Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[NH2:2].CO[CH:40](OC)[N:41]([CH3:43])[CH3:42]>C(Cl)Cl.O>[CH3:40][N:41]([CH:43]=[N:2][C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:3])[CH3:42]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(CC(CCC(C)(C)F)C(=O)N=CN(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of acetic acid 3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester (522 mg, 1.03 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was heated to 50° C. for two hours, cooled to ambient temperature and diluted with methylene chloride and water. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (580 mg, 100%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:11][CH2:12][CH2:13]O.Br>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=2[NH:11][CH2:12][CH2:13]1
Reactant: Nc1cccc(N)c1NCCO
Agent: Br
Agent: Cl
Product: Nc1cccc2c1NCCN2
Temperature: -20 °C

Procedure:
25 g (0.104 mol) of 2-[(2,6-diaminophenyl)amino]ethanol dihydrochloride are heated at 160° C. for 3 hours in 300 ml of a 62% hydrobromic acid solution. The reaction mixture is cooled to -20° C. until crystallization takes place and the precipitate obtained is dried, under nitrogen, with a mixture of methanol and ether. It is taken up in water, the pH is adjusted to alkaline with a concentrated sodium hydroxide solution and extraction is carried out with a dichloromethane/ether (50/50) mixture. Drying and evaporation are carried out.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]([NH2:21])=O)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1COCC1>[CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19](=[S:31])[NH2:21])[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: NC(=S)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Yield: 87.4 %

Procedure:
A solution of the compound (284 mg, 0.99 mmol) obtained in step 1 and Lawesson's reagent (360 mg, 0.89 mmol) in THF (4 mL) was stirred at 60° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 5→95% ethyl acetate/hexane) to give 1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazole-4-carbothioamide (236 mg, 0.778 mmol, 79%) as a white powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:15])([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][C:7]#[CH:8].N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].CCCCCC>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:15][Si:22]([CH3:25])([CH3:24])[CH3:23])([C:9]#[C:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6][C:7]#[CH:8]
Reactant: C#CCC(O)(C#C[Si](C)(C)C)CCCCl
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(C#C[Si](C)(C)C)(CCCCl)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a stirred mixture of 8.5 grams of 7-chloro-4-hydroxy-4-trimethylsilylethynyl-1-heptyne and 6.2 grams of imidazole in 24 ml of dry dimethylformamide is added, under nitrogen, 5.7 ml of chloro-trimethylsilane, in a slow stream, via a syringe. The mixture is stirred in an ice bath for one hour and then at room temperature overnight. The mixture is poured into hexane, washed with saturated sodium bicarbonate solution, water and then brine and dried over sodium sulfate. The solvents are evaporated to dryness yielding the desired product.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].P1(O)(OC2C=CC3C(C=2C2C4C(C=CC=2O1)=CC=CC=4)=CC=CC=3)=O>[F:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Fc1c(Br)cccc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1c(N2CCNCC2)cccc1C(F)(F)F
Temperature: 80 °C
Yield: 54.5 %

Procedure:
To a solution of 3-bromo-2-fluorobenzotrifluoride (1.72 g, 7.1 mmol) in toluene (50 ml) under nitrogen, was added piperazine (0.89 g, 10.6 mmol), potassium tert-butoxide (0.95 g, 9.9 mmol), bis(dibenzylideneacetone)palladium(0) (0.19 g, 0.21 mmol) and (+/−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (0.13 g, 0.21 mmol). The resulting mixture was heated at 80° C. for 20 h. Filtration through a pad of celite and evaporation of the filtrate gave 2.1 g of crude product. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.96 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 23), 207 (10), 206 (bp), 190 (17), 163 (8).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[S-2].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
To a solution of 4-[2-(3-nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidinamine (809 mg, 1.98 mmol) in 1,4-dioxane (16 mL) was added sodium sulfide nonhydrate (1.05 g, 6 mmol) in water (4 mL). The mixture was heated at 90° C. for 5 h, allowed to cool to rt and concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated and the aqueous layer is extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to give a dark solid. The crude material was purified by silica gel chromatography (hexanes/EtOAc 30-50%) to afford the titled product (462 mg, 62% yield). 1H NMR (400 MHz, CDCl3): δ 3.75 (brs, 2H), 6.63 (d, 1H, J=5.3 Hz), 6.78 (m, 1H), 6.91 (m, 1H), 6.96-7.00 (m, 2H), 7.06 (m, 1H), 7.16 (m, 1H), 7.22-7.36 (m, 4H), 7.65 (m, 1H), 8.17 (d, 1H, J=5.3 Hz), 8.42 (m, 1H), 8.52 (m, 1H); ES-LC/MS m/z=379 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:20]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1Cl
Reaction time: 12 h
Yield: 99 %

