Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OO)(=[O:3])C.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[N+:6]1([O-:3])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OO
Reactant: c1ccc2ncccc2c1
Product: [O-][n+]1cccc2ccccc21

Procedure:
Peracetic acid (7.5 mL, 39 mmole, 40%) and quinoline (5 g, 39 mmole) were stirred for 2 hours. Much of the acetic acid was removed from the reaction mixture in vacuo. The resulting residue was dissolved in methylene chloride (50 mL) and washed twice with saturated sodium bicarbonate solution. After drying over MgSO4 the solvent was evaporated and the residue was triturated with ether. The resulting tan solid was collected by filtration. This material was carried on without further characterization.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2C=CC(I)=CC=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][I:25]>CN(C=O)C>[CH3:11][NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:1]1[CH:6]=[CH:5][C:24]([I:25])=[CH:3][CH:2]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(Nc1ccc(I)cc1)c1ccccc1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccccc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 196.6 %

Procedure:
To compound 28 (from Example 18) (500 mg, 1.39 mmol) in DMF (10 mL) were added at room temperature K2CO3 (962 mg, 6.96 mmol), followed by methyl iodide (395 mg, 2.78 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The solvent is then removed and water was added. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were dried and concentrated. Purification by flash chromatography using hexane:ethyl acetate (8:2) afforded 510 mg (98%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28])#[N:21].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:28][C:27]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)([CH3:12])[CH3:11])=[N:6][CH:7]=2)=[CH:23][C:22]=1[C:20]#[N:21]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CC(C)(CNc1ncc(Br)cn1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(CNc1ncc(-c2ccc(F)c(C#N)c2)cn1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 75.5 %

Procedure:
To a 5 mL microwave reaction vessel was added 5-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine (267 mg, 0.8 mmol, 1.0 equiv), 3-cyano-4-fluorophenylboronic acid (203 mg, 1.2 mmol, 1.5 equiv), Cl2Pd(dppf) (60 mg, 82 μmol, 0.1 equiv), potassium carbonate (1.2 mL of a 2N aqueous solution, 2.4 mmol, 3.0 equiv), and dioxane (4 mL). The reaction was heated in a microwave reactor at 120° C. for 20 min. The aqueous layer was removed from the reaction, and the organic layer was directly purified by reverse phase column chromatography to give 220 mg (73%) of 2-fluoro-5-(2-(2-(4-fluorophenyl)-2-methylpropylamino)pyrimidin-5-yl)benzonitrile as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:40])([CH3:39])[CH2:21][C:22]1[N:27]=[C:26]([CH2:28]O)[CH:25]=[CH:24][C:23]=1[C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[F:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:28][C:26]3[CH:25]=[CH:24][C:23]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:22]([CH2:21][C:20]([CH3:40])([CH3:39])[CH3:19])[N:27]=3)[CH:11]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1ccc(OC)c(O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1ccc(OC)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 3-cyclopropyl-3-(3-hydroxy-4-methoxyphenyl)propanoate (168 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (202 mg) in toluene (15 mL) were added 1,1′-(azodicarbonyl)dipiperidine (268 mg) and tributylphosphine (262 and the mixture was stirred at room temperature for 15 hr. Hexane and ethyl acetate were added to the reaction mixture, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (190 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2>>[CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=[C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[CH:24][C:16]=4[CH3:15])[NH:20][C:19]3=[O:25])[CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Reactant: Cc1cccc2c1CC(=O)N2
Product: Cc1cccc2c1C(=Cc1ccc3c(c1)CCC(C)(C)O3)C(=O)N2

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 4-methyl-2-oxindole to give 0.25 g of 3-(2,2-dimethylchroman-6-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:37])[NH:19][C:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:36])=[C:28]([CH:35]=3)[CH2:29][S:30]([NH:33][CH3:34])(=[O:32])=[O:31])=[N:21]2)=[C:16]([CH3:38])[N:15]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[OH:3][CH:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:37])[NH:19][C:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:36])=[C:28]([CH:35]=3)[CH2:29][S:30]([NH:33][CH3:34])(=[O:32])=[O:31])=[N:21]2)=[C:16]([CH3:38])[N:15]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CNS(=O)(=O)Cc1cc(Cc2nn3c(C(CCCc4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)ccc1C
Agent: [BH4-]
Agent: [Na+]
Product: CNS(=O)(=O)Cc1cc(Cc2nn3c(C(CCCc4ccccc4)C(C)O)nc(C)c3c(=O)[nH]2)ccc1C

