Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][CH2:23][C@@H:22]([C:25]([O:27]C)=[O:26])[C@H:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:32]([O:31][C:29]([C@@H:21]1[CH2:20][C@H:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23][C@H:22]1[C:25]([OH:27])=[O:26])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]1C(=O)O
Yield: 63 %

Procedure:
A solution of compound 37 (4.2 mmol) and LiOH (16.8 mmol) in THF/H2O 1/1 (40 mL) was stirred at room temperature for 16 hrs. The reaction mixture was neutralized with 1N HCl to pH 2, and then extracted with DCM (100 mL). Organics were concentrated under reduced pressure and purified by chromatography on silica gel (Cyclohexane/EtOAc) to yield compound 38 as pale yellow oil in 63% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Ni].O>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C#N)CCC1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(CN)CCC1
Temperature: 40 °C
Yield: 71.9 %

Procedure:
1-Cyano-cyclobutanecarboxylic acid ethyl ester (2.00 g, 13.0 mmol) was dissolved in ethanol (30 ml) and treated with Raney Nickel (1 ml as a slurry in water) and hydrogen gas at 4 bar and heating at 40° C. for 18 h. The reaction mixture was filtered through Dicalite and washed through with ethanol (50 ml). The solvent was removed under reduced pressure to give 1-aminomethyl-cyclobutanecarboxylic acid ethyl ester as a yellow oil (1.47 g, 72%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH2:18][C:19]([N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])=[O:20])=[N:13][C:12]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:8]=[CH:7][N:6]=1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH2:18][C:19]([N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])=[O:20])=[N:13][C:12]=2[C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nc(SCC(=O)N(CCO)CCO)n2C)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(SCC(=O)N(CCO)CCO)nc(-c2ccc(F)cc2)c1-c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
50 ml of HCl 10% are added to 2-[5-(2-acetylaminopyridin-4-yl)-4-(4-fluorophenyl)-1-methyl-1H-imidazol-2-ylsulfanyl]-N,N-bis(2-hydroxyethyl)acetamide (0.6 mmol/0.293 g), and the mixture is stirred at room temperature for 6 h. The mixture is then slowly neutralized using 2N NaOH, resulting in the precipitation of 2-[5-(2-aminopyridi n-4-yl)-4-(4-fluorophenyl)-1-methyl-1H-imidazol-2-ylsulfanyl]-N,N-bis(2-hydroxyethyl)acetamide as a whitish powder. The precipitate is filtered off with suction, washed with a little ice-cold water and dried over P2O5.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1>>[CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=2)=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(CNCc1ccccc1)c1ccc(O)cc1
Product: CC(CNCc1ccccc1)c1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Using a method similar to example 1, 4-(2-benzylamino-1-methyl-ethyl)-phenol is reacted with 6-chloronicotinamide to afford the title compound. The crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform gives the title compound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 4.52 minutes, Purity: 99.1%; mass spectrum (ion spray): m/z=362.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([OH:16])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccccc1-2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
A solution of 2-methoxy-9-fluorenon (6 g, 28.5 mmol) in 30 mL of THF was charged with 1M THF solution of BH3 -THF complex (60 mL, 60 mmol) at 0° C. The reaction mixture was stirred for 6 hr at room temperature, then quenched with water (100 mL). The resulting precipitate was filtered off, washed with water and dried to afford 5.6 g (93.3%) of pure 2-methoxy-9-fluorenol.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH:3](SC1C=CC=CC=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:41]C(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:41])=[O:5]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(O)C(Sc3ccccc3)C(=O)OC)cc2)cc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 37.5 %

