Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 71 °C
Yield: 52 %

Procedure:
To a dry 100.0 ml one necked round bottom flask equipped with a stirring bar is added (S)-1-N-Boc-piperazine-2-carboxylic methyl ester (800 mg, 3.275 mmol) under N2. Anhydrous acetonitrile (20 ml) is added to the flask followed by benzyl chloride (0.38 ml, 3.275 mmol) and triethylamine (1.28 ml, 9.17 mmol). Condenser is then put on to the flask and the reaction mixture is heated at 71° C. for 20 minutes. The reaction mixture is allowed to come to room temperature and concentrated under reduced pressure. It is then diluted with dicholoromethane and washed with water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound is flash column purified using hexane and ethylacetate gradient solvent system to yield 570 mg (52%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[CH:23][C:22]=1[S:33](=[O:36])(=[O:35])[NH2:34]>O1CCCC1>[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](=[O:26])[C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:23][C:22]=1[S:33]([NH2:34])(=[O:36])=[O:35]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 0.275 g of 1-(4-bromo-phenyl)-4-methyl-piperazine in tetrahydrofuran (90 mL) is cooled to −78° C. and treated with 1.44 mL of tert-butyllithium (1.5 M in pentane). After 15 min at −78° C. the reaction mixture is treated with 0.1 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (3 mL). The temperature is then increased slowly to 0° C. and after completion the reaction is quenched by addition of 2 mL of saturated aqueous ammonium chloride and extracted with diethyl ether. The organics are washed with water, dried (magnesium sulfate) and concentrated to give 0.32 g of crude product which is purified by silica gel chromatography (95:5 methylene chloride/methanol) to give 2-chloro-5-[4-(4-methyl-piperazin-1-yl)-benzoyl]-benzenesulfonamide as a tan powder. MS (m/z): 394 (M+1); Rf 0.06 (95:5 methylene chloride/methanol).
Reaction SMILES: C([NH:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[N:11]3[C:15]([CH:16]=[CH:17][CH:18]=2)=[N:14][C:13]([NH:19][C:20](=[O:23])[O:21][CH3:22])=[CH:12]3)=[CH:7][CH:6]=1)(=O)C.Cl.[NH4+].[OH-]>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[N:11]3[C:15]([CH:16]=[CH:17][CH:18]=2)=[N:14][C:13]([NH:19][C:20](=[O:23])[O:21][CH3:22])=[CH:12]3)=[CH:24][CH:25]=1
Reactant: COC(=O)Nc1cn2c(Oc3ccc(NC(C)=O)cc3)cccc2n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Nc1cn2c(Oc3ccc(N)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of 5-(4-acetamidophenoxy)pyridine-2-ylamine (Intermediate 9J170.2 mg, 0.7 mmol) in DMF (2 mL) was added N-(methoxycarbonyl)chloroacetoamide (159.0 mg, 1.1 mmol). The mixture was stirred at 80° C. overnight. Additional N-(methoxycarbonyl)chloroacetoamide (159.0 mg, 1.1 mmol) was added and stirred at 80° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave methyl (5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (51.7 mg, 22%). To a solution of methyl (5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (34.0 mg, 0.1 mmol) in water (2 mL) was added 2N HCl (aq) (2.0 mL) then refluxed for 1 hr and stirred at room temperature for 1 hr. The mixture was added NH4OH (aq). Formed precipitate was collected by filtration, washed with water then dried under reduced pressure to give the title compound (22.0 mg, 74%): MS m/e 299 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[N:21]=[C:2]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)=[O:28])=[CH:25][C:24]=3[O:39][CH3:40])[N:3]=[CH:4][C:5]1=2
Reactant: CC1CN(c2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(c1ccccc1)CC(C)C(=O)N2C
Yield: 60.2 %