Procedure:
A solution of 2-chloro-4-(4-formylphenoxy)benzonitrile (1.0 equiv) in DMSO (0.2 M solution) was treated with K2CO3 (0.5 equiv) and 33% H2O2. After 12 h, the reaction mixture was poured into H2O and extracted with ethyl acetate. The combined organic layers were washed twice with water and brine. After drying the extracts over magnesium sulfate and evaporation under vacuum, the crude product was purified by silica gel chromatography using the appropriate eluent (typically mixtures of hexanes/ethyl acetate) to afford the title compound as a solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH2:19])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:21]1[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=1[CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:19][C:21]4[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=4[CH2:23][P:24]([O:25][CH2:26][CH3:27])([O:28][CH2:29][CH3:30])=[O:31])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOP(=O)(Cc1ccccc1N)OCC
Reactant: NC(=O)C1=Cc2cc(C3CCCCC3)ccc2CC1
Product: CCOP(=O)(Cc1ccccc1NC(=O)C1=Cc2cc(C3CCCCC3)ccc2CC1)OCC
Yield: 53 %

Procedure:
7-Cyclohexyl-3,4-dihydronaphthalene-2-carboxamide and diethyl 2-aminobenzylphosphonate were reacted in the same manner as in Example 3 to yield 7-cyclohexyl-N-(2-diethoxyphosphorylmethylphenyl)-3,4-dihydronaphthalene-2-carboxamide (53%), which was then recrystallized from ethanol-water to yield colorless crystals having a melting point of 102°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[N:22][C:21]4[C:16]3=[N:17][CH:18]=[N:19][C:20]=4[NH:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C@H:12]([OH:30])[C@@H:11]2[OH:31])=[CH:4][CH:3]=1>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[N:22][C:21]4[C:16]3=[N:17][CH:18]=[N:19][C:20]=4[NH:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C@H:12]([OH:30])[C@@H:11]2[OH:31])=[CH:4][CH:3]=1
Reactant: O[C@@H]1[C@H](O)[C@@H](C=Cc2ccc(F)cc2)O[C@H]1n1cnc2c(NC3CCOC3)ncnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O[C@@H]1[C@H](O)[C@@H](CCc2ccc(F)cc2)O[C@H]1n1cnc2c(NC3CCOC3)ncnc21
Reaction time: 24 h

