Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH:33]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[N:12]=2)[CH:10]=1)=O)C.[CH3:50][NH2:51]>>[CH3:50][NH:51][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH:33]([C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[N:12]=2)[CH:10]=1)=[O:3]
Reactant: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 65 °C

Procedure:
A mixture of 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 168, step 3) (0.2 g, 0.298 mmol) and 40% aqueous methyl amine solution (5 ml) is heated to 65° C. for 12 h. The reaction mixture concentrated in vacuo and purification of the crude residue by chromatography on silica eluting with 3% methanol in chloroform yields the title compound. LC-MS (0.1% formic acid, acetonitrile): 656 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:21])([F:20])[C:8]1[N:13]=[C:12]2[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[NH:16][C:11]2=[CH:10][CH:9]=1.[CH2:22](O)[CH3:23]>>[F:21][C:7]([F:6])([F:20])[C:8]1[N:13]=[C:12]2[CH:14]=[C:15]([C:17]([O:19][CH2:22][CH3:23])=[O:18])[NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc2nc(C(F)(F)F)ccc2[nH]1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2nc(C(F)(F)F)ccc2[nH]1

Procedure:
1 ml (18.71 mmol) of concentrated sulphuric acid is added to a solution of 0.2 g (0.87 mmol) of 5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid, obtained in step 23.2, in 10 ml of ethanol. The solution is stirred at reflux for 20 hours and then cooled and concentrated under reduced pressure. The resultant residue is subsequently taken up with 50 ml of dichloromethane and then washed successively with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate, 40 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulphate and then concentrated under reduced pressure. 0.19 g of product is obtained, which product is used as it is in the subsequent step.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CCCP(=O)(CCC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCP(=O)(CCC)Cc1ccc(N)cc1
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A mixture of 4-nitrobenzyldipropylphosphine oxide (3.0 g) and 5% Pd-C (0.3 g)in ethanol (50 ml) was vigorously stirred under hydrogen atmosphere for 16 hours, and the Pd-C was filtered off. The filtrate was concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:5→1:4) and recrystallized from ethanol-ethyl acetate to give 4-aminobenzyldipropylphosphine oxide (1.78 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:8](=[O:32])[C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].[C:34]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:8](=[O:32])[C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:10][N:11]([CH3:34])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Compound B (8.0 g, 16.3 mmol) was dissolved in DMF (40 mL) and the reaction mixture was cooled to −10° C. To the reaction mixture was added K2CO3 (6.8 g, 49.1 mmol) followed by addition of MeI (5.1 mL, 81.9 mmol) drop wise and stirred at 0° C. for 1 h. The reaction mixture was filtered and washed with EtOAc. Solvents removed in vacuo and the residue was dissolved in EtOAc (250 mL) and poured into water (500 mL), extracted with EtOAc (2×250 mL), and washed with water (250 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and then concentrated in vacuo, to afford compound C (8.1 g, 98% yield) as a cream solid. LC-MS [M+H] 503.1 (C20H30N4O9S+H, calc: 503.5). Purity >95% (UV/254 nm). Compound C was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]>C(O)(=O)C.Cl.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=CC=CC(=O)O)cc(Cl)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(CCCCC(=O)O)cc(Cl)c1OC