Procedure:
A solution of 0.050 g (0.000165 mole) of (rac)-2-chloro-5,7-dimethyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-51), 0.043 g (0.000165 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.049 (0.00025 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol (4.0 mL) was heated at 180 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25), to give 0.0526 g of (rac)-4-(5,7-dimethyl-6-oxo-9-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-51) as white powder. HRMS (ES+) m/z Calcd for C29H35N7O3+H [(M+H)+]: 530.2874. Found: 530.2870.
Reaction SMILES: [P:1]([OH:40])([OH:39])([O:3][CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:14]=[C:9]2[C:8]([C:22](=[O:38])[C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=2[F:37])=[CH:7]1)[CH3:5])=[O:2].[OH-].[Na+:42]>CC(=O)OCC.C1COCC1.O>[P:1]([O-:39])([O-:40])([O:3][CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:14]=[C:9]2[C:8]([C:22](=[O:38])[C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=2[F:37])=[CH:7]1)[CH3:5])=[O:2].[Na+:42].[Na+:42]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OP(=O)(O)O)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OP(=O)([O-])[O-])c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To the solution of 1-(5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl dihydrogen phosphate (4 g, 6.5 mmol) in EA/THF (30 mL, 2/1) was added NaOH (0.57 g, 14.3 mmol) in H2O (1 mL) at rt. Then the mixture was stirred at room temperature over night. The mixture was filtered and dried under vacuum at 45° C. for 10 h to give the title compound as a white solid (4.0 g, 93%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[Cl:16])[C:10]([NH2:12])=O>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Br:17])[C:15]=1[Cl:16])[C:10]#[N:12]
Reactant: NC(=O)c1cc(Br)c(Cl)c(Br)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Br)c(Cl)c(Br)c1
Yield: 98 %

Procedure:
(328B1): Phosphoryl trichloride (90 ml, 966 mmol) was added to a suspension of 3,5-dibromo-4-chlorobenzamide (148 g, crude, ˜380 mmol) in acetonitrile (1500 ml) at reflux. The reaction mixture was heated to reflux for additional 90 minutes. The reaction mixture was evaporated to dryness, then partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed one more time with aq. NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness to give 3,5-dibromo-4-chlorobenzonitrile (110 g). The material was used without further purification in the next reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12](I)[CH:11]=3)/[CH:4]=[C:3]1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:25]([O:34][CH3:35])(=[O:33])[C:26]1[C:27](=[CH:29][CH:30]=[CH:31][CH:32]=1)[SH:28].C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:1][C:2]1([CH3:24])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([S:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[C:25]([O:34][CH3:35])=[O:33])[CH:11]=3)/[CH:4]=[C:3]1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(I)ccc32)C=C1N1CCOCC1
Reactant: COC(=O)c1ccccc1S
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1Sc1ccc2c(c1)NC(=O)/C2=C1\C=C(N2CCOCC2)C(C)(C)O1
Temperature: 90 °C

Procedure:
A 25 mL reaction vessel was charged with (3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one (100 mg, 0.23 mmol), methyl thiosalicylate (77 mg, 0.46 mmol), PdCl2(dppf).CH2Cl2 (19 mg, 0.023 mmol), cesium carbonate (225 mg, 0.69 mmol) and 8 mL of anhydrous DMF. The mixture was purged with nitrogen and heated in 90° C. bath for 2.5 hours. The mixture was cooled to room temperature, diluted with 50 mL of water and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated NaHCO3 (50 mL), brine (2×50 mL), dried over Na2SO4, and concentrated to give a brown oil. Purification of the oily mixture by silica gel chromatography eluted with 1-10% MeOH/CHCl3 provided methyl 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoate as a brown solid.
Reaction SMILES: [CH2:1]([N:11]1[C:17]([CH3:19])([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[N:2]1[C:8]([CH3:10])([CH3:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH2:20]1[O:23][CH:21]1[CH3:22]>[Cl-].[Li+].CN(C)C=O>[CH2:1]([N:2]1[C:8]([CH3:10])([CH3:9])[C:6](=[O:7])[N:5]([CH2:20][CH:21]([OH:23])[CH3:22])[C:3]1=[O:4])[N:11]1[C:17]([CH3:19])([CH3:18])[C:15](=[O:16])[N:14]([CH2:20][CH:21]([OH:23])[CH3:22])[C:12]1=[O:13]
Reactant: CC1(C)C(=O)NC(=O)N1CN1C(=O)NC(=O)C1(C)C
Reactant: CC1CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)N(CN2C(=O)N(CC(C)O)C(=O)C2(C)C)C(C)(C)C1=O
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A mixture of 268.3 g of 1,1'-methylene-bis-(5,5-dimethylhydantoin) [1 mol], 600 ml of dimethylformamide and 2.11 g of lithium chloride is stirred at 60° C. 134.0 g of propene oxide (2.3 mols) are slowly added dropwise to this mixture over the course of 1 hour and 45 minutes. Thereafter the mixture is heated to 100° C. over the course of 1.5 hours and stirred at 100° C. for a further 2 hours. The hot reaction mixture is now filtered and cooled to room temperature, neutralized with 20% strength sulphuric acid and concentrated to dryness on a rotary evaporator. The crude product is recrystallised from ethanol. 327.0 g of pure 1,1'-methylene-bis-(3-β-hydroxy-n-propyl-5,5-dimethylhydantoin) [85.3% of theory] of melting point 131°-133° C. are obtained. Microanalysis shows 14.50% N (calculated, 14.58% N); analysis by gel permeation chromatography shows that the substance is of uniform molecular weight. The N--NMR (nuclear magnetic resonance) spectrum and the IR (infrared) spectrum can be reconciled with the following structure: ##STR9##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:29][C@@H:28]([OH:30])[CH2:27][CH2:26][NH:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>O1CCCC1.CCOCC>[CH3:42][O:41][C:39]([N:25]1[CH2:26][CH2:27][C@H:28]([OH:30])[CH2:29][C@@H:24]1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:40]
Reactant: COC(=O)Cl
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(OCc2ccccc2)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OC)c(OCc2ccccc2)c1
Reaction time: 0.67 h
Yield: 89.9 %

