Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][C@@H:7]1[C@@H:11]([CH2:12][OH:13])[O:10][C@@H:9]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:8]1)(C)C.[H-].[Na+].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:38]Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[I-].[Na+]>O1CCCC1.CO.C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:38][O:13][CH2:12][C@H:11]1[O:10][C@@H:9]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH2:8][C@@H:7]1[OH:6])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COCc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)O2)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
713 mg (2 mmol) of 3'-O-[(1,1-dimethylethyl)dimethylsilyl]thymidine [Can. J. Chem., 56, 2768 (1978)] were dissolved in 5 ml of tetrahydrofuran, and 175 mg (4 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to the resulting solution under an argon atmosphere. The mixture was then stirred at 60° C. for 2 hours. At the end of this time, the temperature of the mixture was reduced to room temperature, and then 678 mg (2 mmol) of 3,4-dibenzyloxybenzyl chloride was added, followed by 149.9 mg (1 mmol) of sodium iodide, and the resulting mixture was stirred at room temperature for 19 hours, and then at 60° C. for 5 hours. At the end of this time, the solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was washed twice, each time with 50 ml of 0.01N aqueous hydrochloric acid; it was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 4 ml of tetrahydrofuran, and 4 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added to the solution. The mixture was then stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was applied to a chromatography column [LiChroprep (trade mark) Si60, 40-63 μm, Groβe C, Merck] and eluted using a gradient elution method, with methylene chloride containing from 1 to 4% by volume of methanol, to give 345.4 mg (yield 31.7%) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[F:32].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Fc1ccc(N2CCNCC2)cc1F
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)c(F)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3,4-Difluorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz, not F-decoupled) 7.25 (q, 1H), 7.04 (m, 1H), 6.74 (d, 1H), 5.37 (s, 2H), 3.57 (m, 4H), 3.24 (m, 2H), 3.12 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=423.1, found 423.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].[Cl-].[Mg+2].[Cl-].[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1.[Cu]Br.O>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=1)=[O:20]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: BrCCC1OCCO1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CCC2OCCO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (44.3 ml) was added dropwise within 15 minutes under argon and while stirring at a maximum 30° C. to a suspension of Rieke magnesium, prepared from 50.8 g of magnesium chloride, in 1600 ml of absolute tetrahydrofuran. The suspension was stirred at room temperature for 15 minutes, cooled to 0° C. and, after the addition of 49.3 g of copper(I) bromide, stirred at 0° C. for 15 minutes. After cooling to -70° C. 38.5 ml of p-toluoyl chloride were added dropwise within 20 minutes. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature for 2 hours and subsequently hydrolyzed with 1000 ml of saturated ammonium chloride solution while cooling at a maximum 20° C. After the addition of 500 ml of water the mixture was extracted once with 1000 ml of ethyl acetate and twice with 500 ml of ethyl acetate each time. The combined organic extracts were dried over MgSO4 and freed from solvent. 71.0 g of brown oil were chromatographed on 1500 g of silica gel with ethyl acetate/hexane/methylene chloride (1:4:1) as the eluent. 21.8 g (34%) of 3-(1,3-dioxolan-2-yl)-4'-methylpropiophenone were isolated as a yellow-orange oil.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[C:33]=1[Cl:41]>C1COCC1>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:31][C:32]3[S:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[C:33]=3[Cl:41])[C:14]2=[O:19])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1c(CBr)sc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCCC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC(Cc3sc4ccccc4c3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Place cis-1-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one, (300 mg, 0.96 mmol) in 7.0 mL of THF, cool to −78° C. and treat with 2.0 M LDA (0.72 mL, 1.5 mmol). Stir for 5.0 minutes, treat with 2-bromomethyl-3-chloro-benzo[b]thiophene (250 mg, 0.96 mmol) and stir at −78° C. for five hours, and warm to room temperature. Quench reaction with ammonium chloride, extract with dichloromethane, dry over sodium sulfate and purify via silica chromatography (ethyl acetate/hexanes 0-25%) affords 166 mg (35%).
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:7]([CH3:25])[NH:6][C:5]=1[CH2:26][CH2:27][CH2:28][CH2:29]Cl)(=[O:3])[CH3:2].[I-].[Na+].Cl.[C:34]1([C:40]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)(C)C>[ClH:16].[C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:8]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[C:7]([CH3:25])[NH:6][C:5]=1[CH2:26][CH2:27][CH2:28][CH2:29][N:43]1[CH2:44][CH2:45][C:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42]1)(=[O:3])[CH3:2]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: CC(=O)C1=C(CCCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1Cl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)C1=C(CCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1Cl