Procedure:
To a solution of 5-[2-(4-fluorophenyl)vinyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purin-9-yl]oxolane-3,4-diol (40 mg) in ethanol (5 ml) and cyclohexene (2 ml) was added palladium hydroxide (50 mg), and the mixture was stirred for 24 hours. The catalyst was filtered off, and solvent removed under reduced pressure. The residue was purified by preparative thin layer chromatography, to give pure (4S,2R,3R,5R)-5-[2-(4-fluorophenyl)ethyl]-2-[6-(oxolan-3-ylamino)purin-9-yl]oxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=1[Cl:19].[CH3:21][S:22]([CH3:24])=[O:23].C1COCC1>C1COCC1>[Cl:19][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3](=[O:20])[CH2:21][S:22]([CH3:24])=[O:23]
Reactant: CS(C)=O
Reactant: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)CS(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid methyl ester (3.3 g, 10.6 mmol) is dissolved in 30 ml of dry THF and added to a solution of dimsyl anion (JACS, 84, 866, 1982) (31.9 mmol) in 60 ml of 1:1 DMSO/THF at 0° C. under argon. When addition is complete, the ice bath is removed and the reaction mixture is stirred at room temperature for five hours. The reaction is quenched with 400 ml of 1N hydrochloric acid, and extracted twice with 300 ml of chloroform. The combined chloroform extract is washed with 300 ml of water three times, and once with 300 ml of brine. This chloroform layer is dried over magnesium sulfate and evaporated. The residue solidifies after being dried at room temperature under vacuum for 12 hours. Recrystallization from methylene chloride in hexane gives 1.0 g of 1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone (26% yield); mp 152°-154° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([O:18][CH3:19])[C:14](=[O:20])[C:13]=2[CH:21]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CC(=O)CC>[OH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]=[C:15]([O:18][CH3:19])[C:14](=[O:20])[C:13]=3[CH:21]=2)[CH2:33][CH2:32]1
Reactant: OC1CCNCC1
Reactant: COc1coc2ccc(OCCCCCCCl)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1coc2ccc(OCCCCCCN3CCC(O)CC3)cc2c1=O
Yield: 82.8 %

Procedure:
A mixture of 2 g of 6-(6-chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one, 1 g of sodium iodide, 0.6 g of potassium carbonate, and 1.4 g of 4-hydroxypiperidine was refluxed in butanone for 96 hours. The solvent was removed and the residue stirred with ethyl acetate and filtered. The solution was washed with water and then dried over sodium sulfate. The solvent was removed to give an oil which was chromatographed over silica gel to give 2 g of 6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methoxy-4H-1-benzopyran-4-one which was converted to the hydrochloride salt by dissolving in ethyl acetate and adding 1N ethereal HCL: mp 124°-125° C.
Reaction SMILES: C(O)C.O.O1CCOCC1.[C:11]([N:15]1[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26]CC)=[O:25])[CH:17]=[N:16]1)([CH3:14])([CH3:13])[CH3:12].O.[OH-].[Li+]>O.Cl>[C:11]([N:15]1[C:19]([C:20]([F:22])([F:23])[F:21])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Temperature: 40 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
In a solution of ethanol:water:dioxane (1:1:1, 9 mL) was placed ethyl 1-tert-butyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (750 mg, 2.84 mmol) and lithium hydroxide hydrate (357 mg, 8.51 mmol). The mixture was stirred at 40° C. for 3 hrs and then at RT overnight. The mixture was diluted with water (25 mL) and 1N HCl (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4) and evaporated at reduced pressure to afford 1-tert-butyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (646 mg, 94% yield) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 9H), 7.92 (s, 1H); MS (ESI) m/z: 259.0 (M+Na+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:28]1([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[C:34]([CH2:33][N:28]5[CH2:29][CH2:30][CH2:31][CH2:32]5)[CH:35]=4)[CH:21]=3)[C:12]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccc(CN5CCCC5)c4)c3)C(C)(C)C2=O)cc1
Temperature: 90 °C
Yield: 3.8 %

Procedure:
To a solution of 1.15 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 50 mL of dioxane are successively added, under argon, 520 mg of 3-(pyrrolidin-1-ylmethyl)aniline obtained in stage c) below, 3.4 g of caesium carbonate, 207 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) [xantphos] and 67 mg of palladium diacetate. The reaction mixture is heated at 90° C. for 6 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 59 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-{[3-(pyrrolidin-1-ylmethyl)phenyl]amino}pyridin-4-yl)methyl]imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)[CH3:7])=[O:5])C.Cl>CO.[OH-].[Na+]>[C:4]([CH:6]([O:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:10]1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OC(C)C(=O)O)cc1