Procedure:
To a solution of methyl 3-hydroxy-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}-2-(phenylsulfanyl)propanoate (0.05 g, 0.09 mmol) in benzene was added AIBN (catalytic amount) and tributyl tin hydride, the resulting mass was refluxed at 80° C. for 4 h. RM quenched with water extracted with ethyl acetate, Organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated to yellow oil which was further purified by Preparative TLC using 10% ethyl acetate in chloroform to get the titled compound as yellow oil (0.015 g, Yield: 37.5%) 1H NMR (300 MHz, CDCl3): δ 7.63-7.65 (m, 2H), 7.32-740 (m, 5H), 7.23-7.26 (d, 2H), 6.9-6.93 (m, 4H), 5.37-5.38 (d, 1H), 5.22 (s, 2H), 4.98 (s, 2H), 4.85-4.92 (t, 1H), 3.99 (s, 3H), 3.57 (s, 3H), 3.15-3.17 (d, 1H), 2.57-2.59 (d, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])C(O)=O)=[CH:10][CH:9]=1)([OH:3])=O.ClCCl.FC(F)(F)[C:28]([O:30]C(=O)C(F)(F)F)=[O:29].Cl>O>[O:3]=[C:1]1[C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=2[CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:18][C:28]([OH:30])=[O:29])=[CH:12][C:13]1=2
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2C(=O)O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A stirred suspension of 4-(2-carboxybenzyloxy)phenylpropanoic acid (47.14 g, 0.157 mol) and dichloromethane (500 ml) was treated over 30 seconds with trifluoroacetic anhydride (75.61 g, 0.36 mol). The solid material slowly dissolved. The solution was heated 6 hours under reflux with exclusion of moisture. The cooled solution was treated with water (100 ml) and stirred 20 minutes at ambient temperature (mild exotherm). The mixture was strongly acidified with 5% hydrochloric acid and thoroughly agitated. The organic phase was washed with water (200 ml), dried (Na2SO4) and evaporated to dryness. Recrystallization from 65 ml of isopropanol afforded 35.3 g (79.6%) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-propanoic acid, m.p. 138.5°-139.5° C. The compound appeared pure and chromatographically identical with material which had previously been prepared according to procedure 6C below except that it is postulated that the product exists in two polymorphic forms and interconversion by partial melting followed by solidification to afford the higher melting form occurs at 128°-130° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C:19]2[CH:24]=[C:23]([C:25](=[O:30])[NH:26][CH:27]3[CH2:29][CH2:28]3)[CH:22]=[CH:21][C:20]=2[CH3:31])=[CH:6][CH:5]=1.O.[NH2:34][NH2:35]>CO>[CH:27]1([NH:26][C:25](=[O:30])[C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([N:14]3[CH:13]=[N:12][C:11]4[C:15]3=[N:16][CH:17]=[N:18][C:10]=4[C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:34][NH2:35])=[O:2])=[CH:5][CH:6]=3)[CH:24]=2)[CH2:29][CH2:28]1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2ncnc3c2ncn3-c2cc(C(=O)NC3CC3)ccc2C)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)NN)cc3)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of the 4-[9-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-9H-purin-6-yl]-benzoic acid methyl ester (65 mg, 0.15 mmol) in 1 mL of methanol was added 1 mL of hydrazine monohydrate. The reaction mixture was stirred at room temperature for 4 hours. The methanol was removed and then 2 mL of water was added. The product was collected by filtration to give a colorless solid (47 mg, 72%). HPLC tR=1.62 min; MS m/z 428 [M+H]+.
Reaction SMILES: [Na].C[O-].[Na+].[N+:5]([NH:8][C:9]([NH2:11])=[NH:10])([O-:7])=[O:6].[CH:12]([CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15](OCC)=O)=[O:13]>CO>[N+:5]([NH:8][C:9]1[NH:11][C:12](=[O:13])[C:14]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:15][N:10]=1)([O-:7])=[O:6]
Reactant: CCOC(=O)C(C=O)Cc1ccncc1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Temperature: 0 °C

