Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C>[Cl-].[Cl-].[Zn+2].O.ClCCl>[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[C:16]([C:17]([O:19][C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)=[O:18])=[CH:20][CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:23]=1
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: O=C1C=C(Cl)CCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)CCC1

Procedure:
To a mixture of 157 mg (1.15 mmol) of 3-chlorocyclohex-2-en-1-one, 16 mg (0.12 mmol) of ZnCl2, 324 mg (1.15 mmol) of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid (preparation described in WO 2001094339) and 2 ml of toluene there are added dropwise, under a nitrogen atmosphere, over the course of 15 minutes, 166 mg (1.27 mmol) of diisopropylethylamine. A further 2 ml of toluene are then added and, with stirring, the reaction mixture is maintained under moderate reflux for 18 hours in an oil bath. The reaction mixture is then brought to ambient temperature and 30 ml of dichloromethane and 20 ml of water are added. The organic phase is separated off and washed twice with 0.1M hydrochloric acid (20 ml) and twice with water (10 ml). After drying using magnesium sulfate and concentration in vacuo, 226 mg of 3-(2-methoxyethoxymethyl-6-trifluoromethyl-pyridin-3-ylcarbonyloxy)-cyclohex-2-en-1-one are obtained in the form of an orange-brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=O)=[CH:7][CH:6]=2.Cl.[CH3:16][NH:17][CH3:18]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([N:17]([CH3:18])[CH3:16])=[O:14])=[CH:7][CH:6]=2
Reactant: O=C(O)c1ccc2cnc(Cl)cc2c1
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1ccc2cnc(Cl)cc2c1

Procedure:
The title compound was prepared according to the method described for Preparation 52 using 3-chloroisoquinoline-6-carboxylic acid (Preparation 54) and dimethylamine hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:14][CH2:13][C@@:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[C:11]([CH3:24])([CH3:23])[CH2:10]1)=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38].CS(C)=O>CCOC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@:12]2([OH:15])[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C@H:6]([NH:5][C:3](=[O:4])[CH2:2][O:34][C:35]3[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=3[C:37]([O:39][CH3:40])=[O:38])[CH:25]([CH3:27])[CH3:26])[CH2:10][C:11]2([CH3:23])[CH3:24])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1O
Reactant: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1OCC(=O)N[C@@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Yield: 40.5 %

Procedure:
2-Chloro-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide (35 mg, 0.084 mmol), potassium carbonate (35 mg, 0.253 mmol), methyl 2-hydroxybenzoate (13 mg, 0.084 mmol) and DMSO (3 mL) were mixed with stirring at 25° C. The reaction was stirred for 20 hours, diluted with EtOAc, and then rinsed 4 times with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give an amber oil which was purified over silica gel in (3:1 to 1:1 hexanes/EtOAc to 100% EtOAc) to obtain methyl 2-(2-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethoxy)benzoate (18 mg, 0.034 mmol, 40% yield) as a white glass. MS found: (M+H)+=531.21.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:11]([CH2:17][CH2:18][OH:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>ClCCl>[C:27]([O:19][CH2:18][CH2:17][N:11]1[C:12]([CH:14]([CH3:16])[CH3:15])=[CH:13][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)c1cc(OCc2ccccc2)nn1CCO
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(OCc2ccccc2)nn1CCOC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of 3-benzyloxy-1-(2-hydroxyethyl)-5-isopropyl-1H-pyrazole (2.41 g) in dichloromethane (45 mL) were added triethylamine (1.40 g) and benzoyl chloride (1.43 g) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/6-1/1) to give the title compound (1.35 g).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[N:10][C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:19][C:18]=1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C#N)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1
Product: CC(C)(C#N)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionitrile and 4-fluoro-3-(pyridin-3-yl)benzeneboronic acid were coupled following the procedure in Example 65 to give 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionitrile as a white solid: δH (360 MHz, CDCl3) 1.86 (6H, s), 7.32 (1H, d, J 7), 7.38-7.45 (2H, m), 7.53-7.62 (2H, m), 7.86-7.97 (1H, m), 7.91 (1H, d, J 3), 8.62 (1H, d, J 7), 8.67 (1H, dd, J 8 and 3), 8.84 (1H, s); m/z (ES+) 358 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][N:10]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)Br
Reactant: Clc1nccc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(I)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (103) (50 mg, 0.179 mmol) in DMF (1 mL) was cooled to 0° C., NaH (8.6 mg, 1.2 eq, 0.215 mmol) was added slowly and then 2-bromopropane was added dropwise. The solution was stirred overnight at room temperature. The mixture was concentrated in vacuo. The crude product was then purified by column chromatography using a gradient of CH2Cl2 in hexanes to afford 4-chloro-3-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridine (301) (30 mg, 53% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10]Br.[NH2:12][CH2:13][CH2:14][OH:15]>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][NH:12][CH2:13][CH2:14][OH:15]
Reactant: BrCCOc1ccccc1Br
Reactant: NCCO
Solvent: CC(C)O
Product: OCCNCCOc1ccccc1Br
Temperature: 25 °C

