Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH2:21][C:22]2=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>O1CCOCC1.O>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][CH:21]([C:3]([O:6][CH3:7])=[O:8])[C:22]2=[O:27])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1CCc2c(OCc3ccccc3)cccc2C1=O
Temperature: 82.5 °C
Yield: 98.2 %

Procedure:
Under an argon atmosphere, 2.09 g of 60% sodium hydride was suspended in 30 ml of anhydrous dioxane and 11.51 g of dimethyl carbonate was added. While stirring with heating in an oil bath at 80 to 85° C., a solution of 6.58 g of 5-(benzyloxy)-1-tetralone in 15 ml of dioxane was added dropwise over about one hour. After stirring for one hour, the reaction solution was ice-cooled and 52 ml of an aqueous 1N acetic acid solution was added dropwise. The reaction solution was diluted with water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.95 g of the desired compound as a pale yellow oily substance.
Reaction SMILES: C[Mg]Cl.[CH2:4]([CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:5][CH2:6][CH2:7][CH3:8].[C:15](O)(=O)C.O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:15][C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)O
Reactant: CCCCCC1CCCC1=O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCCC1(C)O
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
A 3-L reaction flask was charged with methylmagnesium chloride (MeMgCl) solution in tetrahydrofuran (THF) (800 mL, 2.4 mol) and THF (500 mL). The reaction flask was cooled to 5-10° C. 2-Pentyl-cyclopentanone (370 g, 2.4 mol) (prepared as above in EXAMPLE I) was fed into the reaction mixture over an hour. The reaction was aged for 4 hours and then neutralized with acetic acid (CH3COOH) (160 g) while the temperature was maintained at 5-10° C. The reaction mixture was poured into H2O (3 L) and toluene (1 L). The organic layer was separated and fractional distilled to afford 1-methyl-2-pentyl-cyclopentanol (245 g) having a boiling point of 150-152° C. at 3 mmHg.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][NH:71][C:72](=[O:75])[CH2:73][NH2:74]>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][CH2:73][C:72]([NH:71][CH3:70])=[O:75])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CNC(=O)CN
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(=O)NC)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and N1-methylglycinamide (12.5 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 30%). LC-MS m/z 592 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26]([OH:32])[C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29].[OH-].[Na+].I[CH3:36]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH:26]([O:32][CH3:36])[C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29]
Reactant: CI
Reactant: CCC(C)(C)C(O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(C)(C)C(OC)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-2,2-dimethylbutan-1-ol (53.8 mg) in DMF (1227 μL) were added 60% sodium hydroxide (9.8 mg) and iodomethane (15.3 μL) at 0° C., and the mixture was stirred for 5 hr. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (42.1 mg) as a transparent gummy substance.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:11].[N+](=[CH2:27])=[N-].C(O)(=O)C>C(OCC)C>[CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:14]([O:16][CH3:27])=[O:15])=[O:11]
Reactant: Cc1ccc(CC(CC(=O)N2C[C@H]3CCCC[C@H]3C2)C(=O)O)cc1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccc(C)cc1
Temperature: 0 °C

Procedure:
To a suspension of 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionic acid (100 mg) in diethyl ether (10 ml) was added a solution of diazomethane in diethyl ether (10 ml) with stirring at 0° C. After the mixture was stirred at room temperature for 1 hour, excess diazomethane was decomposed with acetic acid. The reaction mixture was washed successively with saturated sodium bicarbonate solution and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to give 60 mg of methyl 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionate as a colorless viscous oil.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].[Br-].C1(C([PH3+])([C:25]2[CH:30]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:42]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([N+:52]([O-:54])=[O:53])[CH:45]=2)=O)[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1>C1COCC1>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([C:42]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([N+:52]([O-:54])=[O:53])[CH:45]=2)=[CH:25][C:30]#[N:5])[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.8 %