Procedure:
100 mg (0.19 mmol) of 5-{[7-(1-acetyl-4-phenylbutyl)-5-methyl-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl]methyl}-N,2-dimethylbenzylsulphonamide are reacted analogously to Example 12 with 7.2 mg (0.19 mmol) of sodium borohydride to give 5-({7-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-methyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl}methyl)-N,2-dimethylbenzylsulphonamide.
Reaction SMILES: C([O-])(=O)C.[Ni+2:5].C([O-])(=O)C.[CH2:10]([C:12]1[C:32]2[N:33]=[C:14]([CH:15]=[C:16]3[NH:43][C:19](=[CH:20][C:21]4[C:22]([CH2:41][CH3:42])=[C:23]([CH2:39][CH3:40])[C:24]([N:38]=4)=[CH:25][C:26]4[NH:30][C:29]([CH:31]=2)=[C:28]([CH2:34][CH3:35])[C:27]=4[CH2:36][CH3:37])[C:18]([CH2:44][CH3:45])=[C:17]3[CH2:46][CH3:47])[C:13]=1[CH2:48][CH3:49])[CH3:11]>>[Ni:5].[CH2:39]([C:23]1[C:24]2[N:38]=[C:21]([CH:20]=[C:19]3[NH:43][C:16](=[CH:15][C:14]4[C:13]([CH2:48][CH3:49])=[C:12]([CH2:10][CH3:11])[C:32]([N:33]=4)=[CH:31][C:29]4[NH:30][C:26]([CH:25]=2)=[C:27]([CH2:36][CH3:37])[C:28]=4[CH2:34][CH3:35])[C:17]([CH2:46][CH3:47])=[C:18]3[CH2:44][CH3:45])[C:22]=1[CH2:41][CH3:42])[CH3:40]
Reactant: [Ni+2]
Agent: CC(=O)[O-]
Agent: CCC1=C(CC)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(CC)c5CC)C(CC)=C4CC)c(CC)c3CC
Product: [Ni]
Temperature: 25 °C

Procedure:
The nickel acetate is added to the octaethylporphyrin solution; the mixture which results is refluxed for about 24 hours until the electronic spectrum of the reaction mixture indicates that chelation is complete. The reaction mixture is then concentrated to 7 mL and allowed to cool to room temperature of about 22°. Product which precipitates is recovered by filtration, dissolved in a mixed solvent composed of 5 mL dichloromethane and 2 mL methanol, and recrystallized, yielding Ni octaethylporphyrin.
Reaction SMILES: C[O:2][C:3]1[C:11]2[S:10][C:9]([CH3:12])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:12][C:9]1[S:10][C:11]2[C:3]([OH:2])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: COc1cccc2nc(C)sc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc2cccc(O)c2s1
Temperature: 165 °C

Procedure:
7-Methoxy-2-methyl-benzothiazole (400 mg, 2.23 mmol) was mechanically mixed with solid pyridine hydrochloride (6.00 g, 52 mmol) and then heated to 160-170° C. in a sealed vessel for 16 hours. Water (40 mL) was added to the warm mixture, the pH was adjusted to neutrality with NaHCO3 and the mixture was extracted with 1:1 CHCl2 /CHCl3 (4×10 mL). The pooled organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to provide 2-methyl-benzothiazol-7-ol as a waxy yellow solid. (260 mg; GC-MS m/z 165).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH:33]([CH3:35])[CH3:34])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:36])=[CH:16][C:15]=2[F:37])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH:33]([CH3:35])[CH3:34])[C:23]4[N:24]=[C:25]([NH:39][CH3:38])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:36])=[CH:16][C:15]=2[F:37])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C(C)C)c2n1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C(C)C)c2n1
Yield: 50 %

Procedure:
In a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea (0.1 g, 0.2 mmol) and methylamine were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea (45 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.78 (brs, 1H), 8.57 (brs, 1H), 7.85 (d, J=9 Hz, 1H), 7.75 (brs, 1H), 7.62 (s, 1H), 7.15 (d, J=12 Hz, 1H), 6.00 (s, 1H), 5.74 (m, 1H), 2.89 (d, J=5 Hz, 3H), 2.07 (s, 3H), 1.56 (d, J=6 Hz, 6H), 1.21 (s, 9H); MS (ESI) m/z: 508.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:14].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].N12CCCN=C1CCCCC2>O1CCOCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([C:22]2[O:14][C:4]3[C:3]([O:2][CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]=3[CH:6]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1cc([N+](=O)[O-])cc(C=O)c1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])cc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Temperature: 100 °C
Yield: 57.1 %