Procedure:
A solution containing 6.2 g of the above product obtained in Example 32 was dissolved in a mixture of 30 ml of acetic acid and 3 ml of conc. hydrochloric acid. Palladium on charcoal catalyst (10% Pd) was added and the mixture was hydrogenated at normal pressure and room temperature. After filtration the solvents were evaporated in vacuo. Yield 3.2 g (55%), a viscous oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([OH:45])=O)=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[C:55]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:60]=[CH:59][C:58]([CH2:61][CH:62]([C:64]2[S:65][CH:66]=[CH:67][N:68]=2)[NH2:63])=[CH:57][CH:56]=1>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:63][CH:62]([C:64]3[S:65][CH:66]=[CH:67][N:68]=3)[CH2:61][C:58]3[CH:57]=[CH:56][C:55]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[CH:60][CH:59]=3)=[O:45])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: NC(Cc1ccc(-c2ccccc2)cc1)c1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4ccc(-c5ccccc5)cc4)c4nccs4)ccc23)CC1
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (26 mg, 0.070 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) in N,N-Dimethylformamide (1 mL) and N,N-Diisopropylethylamine (12 uL, 0.070 mmol). The reaction was stirred for 10 min., and the 2-biphenyl-4-yl-1-(1,3-thiazol-2-yl)ethanamine (20 mg, 0.070 mmol) was added. The reaction was stirred for 1 h. at r.t. The final product was purified by prep RP-HPLC (pH=10) to afford the desired compound (0.003 g, 20%) as an amorphous white solid. Analytical LCMS (M+H)+: m/z=550.0.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][C:21]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(COC)OC.CS(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:22][C:21]=1[O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
N-hydroxyphthalimide (2.19, 0.018 mole) was dissolved in a mixture of dry dimethoxyethane (15 ml) and dry dimethyl sulphoxide (4 ml). The clear yellow solution was cooled to 25° and potassium carbonate (1.24 g, 0.009 mol) was added. A red suspension resulted. 4-Fluoro-3-phenoxybenzyl bromide (5 g, 0.018 mol) was added dropwise over 5h at 22°-28°. The reaction mixture was stirred at room temperature overnight, after which most of the dimethoxyethane was removed in vacuo, and the solution then quenched by pouring into dilute hydrochloric acid (100 ml 1%). The resulting slurry was filtered, and the crystals washed with distilled water and dried in vacuo to give N-(4-fluoro-3-phenoxybenzyloxy)phthalimide as white crystals (6.4 g), (98%), m.p. 88.2°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[CH:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:9][S:10]2)=[CH:5][CH:4]=1.O1CCC[CH2:23]1.C([N-]C(C)C)(C)C.[Li+].CI>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)([CH3:23])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Reaction time: 0.75 h
Yield: 72 %

Procedure:
To 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (725 mg, 2.41 mmol) obtained in Example 25 was added dry tetrahydrofuran (30 ml). Then lithium diisopropylamide (2.41 ml, 4.83 mmol, 2.0 mol hexane/tetrahydrofuran solution) was added dropwise thereto at -78° C. The reaction mixture was stirred for 45 minutes and methyl iodide (7.5 ml, 120.6 mmol) was added thereto. The reaction solution was stirred for one hour at -78° C. and for 24 hours at -10° C. and, after adding water, extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=9:1) to obtain 550 mg (yield: 72%) of the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]2[N:13]=[C:14]([CH3:16])[CH:15]=[C:11]2[N:10]=[C:9]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[CH:21][CH:20]=2)[CH:8]=1>CO>[OH:27][CH2:26][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][C:9]2[CH:8]=[C:7]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:11]3[N:10]=2)=[O:30])=[CH:24][CH:23]=1)([CH3:29])[CH3:28]
Reactant: C1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(N3CCCC3)n2n1
Yield: 76 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G, 44 mg, 1.0 equivalent) and pyrrolidine (4.0 equivalents) in DMF (0.10 M with respect to 4G) was stirred at 80° C. for 1 h. After cooling, the mixture was diluted with methanol and purified by preparative LC-MS to afford the titled compound (76%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6H), 1.85-2.07 (m, 4H), 2.33 (s, 3H), 3.47 (s, 2H), 3.96 (br. s., 4H), 6.13 (s, 1H), 6.75 (s, 1H), 7.53 (d, J=8.59 Hz, 2H), 7.97 (d, J=8.59 Hz, 2H), 10.89 (s, 1H). ESI-MS: m/z 394.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:42][CH2:43]I>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([O:23][CH2:43][Cl:42])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(N-benzyloxycarbonyl-L-valyloxy)propanoic acid (5.2 g, 16.08 mmole) in 1,4-dioxane (50 ml) was added a 40% solution of tetrabutylammonium hydroxide (10.43 g, 16.08 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 40 ml dichloromethane and chloroiodomethane (28.4 g, 160 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Ethyl acetate (100 ml) was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2.2 g=35%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCC(F)(F)F
Temperature: 100 °C
Reaction time: 40 h
Yield: 32 %