Procedure:
5.6 g (12.2 mmol) 3-acetyl-5-tert-butoxycarbonyl-1,4-dihydro-4-(2,3-dichlorophenyl)-2-(4-chlorobutyl)-6-methyl-pyridine are reacted first with 3.6 g (24.4 mmol) sodium iodide, as described for starting compound B, and then with 6 g (21 mmol) 4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=8/2. The product thus obtained is taken up in 30 ml isopropanol. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 5.2 g (60%). M.p. 154°-156° C. decomp. (acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[C:16]([NH2:18])[N:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.Cl[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1(P(C(C)(C)C)F)CCCCC1.CC(C)([O-])C.[Na+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[C:16]([NH:18][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[N:17]=3)[CH:10]=[N:9]2)=[CH:19][CH:20]=1
Reactant: Clc1ccccn1
Reactant: COc1ccc(Cn2cc(-c3nc(N)cs3)cn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(F)C1CCCCC1
Solvent: COCCOC
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)cs3)cn2)cc1
Yield: 55.7 %

Procedure:
According to Scheme 1 Step 9: A solution of 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-amine (0.70 mmol, 200 mg), 2-chloropyridine (0.70 mmol, 65.6 μL), CyPF-tBu (52 μmol, 29.4 mg), Pd(OAc)2 (52 μmol, 11.8 mg) and sodium tert-butoxide (0.98 mmol, 71.4 mg) in DME (698 μL) was stirred at 80° C. for 12 hours under nitrogen in a microwave tube. After filtration through celite, the resulting crude product was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 95:4.5:0.5) as eluent to afford N-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-yl)pyridin-2-amine (0.39 mmol, 144 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]3[C:10]=1[NH:11][C:12](=[O:13])[C:8]3=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[C:23]1(=[O:32])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:11]2[C:10]3=[C:2]([CH3:1])[N:3]=[C:4]4[CH:5]=[CH:6][CH:7]=[C:8]([N:9]34)[C:12]2=[O:13])[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: Cc1nc2cccc3c(=O)[nH]c1n23
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3c(=O)n(CCCCCN4C(=O)c5ccccc5C4=O)c1n23
Yield: 66 %

Procedure:
To a suspension of 277 mg (1.60 mmol) of 3,4-dihydro-2-methyl-1,3,7b-triazacyclopent[cd]inden-4-one in 3 ml of DMF was added, while stirring under ice-cooling, 77 mg (1.93 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added 521 mg (1.76 mmol) of N-(5-bromopentyl)phthalimide. The mixture was stirred for one hour at 110° C. After cooling, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract solution was washed with an aqueous saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 410 mg of the desired compound (66.0%, a pale brown solid).
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH:30]=[CH:29]1>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:30]3[C:31](=[O:32])[O:33][C:28](=[O:34])[C:29]3=[CH:3]2)=[CH:6][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)c2c1cc1cc(OCc3ccccc3)ccc1c2-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of the alcohol (112 g) from Step 1 in toluene (1.1L) was added maleic anhydride (150 g). The reaction mixture was heated to reflux for 24 hours. After cooling to room temperature, the toluene was evaporated. The residue was triturated in EtOAc at 0° C., filtered and washed with Et2O to afford the title product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH:7]1[NH:11][CH2:10][CH2:9][S:8]1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCCl>[Cl:23][CH2:24][C:25]([N:11]1[CH2:10][CH2:9][S:8][CH:7]1[CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=1[O:2][CH3:1])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1OCC1NCCS1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OCC1SCCN1C(=O)CCl
Reaction time: 1 h

Procedure:
A solution of 2-(o-methoxyphenoxymethyl)thiazolidine (100 g) in 1,2-dichloroethane (250 ml) cooled at 10° is heated, under stirring, with triethylamine (68 ml) and a solution of α-chloroacetylchloride (36.2 ml) in 1,2-dichloroethane (50 ml) is added dropwise. After 1 hour, the mixture is washed with water, dried on Na2SO4 and evaporated to dryness. Subsequent crystallization from propan-2-ol gives 3-α-chloroacetyl-2-(o-methoxyphenoxymethyl)thiazolidine m.p. 87°-88° C. (100 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:2]=1[NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:31]([C:26]2[N:25]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:32]=1)#[N:24]
Reactant: Nc1cccc(-c2ncccn2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(-c3ncccn3)c2)n1
Reaction time: 20 h

Procedure:
A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (100 mg, 0.284 mmol), 3-(pyrimidin-2-yl)aniline (100 mg, 0.584 mmol), K2CO3 (118 mg, 0.855 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(5-cyano-6-(3-(pyrimidin-2-yl)phenylamino)pyrazin-2-ylamino)cyclohexylcarbamate.
Reaction SMILES: [F:1][C:2](F)([F:16])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[C:6](F)([F:8])[F:7].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F>>[F:16][C:2]1([F:1])[C:3]([F:14])([F:15])[C:4]([F:12])([F:13])[C:5]([F:10])([F:11])[C:6]1([F:8])[F:7]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: FC1(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F