Procedure:
Lithium bis(trimethylsilyl)amide (5.3 mL, 5.3 mmol) was added dropwise to a stirred suspension of triphenylmethylphosphonium bromide (1.89 g, 5.3 mmol) in anhydrous THF (30 mL) at 0° C. After 10 min at cold, the reaction mixture was stirred at room temperature for 40 min. The Wittig reagent was then added dropwise to a stirred solution of (3,5-dimethoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanone (1.40 g, 4.4 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The solution was poured into ice water (100 mL) and extracted with CH2Cl2 (4×40 mL). The combined organic layers were washed with water (2×40 mL), brine (40 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave 3-(3,5-dimethoxy-phenyl)-3-(4-methoxy-3-nitro-phenyl)-acrylonitrile as a solid (1.15 g, 83% yield): 1H NMR (CDCl3) δ 3.78 (s, 6H, 2OCH3), 3.98 (s, 3H, OCH3), 5.46-5.47 (d, J=4.3 Hz, 2H, CH2), 6.43-6.47 (m, 3H, Ar), 7.02-7.06 (d, J=8.8 Hz, 1H, Ar), 7.48-7.52 (dd, J=2.4, 8.8 Hz, 1H, Ar), 7.85-7.86 (d, J=2.4 Hz, 1H, Ar); 3C NMR (CDCl3) δ 55.39, 56.62, 100.13, 106.53, 113.18, 115.08, 125.10, 133.67, 133.86, 139.49, 142.53, 147.51, 152.41, 160.75.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: COc1ccc2c(c1)CCC2N
Product: COc1ccc2c(c1)CCC2NC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-5-methoxy-indane
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>C(#N)C>[Br:1][C:2]1[C:3]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Br
Temperature: 0 °C

Procedure:
An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 3.4 ml (24.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.82 g (12.1 mmol) of trans-2-aminocyclohexanol hydrochloride. After 16 hours at room temperature the batch is filtrated and the filtrate is concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate: 1:1). 1.61 g (5.3 mmol, corresponding to 53% of theory) of the product is obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:30].C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=3)=[CH:15][CH:16]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(OC)cc3)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(COc2ccc(CSc3ccc(OCC(=O)O)c(C)c3)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 33C. mp 150-152° C.; HPLC: area %=96.69, r.t.=2.93 min., γ=214 nm, mobile phase=acetonitrile/water with 0.10% TFA; IR (KBr) cm−1: 2929, 1728, 1707, 1513, 1491, 1225; 400 MHz 1H NMR (DMSO-d6): δ 12.98 (br(s), 1H), 7.27-7.34 (m, 2H), 7.02-7.16 (m, 4H), 6.81-6.91 (m, 4H), 6.69 (d, 1H, J=8.6 Hz), 4.91 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 3.69 (s, 3H), 2.08 (s, 3H); MS m/z 423 (M−1). Anal. Calc'd for C24H24O5S: C, 67.90; H, 5.70. found: C, 67.48; H, 5.59.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13]CC(O)C[CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:17]>[C].[Pd].C(C(CCCC)CO)C>[CH2:16]([CH:18]([CH2:23][CH2:22][CH2:21][CH3:20])[CH2:19][OH:1])[CH3:15].[CH3:13][C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[CH2:9].[C:18]1([CH:16]([CH3:17])[CH3:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc(C2=CCC(O)CC2)cc1
Agent: [Pd]
Agent: C=C(C)c1ccccc1
Solvent: CCCCC(CC)CO
Product: CC(C)c1ccccc1