Procedure:
About 1.77 g. of sodium were dissolved in 75 ml. of anhydrous methanol under a positive nitrogen atmosphere. The sodium methoxide in methanol solution was cooled and 7.28 g. of dried nitroguanidine added thereto. The reaction mixture was heated to reflux temperature briefly after which time 14.5 g. of ethyl 2-formyl-3-(4-pyridyl)propionate (prepared by the method of U.S. Pat. No. 4,216,318) were added thereto. This reaction mixture was then heated to refluxing temperature for about 19 hours. Volatile constituents were removed by evaporation and water was added to the residue. The aqueous mixture was extracted 3 times with chloroform and the chloroform extracts discarded. The aqueous solution was then chilled to about 0° C. and 15.4 ml. of 5N aqueous hydrochloric acid added. 2-Nitroamino-5-(4-pyridyl)methyl-4-pyrimidone formed in the above reaction precipitated and the precipitate was collected by filtration. The filter cake was washed with water and dried. 9.9 g. of product were obtained melting at about 228°-229° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.CN([CH:25]=[O:26])C.O=P(Cl)(Cl)Cl>>[CH3:1][C:2]1[CH:7]=[C:6]([CH:25]=[O:26])[C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(Cc3ccccc3)CC2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(N2CCN(Cc3ccccc3)CC2)c(C)cc1C=O
Temperature: 0 °C
Yield: 81.1 %

Procedure:
The 4-(2,5-dimethylphenyl)-1-benzylpiperazine (10 g, 36 mmol) was dissolved in anhydrous DMF (30 mL, 390 mmol) and cooled to 0° C. Fresh POCl3 (70 mL, 750 mmol) was added drop wise with stirring. Once the addition was completed the dark mixture was warmed to 75° C. for five hours or until TLC analysis indicated the disappearance of the starting material. The excess phosphorous oxychloride was distilled off and the entire mixture was diluted with ethyl acetate and added slowly to 500 mL of ice-chips. The solution was neutralized and made basic with concentrated NaOH. The neutralization and basification must be done at low temperatures to avoid creating by-products. The formylated product was extracted with ethyl acetate (5×). The organic layer was washed with water (2×), brine, dried over magnesium sulfate and purified by silica gel column chromatography using gradient hexane/ethyl acetate (10/0 to 8/2). The product (9 g, 81%) was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(NS(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cc(C(=O)O)cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.29 g (1.1 mmol) methyl 2-chloro-6-methanesulphonylamino-isonicotinate in 5.0 mL tetrahydrofuran and 1 mL water were mixed with 79 mg (3.3 mmol) lithium hydroxide and stirred overnight at RT. The reaction mixture was acidified with 1M aqueous hydrochloric acid and evaporated down. The product was reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[C:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccccc2)cc1F
Temperature: 67.5 °C

Procedure:
4-Bromo-2-fluoro-phenylacetic acid (0.25 gm, 1.1 mmole), phenylboronic acid (0.15 gm, 1.2 mmole) and 50% water wet 10% Palladium carbon (0.07 gm, 0.033 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.14 gm, 1.3 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was acidified using 20% H2SO4, filtered and dried (0.2 gm, 83%) H1-NMR INOVA-500 (DMSO d6) δ 3.675 (s, 2H), 7.382-7.518 (m, 6H), 7.707 (d, J=7.51 Hz, 2H), 12.498 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN[C@@H]3CCN(Cc4ccccc4)C3)cc2)nc1
Yield: 30.9 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), (3R)-1-benzylpyrrolidin-3-yl amine (0.22 mL, 1.27 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.154 g (31%) of the title compound as a white foam (chromatography solvent:ethyl acetate→4:1 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C24H27N4O2 403.2134, found 403.2131; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H), 7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3 Hz), 3.79 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J=12.7 Hz), 3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t 2H, J=6.8 Hz), 2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH:5]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].Cl>O1CCCC1.CCCCCC>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([CH:30]=[O:31])[CH:3]=2)=[CH:7][CH:8]=1
Reactant: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(Br)c2)CC1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(C=O)c2)CC1
Temperature: -78 °C

