:25][CH2:24]3)=[N:20][CH:19]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=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+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:12]=[C:13]([C:18]3[S:22][C:21]([C:23]4([OH:27])[CH2:26][CH2:25][CH2:24]4)=[N:20][CH:19]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[N:7]=1)=[CH2:9]
Reactant: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Reactant: C=Cc1ccnc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C=Cc1ccnc(Nc2cc(C)cc(-c3cnc(C4(O)CCC4)s3)c2)n1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
A mixture of 2-chloro-4-ethenylpyrimidine (400 mg, 2.85 mmol), Intermediate 15 (815 mg, 3.13 mmol), Pd(OAc)2 (70.3 mg, 0.313 mmol), Xantphos (247 mg, 0.427 mmol) and cesium carbonate (1.85 g, 5.69 mmol) in 1,4-dioxane (14 mL) was purged with nitrogen for 8 min, and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to afford 1-(5-{3-[(4-ethenylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol (330 mg, 0.905 mmol). MS ESI: [M+H]+ m/z 365.1. 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.49 (d, J=4.9, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.53 (s, 1H), 7.07 (s, 1H), 6.94 (d, J=5.1, 1H), 6.71 (dd, J=10.5, 17.4, 1H), 6.51 (s, 1H), 6.49 (d, J=16.1, 1H), 5.70 (d, J=10.5, 1H), 2.56-1.85 (m, 6H), 2.31 (s, 3H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:21][CH2:22][CH3:23])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:7]([NH2:20])[N:6]=1.C1C(=O)N([Br:32])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:32][C:10]1[N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:20])[N:6]=[C:5]([O:4][CH2:3][C:2]([CH3:24])([CH3:1])[CH2:21][CH2:22][CH3:23])[N:13]=2
Reactant: CCCC(C)(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCC(C)(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To 2-[(2,2-dimethylpentyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (372 mg) in dry chloroform (4.05 mL) at 0° C. was added NBS (209 mg) in a single portion. The reaction was warmed to room temperature and was stirred for 5 h. The mixture was taken up into DCM (20 mL) and washed with water (30 mL). The organics were separated and dried using a hydrophobic frit then concentrated in vacuo to afford the title compound as a green/brown viscous foam (475 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH3:8])[S:5][CH:6]=1.O.[NH2:11][C:12]([NH2:14])=[S:13]>C(OCC)C.BrBr.CCO>[NH2:14][C:12]1[S:13][CH:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1cc(Cl)cs1
Agent: BrBr
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Nc1nc(-c2cc(Cl)cs2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a solution of 4.18 g of 4-chloro-2-acetylthiophene in 30 ml of diethylether, 1.5 ml of bromine was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the organic phase was extracted. The obtained organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain brominated compound. To a solution of the brominated compound in 30 ml of EtOH, 2.1 g of thiourea was added at room temperature, and the mixture was stirred at 80° C. overnight. The precipitate was filtered, and obtained solution was evaporated under reduced pressure. Chloroform was added and then an organic layer was washed with aqueous potassium carbonate and brine, and dried over sodium sulfate. The residue obtained by the evaporation of the solvent under reduced pressure was washed with hexane:EtOAc=1:1 to obtain 2.57 g of 2-amino-4-(4-chlorothiophen-2-yl)thiazole.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O.[ClH:18].CO>>[ClH:18].[CH3:1][O:2][CH:3]([O:16][CH3:17])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1
Reactant: COC(OC)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(OC)[C@@H]1CCCN1

Procedure:
tert-Butoxycarbonyl-L-prolinal dimethyl acetal (1.0 g, 4.08 mmol) is stirred for one hour at room temperature in 10% HCl-methanol (8.2 ml) and the mixture is evaporated to dryness under reduced pressure to give quantitatively L-prolinal dimethylacetal hydrochloride as a solid. The product is dissolved in dimethylformamide (5 ml) containing p-anisic acid (938 mg, 6.16 mmol) and diethyl-phosphoryl cyanide (0.65 ml, 8.25 mmol). To the solution is added dropwise triethylamine (1.15 ml, 8.25 mmol) under cooling and agitation in an ice-methanol bath. After the dropwise addition the mixture is stirred for one hour under cooling and then for one hour at room temperature. Benzene-ethyl acetate (2:1, 150 ml) is added to the reaction mixture and the organic layer was separated, washed successively with a saturated aqueous solution of sodium hydrogen carbonate (15 ml), water (15 ml) and a saturated aqueous solution of edible salt (15 ml), dried over sodium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane-dichloromethanemethanol, 6:4:1) to give 747 mg (65%) of the title compound as white crystals.