Procedure:
5.0 g (1.0 equivalent) of 3-methoxy-5-nitrosalicylaldehyde and 6.03 g (1.1 equivalents) of p-nitrobenzyl bromide were dissolved in 15 ml of 1,4-dioxane, and then 13.5 g (3.5 equivalents) of 1,8-diazabicyclo[5.4.0]undeca-7-ene was added thereto. The resulting mixture was heated at about 100° C. for three hours with stirring, and then cooled to room temperature. Thereafter, the resulting solid substance was filtered off and sufficiently washed with ethanol. Thus, 4.55 g of 2-(p-nitrophenyl)-5-nitro-7-methoxybenzo[b]furan was obtained (yield: 70%).
Reaction SMILES: ClC1C=CC=CC=1C1C(C(OC)=O)=C(C)NC(COCCO)=C1C(OCC)=O.Cl[C:30]1[CH:35]=[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[N:33]=[CH:32][N:31]=1>>[N:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][O:36][C:34]1[N:33]=[CH:32][N:31]=[CH:30][CH:35]=1
Reactant: Clc1cc(OCc2ccccn2)ncn1
Agent: CCOC(=O)C1=C(COCCO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Product: c1ccc(COc2ccncn2)nc1

Procedure:
4-<2-{[4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}ethoxy>-6-(2-pyridylmethoxy)pyrimidine was prepared by the method described in Example 13 using 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine and 4-chloro-6-(2-pyridylmethoxy)pyrimidine as the starting materials. The product had m.p. 64°-67° C.
Reaction SMILES: [Br:1][CH:2]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:3]1=[O:31].[Li+].[CH3:33][Si]([N-][Si](C)(C)C)(C)C.C1COCC1.IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1([CH3:33])[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[CH:9]=[C:4]2[C:3]1=[O:31]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2OC2(CCCCC2)C1Br
Agent: [Li+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(Br)C(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2OC12CCCCC2
Reaction time: 0.17 h

Procedure:
To the product (0.08 g, 0.15 mmol) from Step A in DMF (1 mL) at −78° C., was added 1 M LiHMDS in THF (0.19 mL, 0.19 mmol) and the reaction was stirred for 10 min. Iodomethane (0.05 mL, 0.77 mmol) was added and the reaction was allowed to come to rt. The reaction was stirred an additional 20 min. The reaction was diluted with EtOAc and washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc in hexane.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])=O)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]2[O:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccccc1O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Fc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
After the flask containing 4-Fluoro-N-(2-hydroxyphenyl)-benzamide in 250 ml of toluene of step 1 was equipped with a Dean-Stark apparatus, p-toluenesulfonic acid (12.2 g, 64 mmol, 0.2 eq) was added. The mixture was stirred at 110° C. for 8 hours. Then heating was stopped and the solution was subsequently washed with 100 ml of water, 2*100 ml of (0.2M) NaOH solution and 100 ml of water. Toluene was removed via rotary evaporator yielding 64 g (94%) of slightly off white 2-(4-fluorophenyl)-1,3-benzoxazole.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C@H:13]3[CH2:18][CH2:17][C@H:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:15][CH2:14]3)[C:8]2=[O:27])=[C:4]([Cl:30])[CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[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>[C:23]([Si:20]([CH3:21])([CH3:22])[O:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([N:9]2[CH2:10][CH2:11][CH2:12][CH:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[CH:3][C:4]=3[Cl:30])[C:8]2=[O:27])[CH2:14][CH2:15]1)([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCC(Cc3ccc(Br)cc3Cl)C2=O)CC1
Reactant: OB(O)c1cccnc1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCC(Cc3ccc(-c4cccnc4)cc3Cl)C2=O)CC1
Temperature: 25 °C

Procedure:
Combine trans-3-(4 bromo-2-chloro-benzyl)-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one (Preparation 65) (0.2 g, 0.49 mmol), 3-pyridine boronic acid (0.2 g, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.05 mmol), Na2CO3 (1.1 g, 9.95 mmols), water (1.5 mL), 1,2-dimethoxy-ethane (7 mL) and heat at 80° C. for 24 hours. Cool the reaction mixture to room temperature, add saturated aqueous NaHCO3 (5 mL) and extract with EtOAc (3×10 mL). Dry the organic.layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 50 to 100% EtOAc in hexane) to obtain trans-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2-chloro-4-pyridine-3-yl-benzyl)-piperidin-2-one as a white solid (0.2 g, 80%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21](F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[CH:42]1(C(Cl)=O)C[CH2:43]1>C(Cl)(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([CH:21]4[CH2:43][CH2:42]4)=[O:25])[CH2:16][CH2:15]3)[CH:10]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[CH2:9]2)=[O:7])[CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1
Reactant: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C3CC3)CC2)cc1

Procedure:
The title compound, MS: m/e=568.3 (M+H+), [α]58920=−6.48 (c=0.4012, chloroform), was prepared in accordance with the general method of example 102 (part1) and example 38 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-p-tolyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and cyclopropyl carbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]