Procedure:
A 300-ml four-necked glass flask was charged with 38.0 g (0.20 mole) of 4-(4-hydroxyphenyl)-3-cyclohexene-1-ol, 0.4 g of 5% palladium carbon, 59.1 g (0.50 mole) of α-methylstyrene and 100 ml of 2-ethylhexanol. The mixture was reacted at 160° C. for 4 hours in a nitrogen atmosphere. The reaction mixture was hot filtered at 150° C. to recover the palladium-carbon. 2-Ethylhexanol, α-methylstyrene and cumene formed were distilled off from the filtrate under reduced pressure. 37.2 g of white crystals of 4,4'-biphenol were obtained. The product had a purity of 98.6% based on liquid chromatography, a p-phenylphenol content of 0.9% and a yield converted to a purity basis of 98.5%.
Reaction SMILES: I[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.I[CH2:17][C@H]1CC[C@H](CCC)CC1.FC1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][SiH:37]([CH2:40][Mg]Cl)[CH2:36][CH2:35]2)=CC=1>>[CH2:31]([C@H:34]1[CH2:35][CH2:36][Si@H:37]([CH2:40][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:38][CH2:39]1)[CH:32]([CH3:33])[CH3:17]
Reactant: Fc1ccc(C2CC[SiH](C[Mg]Cl)CC2)cc1
Reactant: CCC[C@H]1CC[C@H](CI)CC1
Reactant: Fc1ccc([C@H]2CC[C@H](CI)CC2)cc1
Product: CC(C)C[C@H]1CC[Si@H](CC[C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 30, except that 6.3 g (19.9 mmol) of trans-1-iodomethyl-4-(p-fluorophenyl)cyclohexane and (4-n-isobutyl-1-silacyclohexyl) methylmagnesium chloride were used instead of 4.5 g (19.9 mmol) of trans-1-iodomethyl-4-n-propylcyclohexane and (4-(p-fluorophenyl)-1-silacyclohexyl)methylmagnesium chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]=O.[NH2:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[C:20]([CH:29]2[CH2:31][CH2:30]2)[CH:19]=1>>[NH2:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:21]=[C:20]([CH:29]2[CH2:31][CH2:30]2)[C:19]=1[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: C=O
Reactant: Nc1cc(C2CC2)nn1-c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(Cc2c(C3CC3)nn(-c3ccccc3)c2N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine (2.4 g), 37-40% aqueous formaldehyde solution (0.9 ml) and industrial methylated spirit (30 ml) was stirred at ambient temperature under nitrogen for 18 hours, then a slurry of 5-amino-3-cyclopropyl-1-phenylpyrazole (2.5 g) in industrial methylated spirit (60 ml) was added in one portion. The stirred mixture was heated under reflux for 24 hours then the solvents were removed in vacuo. The residue was purified by reduced pressure column chromatography over silica using a 19:1 mixture of dichloromethane and industrial methylated spirit as eluant. Appropriate fractions were combined and the solvents removed in vacuo. The residue was triturated with acetone and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 5-amino-3-cyclopropyl-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-1-phenylpyrazole as a white solid (1.4 g), m.p. 70-74° C.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[C:17]([CH3:23])[N:16]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[NH2:14][C:15]1[N:20]=[C:19]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:18]([CH3:22])=[C:17]([CH3:23])[N:16]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Cc1nc(N)nc(Cl)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(-c2cccc3ccccc23)c1C
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A stirred heterogeneous solution of 1-naphthyl boronic acid (0.382 g), 2-amino-4-chloro-5,6-dimethylpyrimidine (0.350 g), tetrakis(triphenylphosphine)palladium(0) (0.153 g), ethyl alcohol (8 mL), water (4 mL), 1,2-dimethoxyethane (8 mL) and sodium carbonate (0.85 g), was heated to reflux (about 80° to 90° C.) for 14 hours. The solution was then cooled to room temperature, filtered and extracted with ethyl acetate. The solvent was removed under reduced pressure and the resultant yellow solid was recrystallized to give 2-amino-5,6-dimethyl-4-(naphth-1-yl)-pyrimidine (0.213 g), m.p. 213.5-215.1° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:17][N:16]([C:18]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)=[O:19])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:31]OS(OC)(=O)=O.C(Cl)Cl>C1COCC1.CO>[NH3:5].[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:15][N:16]([C:18]([C:20]4[N:21]([CH3:31])[C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)=[O:19])[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(=O)N2CC(C(=O)N3CCCN(C4CCC4)CC3)C2)nc2ccccc21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.6 %

Procedure:
To a stirred solution of 2-({3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-1-yl}carbonyl)-1H-benzimidazole (170 mg, 0.45 mmol) in THF (10 ml) was added NaOH (1.12 ml of a 2.5 M aqueous solution, 2.8 mmol). After 5 minutes, dimethylsulfate (0.2 ml, 2.1 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction was then concentrated at reduced pressure and purified directly via FCC (using a gradient of eluents; 98:2 to 95:5 DCM:2M NH3 in MeOH) to give the title compound (45 mg, 25% yield) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13](=[O:16])([O-])[O-].[K+].[K+].O>C(COC)OC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:2]2[CH:3]=[CH:4][C:13]([OH:16])=[CH:9][CH:10]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2ccc(O)cc2)c2c1C(=O)NC2
Yield: 181.6 %