Procedure:
Emulsions of dodecafluoropentane (boiling point 28°-29° C.), a mixture of dodecafluoropentane and decafluorobutane with a boiling point of 20.0° C., and perfluorocyclopentane (boiling point of 22.5° C.) were formed and their echogenicity tested. The emulsions contained Fluorad 170 C as surfactant and were formed by applying acoustic energy from a waterbath sonicator. Echogenicity was tested by adding 0.2 mL of each emulsion to 1000 mL of water at 37° C. through a 1.2 micron filter and measuring the videodensity by the methods described in Example 1. The emulsion containing dodecafluoropentane produced a grayscale intensity six seconds following administration of 58.5 units (background of 2.9), the mixture of fluorocarbons produced an increase of 3.0 to 133.3 under the same conditions, and the perfluorocyclopentane produced the greatest increase, of from 3.6 to 158.9. Thus, the lower boiling fluorocarbons produced greater echogenicity than the higher boiling fluorocarbons.
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:20][OH:21])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]([OH:24])=[O:21])([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of diallyl 2-(hydroxymethyl)-6-methylbenzyl phosphate (1.22 g, 4.02 mmol) obtained from Example 22-(4) in acetone (25 ml) was cooled to 0° C., and Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 6 ml, ca. 16 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then 2-propanol (1 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give an oily residue. The residue was dried using a vaccum pump, and then subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:dichloromethane=1:1) to afford the title compound (905.3 mg, 71% yield) as a colorless oil.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1.Cl[C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32]>C(Cl)Cl>[CH3:12][S:9]([C:7]1[CH:8]=[CH:3][C:4]([NH:13][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:25][CH2:26][N:27]([C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32])[CH2:28][CH2:29]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1)(=[O:11])=[O:10]
Reactant: CC(OC(=O)Cl)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c2OCCN3C2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Product: CC(OC(=O)N1CCC(N2CCOc3c(Nc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1)C(F)(F)F
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1H), 8.31 (brs, 1H), 8.14 (s, 1H), 7.59-7.78 (m, 2H), 5.18-5.34 (m, 1H), 4.78-4.93 (m, 1H), 4.22-4.41 (m, 4H), 3.47-3.55 (m, 2H), 3.04 (s, 3H), 2.88-3.07 (m, 2H), 1.79 (m, 2H), 1.60-1.75 (m, 2H), 1.42 (d, J=6.60 Hz, 3H)). LRMS (ESI) 548 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[OH2:12].[OH-].[Na+]>P(=O)(O)(O)O>[OH:12][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2
Reactant: O
Reactant: Cn1ncc2cc(N)ccc21
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1ncc2cc(O)ccc21
Temperature: 180 °C

Procedure:
5-Amino-1-methylindazole (1.56 g) in phosphoric acid (13 ml) containing water (3 ml) was heated to 180° C. for 18 hours, cooled to ambient temperature, poured into water (5 ml) then neutralised with aqueous sodium hydroxide. The solid that precipitated was filtered from solution, washed with cold water then sucked to dryness to give was hydrolysed to give 5-hydroxyl-1-methylindazole as a brown solid, (1.18 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[Li+]>CO.CC(C)=O.O1CCCC1.C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@@H:10]([OH:17])[CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CO
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g. (3.3 mmole) of ethyl (3S,4S)-4-t-butoxycarbonylamino-3-hydroxy-6-methylheptanoate prepared according to the method of D. Rich [J. Org. Chem., 43, 3624 (1978)] in 10 ml. of a 3:2 by volume mixture of ethanol and tetrahydrofuran was added to a suspension of 375 mg. (9.9 mmole) of sodium borohydride and 420 mg. (9.9 mmole) of lithium chloride in 30 ml. of a 3:2 by volume mixture of ethanol and tetrahydrofuran. The mixture was stirred overnight at room temperature, and then the excess reagents were decomposed with acetone. The solution was then concentrated by evaporation under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulphate and then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/ethyl acetate). There were obtained 766 mg. of the desired product as an oil, [α]25 -38.2° (C=0.92, methanol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([S:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24](OC)=[O:25])[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>O1CCCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([S:20][C:21]4[CH:22]=[C:23]([CH2:24][OH:25])[CH:28]=[CH:29][CH:30]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a stirred mixture of methyl 3-(2-(4-morpholinophenylamino)pyrimidin-4-ylthio)benzoate (4.00 g, 9.46 mmol) in anhydrous tetrahydrofuran, was added lithium aluminum hydride (360 mg, 9.46 mmol) in small portions while the mixture was gently warmed to 40° C. The mixture was stirred at this temperature for about 4 hours. It was then cooled on an ice bath, cold 10% aqueous sodium bicarbonate solution was added slowly to quench the reaction. The whole mixture was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The aqueous layer was re-extracted with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4). Removal of the solvent in vacuo afforded the product (2.50 g, 80%).