Procedure:
1-(3-Bromo-4'-chlorobenzhydryl)-4-methylpiperazine (see U.S. Pat. No. 4,757,074) (1.00 g, 2.63 mmole) was dissolved in 12 ml of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.1 M n-butyllithium in hexane (2.4 ml) was added dropwise and the reaction was stirred for ten minutes. N,N-Dimethylformamide (0.25 ml, 3.2 mmole) was added in one portion and the reaction was allowed to warm to -40° C. Hydrochloric acid (1.0 M, 20 ml) was added and the reaction was warmed to room temperature. The solution was washed with 20 ml of diethyl ether and the ethereal wash was discarded. The aqueous solution was made basic with aqueous sodium hydroxide and extracted with two 15 ml portions of chloroform. The combined chloroform extracts were dried over sodium sulfate and the solvent removed to give 738 mg of crude 1-(4-chloro-3'-formylbenzhydryl)-4-methylpiperazine as a dark oil.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[CH:17]=O)[CH2:2][CH2:3][CH3:4].[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:17]/[C:6]1[CH:7]=[C:8]([O:15][CH3:16])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1c(C=O)cc(OC)c2ccccc12
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)OC)cc(OC)c2ccccc12

Procedure:
As in Example 111, 1-butyl-4-methoxy-2-naphthalenecarboxaldehyde (4.05 g) and (carbomethoxymethylene)triphenylphosphorane (6 g) in dichloromethane (40 mL) was stirred at room temperature for 42 hours. Crystallization of the crude reaction product from the normal work up gave 4.1 g of (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid methyl ester, mp 63°-64° C. Anal. Calcd for C19H22O3 : C, 76.48; H, 7.43 Found: C, 75.89; H, 7.26
Reaction SMILES: C([NH:4][C:5]1[C:6]([Cl:14])=[N:7][C:8]([C:11](=[O:13])[CH3:12])=[CH:9][CH:10]=1)(=O)C.C([O-])(O)=O.[Na+]>Cl.CO>[C:11]([C:8]1[N:7]=[C:6]([Cl:14])[C:5]([NH2:4])=[CH:10][CH:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ccc(C(C)=O)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc(N)c(Cl)n1

Procedure:
5 g (24 mmol) of 3-acetamido-6-acetyl-2-chloropyridine are boiled under reflux in a mixture of 25 ml of concentrated aqueous HCl and 25 ml of methanol for one hour. After cooling, the mixture is carefully added to 600 ml of saturated NaHCO3 solution and extracted three times with 200 ml of methylene chloride each time. The collected organic phases are dried with Na2SO4 and evaporated. The residue is recrystallized from toluene/petroleum ether.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Br:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([I:20])=[CH:13][CH:14]=3)[C:9](=[O:21])[C:8]=2[CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([I:20])=[CH:13][CH:14]=3)[C:9]([CH:1]=[CH2:2])([OH:21])[C:8]=2[CH:7]=1
Reactant: O=c1c2cc(Br)ccc2oc2ccc(I)cc12
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(Br)ccc2Oc2ccc(I)cc21
Temperature: -10 °C
Yield: 100 %

Procedure:
To a solution of vinylmagnesium chloride (6.86 mL, 10.97 mmol) at −78° C. under nitrogen atmosphere was added drop wise a solution of 2-bromo-7-iodo-9H-xanthen-9-one (2.00 g, 4.99 mmol) in THF (30 mL). The reaction mixture was allowed to slowly warm to −10° C., then the reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc followed by a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by filtration over silica gel (10% EtOAc/hexane) to give 2.14 g of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol as a white solid. Step 2: To a solution of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol (0.50 g, 1.16 mmol) and thiourea (0.18 g, 2.33 mmol) in acetic acid (2.00 mL) was added TFA (4.00 mL). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc, followed by a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (10%-100% EtOAc/hexane) to provide 0.36 g of 2′-bromo-7′-iodo-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:49]([C:51]1[N:52]=[C:53]([C:64]([O-])=[O:65])[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=1)#[N:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][C:19]1([CH3:23])[CH2:20][CH2:21][C:16]([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:15])[NH:11][C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:64]([C:53]2[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=[C:51]([C:49]#[N:50])[N:52]=2)=[O:65])=[CH:17][CH2:18]1
Reactant: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(C3CC(=O)NC(=O)C3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 76.3 %

Procedure:
A solution of 140 mg (0.448 mmol) of 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 313 mg (0.672 mmol) of PyBroP, 151 mg (0.493 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 234 μL (1.34 mmol) of DIEA at RT for 30 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 10-42% EtOAc-hexane afforded 192 mg (76%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C30H39N5O4Si, 562.3 (M+H), found 562.0.