Procedure:
A stirred mixture of 3.14 g of 4-fluoro-2-nitrophenol, 13 g of cesium carbonate and 20 mL of anhydrous dimethylformamide was heated at 100° C. for 4 hours. 6.65 g of 2,2,2-trifluoroethyl p-toluenesulphonate was then added and the mixture was stirred at the same temperature for 40 hours. The solvent was removed under reduced pressure, and 50 mL of water was added to the residue. The mixture was acidified with 37% hydrochloric acid and extracted with 3×40 mL of ethyl acetate. The organic layer was washed with 20 mL of brine, dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate 100:7) to afford 1.53 g (32%) of Compound 8A as an oil.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1([CH3:14])[CH2:11][C:10]2([CH3:12])[CH:7]([CH2:8][CH2:9]2)[C:6](=[O:13])[CH2:5]1.[Cl-].[NH4+]>[Mg].CCOCC>[CH3:1][C:6]1([OH:13])[CH2:5][C:4]([CH3:14])([CH3:3])[CH2:11][C:10]2([CH3:12])[CH:7]1[CH2:8][CH2:9]2
Reactant: CI
Reactant: CC1(C)CC(=O)C2CCC2(C)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)CC(C)(O)C2CCC2(C)C1
Yield: 96.7 %

Procedure:
To 0.97 g. (0.04 g. atom) of magnesium in a 250 ml. 3-necked round bottomed flask fitted with dropping funnel, magnetic stirrer, and nitrogen inlet was added 25 ml. of ether. Then 5.0 g. (0.035 mole) of methyl iodide in 100 ml. of ether was added from a dropping funnel at such a rate that reflux was maintained as the Grignard reagent was formed. After all the methyl iodide was added, the solution was stirred and refluxed for an additional 1 hour. Then, 4.98 g. (0.03 mole) of 4,4,6-trimethylbicyclo[4.2.0]octane-2-one was added in 75 ml. of ether over 30 minutes. After all of the ketone was added, the solution was stirred for an additional 1 hour and then 50 ml. of saturated aqueous ammonium chloride was added. The layers were separated and the aqueous layer was extracted twice with 50 ml. portions of ether. The combined ether layers were dried over sodium sulfate and concentrated in vacuo to yield a solid which was sublimed. The recovered product was 5.3 g. (0.029 mole, 97% yield) of 2,4,4,6-tetramethylbicyclo[4.2.0]octane-2-ol. m.p. 54° - 55° C. nmr: (deuterochloroform): 0.92δ (S-34); 1.02δ (S-34); 1.13δ (S-34); 1.21δ (S-34); 1.28δ - 2.25δ (complex multiplets-10H). IR: 3610 cm-1.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:4][CH2:3][CH:2]([OH:1])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(O)COc1cccc(CN2CCCCC2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(O)COc1cccc(CN2CCCCC2)c1

Procedure:
A solution of 2-[2-hydroxy-3-[3-(1-piperidinylmethyl) phenoxy]propyl]-1H-isoindole-1,3-(2H) dione (17.6 g) and hydrazine hydrate (2.5 g) in ethanol (60 ml) was heated under reflux for 3 h. The resulting mixture was evaporated to a solid residue which was suspended in 1N hydrochloric acid (30 ml) and filtered. The filtrate was basified with an excess of potassium carbonate and extracted with isopropanol (3×40 ml). The isopropanol extracts were dried (Na2CO3) and evaporated to a gum which was chromatographed using System A. Crystallisation of the product from n-hexane:ether (20:1) gave the title compound as colourless grains (7.7 g), m.p. 74°-76.5°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.O.O.[OH-].[Li+]>CO>[CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
Methyl 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxyl}pyrazine-2-carboxylate (423 mg, 0.907 mmol) synthesized in Example (62c) was dissolved in methanol (10 mL), and water (2 mL) and lithium hydroxide monohydrate (76.2 mg, 1.82 mmol) were added, followed by stirring at 50° C. for 1 hour under nitrogen atmosphere. To the reaction solution, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: dichloromethane/methanol=0%-10%) to afford the desired compound (269 mg, yield 66%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:20]=2)[C:11]([O:13]C(C)(C)C)=[O:12])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([C:21]([OH:30])([C:22]([F:25])([F:23])[F:24])[C:26]([F:27])([F:28])[F:29])[CH:20]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)nc1
Temperature: 25 °C