Procedure:
To a 0° C. solution of 193 mg (0.471 mmole) of cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol and 0.29 ml triethylamine in 2.2 ml tetrahydrofuran is added dropwise 40 microliters (0.518 mmole) of methyl chloroformate. The reaction is stirred 40 minutes and then another 10 microliters of methyl chloroformate is added. The reaction is stirred 40 minutes longer, diluted with ether and filtered. The filtrate is washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product is purified via column chromatography on 10.4 g of silica gel eluting in 3 ml fractions with 1:3 ethyl ether/hexane to yield (fractions 16-30) 198 mg (80%) of the title compound as an oil.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)C=CC=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][C:30]=1[Br:31])[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:20]3[CH:28]=[CH:29][C:30]([Br:31])=[C:18]([Br:17])[CH:19]=3)[CH2:27][CH2:26]2)=[O:16])=[N:11][CH:12]=1
Reactant: Brc1ccc(CN2CCNCC2)cc1Br
Reactant: O=C(Nc1ccncn1)Oc1ccccc1
Product: O=C(Nc1ccncn1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1

Procedure:
The title compound was prepared from pyrimidin-4-yl-carbamic acid phenyl ester and 1-(3,4-dibromo-benzyl)-piperazine in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.40 (s, 1H), 8.10-7.80 (m, 1H), 7.70-7.50 (m, 1H), 7.58-7.45 (m, 1H), 7.14-7.10 (m, 1H), 6.55-6.40 (m, 1H), 3.40 (s, 2H), 2.87 (t, J=4.8 Hz, 4H), 2.38 (t, J=4.8 Hz, 4H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[C:27]([OH:34])[C:26]=2[CH:35]([CH3:37])[CH3:36])=[O:23])[CH2:17][CH2:16]1.I[CH3:39]>CN(C=O)C.O>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:28]=[C:27]([O:34][CH3:39])[C:26]=2[CH:35]([CH3:37])[CH3:36])=[O:23])[CH2:17][CH2:16]1
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c1C(C)C
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
Sodium hydride (21 mg, 0.48 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (200 mg, 0.40 mmol) in DMF (2 ml), the mixture was stirred at 40° C. for 10 minutes and iodomethane (68 mg, 0.48 mmol) was added thereto followed by stirring for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=50:1) to provide 47 mg (yield 23%) of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]-piperazin-1-yl]-N-(2,6diisopropyl-3-methoxyphenyl)acetamide. This was made into a dihydrochloride and recrystallized to provide the desired compound as colorless powdery crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Mg]>C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: Nc1cccc(B(O)O)c1