Procedure:
To a solution of 4-bromo-2-nitroaniline (217 mg, 1 mmol) in DMF (6 mL) was added 3-pyridine boronic acid (148 mg, 1.2 mmol), potassium phosphate (276 mg, 1.3 mmol), and dichloro-(diphenylphosphinoferrocene)palladium (75 mg, 0.1 mmol).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Cl:22])[CH:5](C)[CH2:6][C:7]1[C:15]2([CH3:16])[CH:10]([CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCC[CH2:31]1>>[C:18]([O:17][CH:11]1[CH:10]2[C:15]([CH3:16])([C:7]([CH:6]([CH3:31])[CH2:5][CH:4]([Cl:22])[CH2:3][OH:2])=[CH:8][CH2:9]2)[CH2:14][CH2:13][CH2:12]1)(=[O:20])[CH3:19]
Reactant: COC(=O)C(Cl)C(C)CC1=CCC2C(OC(C)=O)CCCC12C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CO)=CCC12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 1.01 g (2.95 mmol) of [3aS-[3(αS*, γR*),3aα,7β,7aβ]-7-(acetyloxy)-α-chloro-3a,4,5,6,7,7a-hexahydro-β,3a-dimethyl-1H-indene-3-butanoic acid methyl ester in 25 mL of anhydrous tetrahydrofuran was cooled at 0° C. and treated under argon with 1.47 mL (1.47 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. After stirring for 2 hours at 0° C., additional 0.20 mL of lithium aluminum hydride solution was added and the reaction allowed to proceed for 1 additional hour. It was then quenched by careful addition of 8 mL of a 2N aqueous Rochelle salt solution, then 0.5 mL of 2N hydrochloric acid. After dilution with water, it was extracted with ethyl acetate. The combined extracts were washed with 2N aqueous Rochelle salt solution, then brine, dried and evaporated to dryness to give 0.90 g (93% yield) of the title compound as a colorless, thick oil: [α]23D -30.1° (c 0.6, EtOH); 1H NMR (200 MHz, CDCl3) δ0.93 (s,3H),1.07 (d, J=7.2 Hz, 3H), 2.04 (s, 3H), 2.52 (br m, 1H), 3.73 (m, 2H), 4.00 (m, 1H), 4.97 (td, J=12.0, 4.4 Hz, 1H), 5.27 (br s, 1H) ppm.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[CH2:14][OH:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:22].S(=O)(=O)(O)O>O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]([OH:22])=[O:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1-c1cc(-c2ccccc2)on1
Reactant: CC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.3 g. (0.025 mole) o-(5-phenyl-3-isoxazolyl)benzyl alcohol in 125 ml. acetone is added dropwise at room temperature to 50 ml. (0.1 mole) of a reagent prepared by dissolving 100 g. (1.0 mole) chromium trioxide in 160 g. of concentrated sulfuric acid and diluting with water to form a 500 ml. solution. The mixture is stirred for 3 hours at room temperature and then filtered. The acetone is evaporated in vacuo and the residue partitioned between ether and water. The resulting layers are separated and the ether washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid is triturated with cold ether and filtered to give o-(5-phenyl-3-isoxazolyl) benzoic acid; m.p. 144.5° to 146.5° C.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[C:15](/[CH2:21][CH3:22])=[CH:16]/[CH:17]=[C:18](Br)Br)[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl-].[NH4+]>>[C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[C:15](/[CH2:21][CH3:22])=[CH:16]/[C:17]#[CH:18])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC/C(=C\C=C(Br)Br)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: C#C/C=C(\CC)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
3.2 g (7.2 mmol) of tert-butyl-[3-((E)-4,4-dibromo-1-ethylbuta-1,3-dienyl)phenoxy]dimethylsilane are dissolved in 50 ml and the mixture is cooled to −78° C. 5.7 ml (14.4 mmol) of a 2.5 M solution of butyllithium are added and the medium is stirred for 2 hours, then it is treated with a saturated solution of ammonium chloride. The residue is purified by chromatography on a silica column. A yellow oil is obtained (m=1.0 g; Y=49%).
Reaction SMILES: [OH-].[Na+].Cl.[Cl:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.O>[Cl:4][CH2:5][C:6]1[CH:11]=[CH:10][N+:9]([O-:17])=[CH:8][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: [O-][n+]1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 21 %

Procedure:
A 2 N aqueous sodium hydroxide solution (10 mL) and water (20 mL) were added to 4-(chloromethyl)pyridine hydrochloride (1.6 g, 10 mmol), and the reaction mixture was extracted with chloroform (20 mL) twice. The chloroform layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. m-Chloroperoxybenzoic acid (65%, 5.3 g, 20 mmol) was added to a solution of the resulting residue in dichloromethane (20 mL), and then the mixture was stirred at room temperature for 17 hours. Chloroform (100 mL) and a saturated aqueous sodium hydrogencarbonate solution (120 mL) were added to the reaction mixture, and then the chloroform layer was washed with a saturated aqueous sodium hydrogencarbonate solution (80 ml) and brine (100 mL). The chloroform layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 300 mg of the title reference compound as a brown solid. (Yield 21%)