Procedure:
In a similar manner to Step 1 of Example 152, 7-amino-4-bromoisoindolinone (200 mg, 0.880 mmol) was dissolved in dimethoxyethane (14 mL); and the solution was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (387 mg, 1.76 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (57.4 mg, 0.0704 mmol), potassium carbonate (607 mg, 4.40 mmol) and water (0.32 mL), followed by purification by slurry using chloroform to obtain 7-amino-4-(4-hydroxyphenyl)isoindolinone (192 mg, yield 91%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12](=O)N(C)C)=[C:7]([Cl:17])[CH:6]=1.C[O-].[Na+].[C:22](=O)([O-])N.[F:26][C:27]([F:46])([F:45])[C:28]1[C:32]2[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH2:42]CBr)=[C:36]([CH2:37][CH2:38][CH3:39])[C:31]=2[O:30][N:29]=1>CO>[CH3:22][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:42][CH2:41][O:40][C:35]2[CH:34]=[CH:33][C:32]3[C:28]([C:27]([F:45])([F:26])[F:46])=[N:29][O:30][C:31]=3[C:36]=2[CH2:37][CH2:38][CH3:39])=[C:7]([Cl:17])[CH:6]=1)[C:3]([OH:2])=[O:18]
Reactant: NC(=O)[O-]
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(C(C)C(=O)O)cc2Cl)ccc2c(C(F)(F)F)noc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 3-trifluoromethyl-7-propyl-6-hydroxybenzisoxazole (2.5 grams) in 2-butanone (30 mL) was treated with 1,3-dibromopropane (4.8 mL) and potassium carbonate (5.0 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was flitered through a silica gel plug using methylene chloride and hexane (1:2) to give 3-trifluoromethyl-7-propyl-6-(3-bromopropyloxy)-benzisoxazole. A solution of 3-chloro-4-dimethylcarbamoylthio-phenylacetic acid methyl ester (0.33 grams) in dry methanol (3.5 mL) was treated with a solution of sodium methoxide in methanol (25 wt %; 0.341 mL). The solution was refluxed for 2 hours. HPLC analysis showed the disappearance of the carbamate. The solution was allowed to cool to 50° C. 3-trifluoromethyl-7-propyl-6-(3-bromopropyloxy)-benzisoxazole (0.31 grams) was added and the solution stirred for 1 hour. The reaction was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once more with pH 4 buffer, then water. The organic was dried over magnesium sulfate, filtered and concentrated to an oil. The oil was applied to a silica gel column packed with hexane/methylene chloride (2:1). The column was eluted with this mobile phase until the product began to appear in the eluant. The mobile phase was switched to 100% methylene chloride and elution continued until all the product was recovered.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14]Br)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25]([Cl:32])[N:24]=1>CN(C=O)C>[CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:27]2[C:26]3[C:30](=[N:31][C:23]([NH2:22])=[N:24][C:25]=3[Cl:32])[N:29]=[CH:28]2)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C1CCC(CBr)O1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C1CCC(Cn2cnc3nc(N)nc(Cl)c32)O1
Temperature: 100 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
A solution of (5-Bromomethyl-tetrahydro-furan-2-yl)-phosphonic acid diethyl ester (1.0, 3.32 mmol) in DMF (7mL) was transferred via cannula to a solution of cesium carbonate (1.31 g, 4.98 mmol) and 2-amino-6-chloropurine (845 mg, 4.98 mmol) in DMF (7 mL) which had been previously heated at 100° C. for 0.5 hour . The reaction mixture was stirred at 100° C. for 3 hrs. The reaction mixture was then concentrated and chromatographed, eluting with 8% methanol/dichloromethane to give [5-(2-Amino-6-chloro-purin-7-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester (78 mg, 6%):
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[NH:26]1[C:22]([C:18]2[CH:17]=[C:16]([NH:15][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[CH:21]=[CH:20][CH:19]=2)=[N:23][N:24]=[N:25]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc2ccccc2c1
Yield: 56.9 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 2-naphthalenesulfonyl chloride (13 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 10 mg (57%) of the title compound. MS (ESI+) calcd for C17H13N5O2S 351.078995, found 351.080505