Procedure:
A solution of 1-bromo-2-(2-bromoethoxy)benzene (C21) (5.66 g, 20.22 mmol) and 2-aminoethanol (12.30 g, 202 mmol) in 2-propanol (50 mL) was heated to 80° C. After heating overnight, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was taken up in dichloroethane and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a clear yellow oil. Yield: 5.12 g, 20.18 mmol, 97%. LCMS m/z 259.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.88 (dd, J=5.3, 5.1 Hz, 2H), 3.08 (dd, J=5.1, 5.1 Hz, 2H), 3.67 (dd, J=5.3, 5.3 Hz, 2H), 4.14 (dd, J=5.1, 5.1 Hz, 2H), 6.85 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 6.91 (dd, J=8.2, 1.2 Hz, 1H), 7.26 (ddd, J=8.2, 7.6, 1.5 Hz, 1H), 7.54 (dd, J=8.0, 1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[CH2:12]1COCC1.C[Mg]Br.[NH4+].[Cl-]>C(OCCCC)CCC.C(OCC)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]([OH:5])[CH3:12]
Reactant: C1CCOC1
Reactant: O=Cc1c(F)ccc(F)c1Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: CC(O)c1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry 18×250 mm test tube, 2-Chloro-3,6-difluorobenzaldehyde (1.00 g, 5.66 mmol) and THF (10.0 mL, 123 mmol) were added. The reaction tube was evacuated and filled with N2 3 times. Methylmagnesium bromide (0.810 g, 6.80 mmol) 1.0 M in butyl ether was added slowly at 0° C. The reaction mixture was stirred at room temperature overnight. 5 mL of sat. aq. NH4Cl was added to quench the reaction at 0° C. Diethyl ether was added and aq. layer was extracted with ether 3 times. The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The material was not further purified and ready for the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18]>>[NH2:22][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1cccc(N)c1
Product: Nc1cccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 74.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 3-ethynylaniline (0.07 mL, 0.65 mmol) to provide 260 (100 mg, 74% yield) as a brown solid. LC-MS (M+H=312 obsd.=312).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]([CH2:46][OH:47])([CH2:39]3)[CH2:37]1)[CH2:43]2>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:17]([CH:37]1[C:36]2([NH2:35])[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]1([CH2:46][OH:47])[CH2:39]3)[CH2:43]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: NC12CC3CC(C1)CC(CO)(C3)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(CO)C3
Temperature: -40 °C
Reaction time: 8 h