Procedure:
To a 0° C. DCM (6.8 mL) solution of tert-butyl 3-(5-methylpyridin-2-yl)-5-[92,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoate (0.6 g, 1.38 mmol) from step C was added trifluoroacetic acid (6.9 mL). The mixture was warmed to rt over 2 h and concentrated to dryness to give a gummy solid. The crude title compound was used in step E without further purification. LC-MS (M+H)=380.1
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl)[C:6]=2[N:7]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CC#N>[NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]\[CH2:15][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2C/C=C\CCl)c(=O)[nH]1
Reactant: CCOP(OCC)OCC
Solvent: CC#N
Product: CCOP(=O)(C/C=C\Cn1c(=O)sc2c(=O)[nH]c(N)nc21)OCC

Procedure:
A mixture of 5-Amino-3-[(Z)-4-chloro-2-buten-1-yl]thiazolo[4,5-d]pyrimidine-2,7(3H, 6H)-dione (0.75 g, 2.75 mmol), anhydrous CH3CN (75 mL) and triethyl phosphite (10 mL) was stirred and heated at reflux for 6 days while adding additional quantities of triethyl phosphite (2×5 mL) at 2 day intervals. The mixture was evaporated. The residue was triturated with Et2O (2×50 mL) and then dissolved in MEOH (50 mL). Silica gel (25 g) was added and the mixture was evaporated. The dry powder was placed on a silica gel column (5.5×28 cm) and the column was flash eluted with progressively increasing concentrations of MEOH in CH2Cl2 (%MeOH, vol in L): (0, 1), (1, 1), (2, 1), (3, 2), (5, 2), (10, 2). The eluate containing the product was evaporated and the solid residue was dried in vacuum for 16 h. The light yellow solid was stirred with 2-PrOH (20 mL) to obtain a white solid. The solid was collected and dried in vacuum at 80° C. for 16 h: 0.35 g (0.935 mmol, 34%), mp 186-188° C. Ir (KBr): ν3390, 3310 and 3210 (NH, NH2), 1685 (C=O), and 1660 broad (C=O, C=N, C=C) cm-1. Uv λmax (nm) (ε×10-3): pH 1,302 (10.0), 250 (8.92), 220 (31.2); MEOH, 302 (9.60), 250 (8.79), 220 (29.1); pH 11, 292 (7.94), 248 (8.07), 224 (9.88). 1H nmr (DMSO-d6): δ1.23 (t, 6H, 2 CH3), 2.84 (dd, 2H, PCH2), 3.99 (q, 4H, OCH2), 4.40 (br s, 2H, NCH2), 5.55-5.63 (m,2H, 2 CH), 6.93 (br s, 2H, NH2), and 11.14 (br s, 1H, NH). Anal. Calc'd for C13H19N4O5PS (374.35): C, 41.71; H, 5.11; N, 14.97; P, 8.27. Found: C, 41.55; H, 5.02; N, 14.64; P, 8.00.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].[H-].[Na+].Br[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]>CN(C)C=O>[O:12]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][N:6]1[CH2:5][C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][CH:13]=1)[O:1][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]
Reactant: O=C1CCCCN1Cc1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCCN1Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
In an argon stream with ice cooling, a solution of 2.3 g of the 1-(3-hydroxybenzyl)-2-piperidone obtained in Reference Example 2 in 10 ml of N,N-dimethylformamide was added dropwise to a soltuion of 0.44 g of 60% sodium hydride in 5 ml of N,N-dimethylformamide. Subsequently, a solution of 2.8 g of N-(3-bromopropyl)phthalimide in 10 ml of N,N-dimethylformamide was added dropwise to the mixture at room temperature, followed by stirring at 65° C. for 8 hours. The resulting mixture was cooled, ice-cold water was thereafter added thereto, the mixture was subjected to extraction with diethyl ether, 6N hydrochloric acid was then added to the organic layer for extraction into the aqueous layer, and the aqueous layer was made alkaline with sodium hydroxide, followed by extraction with diethyl ether again. The organic layer was dried over magnesium sulfate and thereafter distilled to remove the solvent, giving N-[3-[3-(2-oxopiperidinomethyl)-phenoxy]propyl]phthalimide. This compound was hydrolyzed with hydrazine in the same manner as in Example 1, (ii) to afford 1.4 g of 3-[3-(2-oxopiperidinomethyl)phenoxy]propylamine (yield 51% ).