Procedure:
A mixture of 1-bromonaphthalene 1, magnesium powder in THF is irradiated for 15 min to produce Grignard reagent 2 which reacts with tributyl borate to yield the boronic ester 3. Hydrolysis of 3 with aqueous sulfuric acid affords 1-naphthalene boronic acid 4 (Song, Y; Ding, Z; Wang, Q; Tao, F. Syn. Comm. 1998, 28, 3757, WO 9964428).
Reaction SMILES: [CH:1]1([C:7]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]#[C:24]CO)[CH3:20]>>[CH:12]1([C:7]([OH:18])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][C:24]#[C:23][CH2:22][N:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:19][CH3:20])=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCN(CC#CCO)Cc1ccc(OC)cc1
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCCC1
Product: CCN(CC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1)Cc1ccc(OC)cc1

Procedure:
reacting methyl α-cyclohexyl-α-hydroxybenzeneacetate with 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butyn-1-ol in the presence of an anhydrous base to produce 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate; and
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Ba+2].[OH-].COCCOC.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>O>[Cl:19][C:20]1[CH:25]=[C:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:23]=[CH:22][N:21]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Clc1cc(-c2ccccc2)ncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 35.9 %

Procedure:
A reaction vessel was charged with 0.17 g of tetrakistriphenylphosphine palladium, 0.91 g of phenylboronic acid, and 3.53 g of barium hydroxide, to which 44 ml of 1,2-dimethoxyethane, 8 ml of water, and 1.11 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 6 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.51 g of 4-chloro-6-phenylpyrimidine, m.p.: 101.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH:10]([C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[OH:11])=[C:4]([CH3:24])[CH:3]=1.CN(C)C=O.[CH2:30](Br)[CH3:31].[H-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH:10]([C:12]2[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=2)[O:11][CH2:30][CH3:31])=[C:4]([CH3:24])[CH:3]=1
Reactant: CCBr
Reactant: Cc1cc(Cl)ccc1OCc1ccccc1C(O)c1nccn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(c1ccccc1COc1ccc(Cl)cc1C)c1nccn1C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a mixture of 0.34 g (0.9 mmol) of 2-[2-(4-chloro-2-methylphenoxymethyl)-α-hydroxybenzyl]-1-methylimidazole, 3 ml of N,N-dimethylformamide and 0.13 ml (1.8 mmol) of ethyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-ethoxybenzyl]-1-methylimidazole (0.30 g, 89.9%) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:6]([CH:10]=1)[C:7]([N:43]([CH2:44][CH3:45])[CH2:41][CH3:42])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Oc1cccc(F)n1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To mixture of 5-bromo-2-(6-fluoropyridin-2-yloxy)benzoic acid (16 g, 51.3 mmol) and TBTU (16.46 g, 51.3 mmol) in 15 mL of DMF was added diethylamine (13.26 mL, 128 mmol). The resulting solution was allowed to stir at rt overnight. The reaction was quenched with saturated NaHCO3, extracted with a 2:1 mixture of EtOAc and hexanes (3×50 mL). The combined organics were washed with brine, and evaporated to dryness. Purification by silica gel chromatography (hexane to CH2Cl2 to CH2Cl2/EA=20:1 to 10:1 to 5:1) provided 5-bromo-N,N-diethyl-2-(6-fluoropyridin-2-yloxy)benzamide as a off-white solid.
Reaction SMILES: [B-](F)(F)(F)CN1CCCC1.[K+].[F:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][CH:19]([C:22]3[CH:34]=[CH:33][C:25]([CH2:26][N:27]4[CH2:32][CH2:31]O[CH2:29][CH2:28]4)=[CH:24][CH:23]=3)[O:18][C:17]=2[CH:35]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][CH:19]([C:22]3[CH:23]=[CH:24][C:25]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:29][CH2:28]4)=[CH:33][CH:34]=3)[O:18][C:17]=2[CH:35]=1
Reactant: Fc1ccc2c(c1)OC(c1ccc(CN3CCOCC3)cc1)CO2
Agent: F[B-](F)(F)CN1CCCC1
Agent: [K+]
Product: Fc1ccc2c(c1)OC(c1ccc(CN3CCCC3)cc1)CO2

Procedure:
The title compound is prepared from G-4 and Potassium 1-trifluoroboratomethylpyrrolidine according to the procedure described for the synthesis of compound 202. 203: LC/MS Method 10; Rt=1.07 min; [M+H]+=354.4.