Procedure:
To a solution of 1.83 g of Boc-L-phenylalanine in 15 ml of dimethylformamide is added 0.76 of N-methylmorpholine. The reaction mixture is cooled to -40° C. and 0.90 ml of isobutylchloroformate is added with stirring. The reaction mixture is stirred for 15 minutes at a temperature below -10° C. then 1.04 g of 3-amino-1-adamantanemethanol is added. The reaction mixture is stirred for 15 minutes at -20° C. then stored overnight at 5° C. The dimethylformamide is removed under reduced pressure and the residue is dissolved in methylene chloride and water. The methylene chloride phase is separated and washed twice with 35 ml of water, 3 times with 35 ml of a 0.5 M potassium bisulfate solution, and twice with 35 ml of water and then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the residue is purified by chromatography on Whatman 10 micron silica gel eluting with a gradient of 1:1 hexane-chloroform to chloroform to give Boc-L-phenylalanyl-3-amino-adamantanemethanol. 2.0 Grams of this product is dissolved in 5 ml of a 6 N solution of hydrogen chloride in dioxane. The reaction mixture is allowed to stand for 20 minutes at room temperature then the solvent is removed under reduced pressure at 30° C., and the residue is stirred with diethyl ether to give the product as a solid. The solid product is collected by filtration and dried under reduced pressure to give L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride which is represented by the following structure ##STR70## When an equivalent quantity of L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride is substituted for the methyl L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride of Example 4 and the procedures detailed in Examples 4 through 9 substantially repeated there is obtained L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride which is represented by the following formula ##STR71##
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.I[CH3:13]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][CH3:13])=[N:8][CH:9]=1
Reactant: CI
Reactant: OCc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Sodium hydride (0.61 g, 60% in mineral oil, 15.32 mmol) was added to a solution of (5-chloropyridin-2-yl)methanol (2 g, 13.93 mmol) in THF (50 mL) and stirred at room temperature until no further gas evolution was observed. Iodomethane (0.95 mL, 15.32 mmol) was injected slowly and the reaction was allowed to stir at room temperature for 18 hours. The reaction was concentrated in vacuo, acidified with 2N HCl in water (25 mL) and extracted with EtOAc (2×20 mL). The aqueous layer was collected, basified with potassium hydroxide and extracted with DCM (3×20 mL). The organic layers were combined, washed with water, dried over sodium sulfate and concentrated in vacuo to afford the title compound (2 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[CH3:5].[C:30]([O:34][C:35](=O)[O:36]C(C)(C)C)([CH3:33])([CH3:32])[CH3:31].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.CN(C1C=CN=CC=1)C>[C:30]([O:34][C:35]([N:9]1[C:8]2[CH2:7][CH:6]([C:4]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:3]([O:2][CH3:1])=[O:29])[CH3:5])[CH2:18][CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([Br:19])[CH:14]=2)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Br)cc23)C1)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Br)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To 1.2 g (2.52 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester (from example 99) in 40 mL of THF were added 31 mg (0.25 mmol, 0.1 eq) of DMAP and 660 mg (3.02 mmol, 1.2 eq) of carbonic acid di-tert-butyl ester at 0° C. The reaction mixture was stirred at RT for 2 hours. EtOAc and a solution of aqueous NaHCO3 were added, the phases were separated, and the organic one was extracted with 1M KHSO4. The organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography afforded 1.3 g (90%) of (RS,SR)-2-(-1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-6-bromo-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as white solid, MS: 575 (M,1Br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[CH:14]=[CH2:15]>[OH-].[K+]>[CH2:15]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[CH:14]=[CH2:13]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Product: C=CCOc1ccc2cc(Br)ccc2c1