Procedure:
A solution of 0.33 g of tert-butyl 3-(1(R,S)-ethoxycarbonylethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 4 ml of methanol and 1 ml of 2N NaOH is stirred at room temperature over 18 hours. The reaction mixture is admixed with 1.5 ml of 4N HCl and extracted with EtOAc. The organic phase is washed with brine, dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellowish oil from the residue. Rt=5.33.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3ccnc3C)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:44][CH2:43][C:29]2([O:34][CH:33]([C:35](O)=[O:36])[CH2:32][N:31]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.[NH2:46][CH2:47][C:48](=[O:50])[CH3:49].CCN(CC)CC>CC1CCCO1>[CH2:47]([NH:46][C:35]([CH:33]1[O:34][C:29]2([CH2:43][CH2:44][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)[CH2:30][N:31]([CH2:38][C:39]([F:41])([F:40])[F:42])[CH2:32]1)=[O:36])[C:48]([CH3:49])=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(C(=O)O)O2
Reactant: CC(=O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 45 °C
Yield: 49.4 %

Procedure:
T3P (591 mg, 553 μL of 50% w/w, 0.93 mmol) was added to a mixture of 9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (142 mg, 0.37 mmol), 1-aminopropan-2-one hydrochloride salt (41 mg, 0.37 mmol) and Et3N (188 mg, 259 μL, 1.86 mmol) in 2-methyltetrahydrofuran (706 μL). The reaction mixture was then heated at 45° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 0-50% EtOAC in DCM as eluent to afford tert-butyl 10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 49%) as a yellow solid. ESI-MS m/z calc. 437.5. found 438.7 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2([CH2:24]S(C3C=CC=CC=3)(=O)=O)[CH2:23][O:22][CH2:21]2)[CH2:16][CH2:15]1)([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.[Mg].Cl>CO.C1COCC1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2([CH3:24])[CH2:21][O:22][CH2:23]2)[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC1(N2CCN(C(c3ccccc3)c3ccccc3)CC2)COC1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(N2CCN(C(c3ccccc3)c3ccccc3)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a suspension of 1-benzhydryl-4-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperazine (2.49 g, 5.38 mmol) in MeOH (50 mL), THF (10 mL) was added MAGNESIUM (0.654 g, 26.9 mmol) which was pretreated with 1.0 N HCl and rinsed with MeOH, stirred at rt overnight. The Et2O was added and followed by Na2SO4.10H2O, stirred at room temperature for 1 hr, filtered, and filtrate was concentrated. The crude was purified by 40 g ISCO silica column, eluted with EA: HX-0-100%, the desired fractions were concentrated to yield 1-benzhydryl-4-(3-methyloxetan-3-yl)piperazine (1.08 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O.P(Br)(Br)[Br:14]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:14]
Reactant: COc1cc(CO)cc(OC)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cc(CBr)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
(Snyder et al., Angewandte Chemie International Edition 2007, 46, 8186-8191.) To a stirred solution of 5 (17.5 g, 104 mmol, 1 equiv) in CH2Cl2 (500 mL) at 0° C. was added PBr3 (12.1 mL, 125 mmol, 1.2 equiv) dropwise. The reaction mixture was slowly allowed to warm to room temperature and stir for 3 h. The crude mixture was quenched with a saturated solution of aqueous. NaHCO3 and allowed to stir at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with Et2O. The organic layers were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to give 22.2 g (92% yield) of 6 as a white solid: Mp 70-72° C.; Rf 0.75 (EtOAc/hexanes, 1:2); IR (CDCl3) 2999, 2954, 1596, 1458, 1428, 1345, 1323, 1297, 1204, 1152, 1062, 930 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.54 (d, 2 H, J=2.0 Hz), 6.39 (d, 1H, J=2.4 Hz), 4.42 (s, 2 H), 3.79 (s, 6 H); 13C NMR (150 MHz, CDCl3) δ 160.9, 139.7, 106.9, 100.6, 55.4, 33.6. Characterization matches that reported by Snyder et al. (Angewandte Chemie International Edition 2007, 46, 8186-8191.)