Procedure:
In reaction D, 6-bromo-2-naphthol and allylbromide, represented by the graphic formulae VIII and XIII, respectively, are refluxed together in ethanoic potassium hydroxide to produce 2-allyloxy-6-bromonaphthalene of graphic formula XIV. 2-Allyloxy-6-bromonaphthalene undergoes a Claisen rearrangement under high temperatures followed by acid catalyzed ring closure to produce 7-bromo-l,2-dihydro-2-methylnaphtho[2,1-b]furan of graphic formula XV. See Organic Reaction Vol. II, 1944, pages 1 to 48. The conversion of 7-bromo-1,2-dihydro-2-methylnaphtho[2,1-b]furan to 7-hydroxy-1,2-dihydro-2-methylnaphtho[2,1-b]furan represented by graphic formuale XVI is accomplished thru a series of steps described in Organic Synthesis Vol.49 pages 90-93, 1972. Other substituted 7-hydroxy-1,2-dihydronaphtho[2,1-b]furans may be synthesized by replacing allylbromide (XIII) with another reactant such as 3-bromo-2-methyl-propene. Coupling the resulting 7-hydroxy-1,2-dihydronaphtho[2,1-b]furan with the appropriate propargyl alcohol would result in compounds represented by graphic formula IB having formula IIB as group A. ##STR8##
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16].O>C(O)(=O)C>[F:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)cc1F
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.3 ml, 13.8 mmol) was added dropwise to a solution of 4-amino-3-fluorophenol (1.0 g, 7.9 mmol) in acetic acid (25 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h and water (2 ml) was added and the stirring was continued for 30 minutes at room temperature. The mixture was evaporated to dryness in vacuo. The yield of the crude product was 1.3 g (100%) and it was used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[H-].[Na+].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>C1(C)C=CC=CC=1.C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[C:12]#[N:13]
Reactant: Clc1ccc2ccccc2n1
Reactant: N#CCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC(c1ccc2ccccc2n1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a solution of 2-quinolylacetonitrile (14.5 g, 86.2 mmol) in toluene (200 mL) was added slowly NaH (6.9 g of 60% oil dispersion, 172 mmol). The reaction mixture was stirred at ambient temperature for 15 min at which point H2 evolution was no longer evident. A solution of 2-chloroquinoline (14.1 g, 86.2 mmol) in toluene (150 mL) was added to the reaction flask, and the reaction mixture was then heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with THF, and quenched with H2O. The organic solution was washed with 1N HCl (200 mL), saturated aqueous solution of NaHCO3, and brine. An orange solid precipitated from the organic layer and was isolated via vacuum filtration. The mother liquor was dried over MgSO4 and the volatile components were removed with a rotary evaporator. The resulting solid was combined with the orange powder isolated via filtration. The solid was washed with a mixture of ether and heptane to afford 14.7 g (57.6%) of product. Results of 1H NMR spectroscopy and electrospray mass spectroscopy are consistent with the product. 1H NMR (300 MHz, CDCl3): δ 7.36 (m, 2H), 7.57 (d, J=9.1 Hz, 2H), 7.64 (m, 4H), 7.73 (d, J=8.8 Hz, 2H), 7.86 (d, J=9.1 Hz, 2H).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10](=O)OCC2C=CC=CC=2)[CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=C(S(C)=O)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:33]2=[N:34][CH:35]=1>C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:29][C:30]1[CH:31]=[C:32]2[C:38]([C:39]3[N:44]=[C:10]([NH:9][C@H:5]4[CH2:6][CH2:7][CH2:8][C@@H:3]([C:1]#[N:2])[CH2:4]4)[C:42]([F:48])=[CH:41][N:40]=3)=[CH:37][N:36]([S:49]([C:52]3[CH:53]=[CH:54][C:55]([CH3:56])=[CH:57][CH:58]=3)(=[O:51])=[O:50])[C:33]2=[N:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: N#C[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](C#N)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 45 °C
Reaction time: 2.25 h

Procedure:
Benzyl N-[(1S,3R)-3-cyanocyclohexyl]carbamate (0.26 g, 1.02 mmol) was dissolved in THF (15 mL) and treated with 0.13 g of 20% Pearlman's catalyst (50% wet by weight). The suspension was degassed with hydrogen for 2 min then placed under static hydrogen atmosphere. After 135 min, TLC showed no remaining starting material. The suspension was filtered through celite, washed with THF and degassed with nitrogen followed by the addition of iPr2NEt (0.21 mL, 1.23 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 1a, (0.48 g, 1.02 mmol). The mixture was allowed to stir overnight at 45° C. then concentrated to dryness, absorbed on silica-gel and purified by silica gel chromatography using 0-60% EtOAc/hexanes gradient to afford 293 mg of a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:17]=2)[C:12]([F:15])=[N:13][CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:18]2[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[N:13][C:12]=3[F:15])[N:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OCc4ccccc4)cnc3F)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(O)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 4-(5-(benzyloxy)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.080 g, 0.145 mmol) in EtOAc (8 mL) under N2 gas was treated with 10% palladium on carbon (Aldrich) (7.72 mg, 0.073 mmol). The reaction mixture was purged with N2 and then stirred at rt under H2 for 2 h. The reaction mixture was passed through Celite® (diatomaceous earth). The filtrate was concentrated. The crude product was purified by column chromatography (12 g, 20% to 30% acetone in hexanes) to give the product as a white solid (0.050 g). m/z (ESI, +ve ion) 462.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 8.03 (dd, J=7.60, 3.07 Hz, 1H); 7.89 (br. s., 1H); 7.23 (d, J=6.43 Hz, 4H); 6.87 (t, J=7.53 Hz, 4H); 5.78 (br. s., 1H); 4.82 (s, 4H); 3.81 (d, J=4.82 Hz, 6H); 2.55 (s, 3H).