Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=O)[C:17]([CH3:23])([CH3:22])[C:18](OC)=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.O.[NH2:26][NH2:27]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[C:17]([CH3:23])([CH3:22])[C:18](=[O:19])[NH:26][N:27]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: O
Product: CC1(C)C(=O)NN=C1c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for the example C1 using methyl 3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2,2-dimethyl-3-oxopropanoate (compound D3) and hydrazine hydrate as starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH:40]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:31])=[CH:25][C:24]=2[O:38][CH3:39])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[C:42](=O)([O-])[O-].CI>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([CH:40]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N:29]([CH3:42])[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:31])=[CH:25][C:24]=2[O:38][CH3:39])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COc1cc(NC(=O)c2ccncc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cc(N(C)C(=O)c2ccncc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-[2-methoxy-4-(pyridin-4-ylcarbonylamino)phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 14-21, 13.9 mg, 0.0251 mmol), cessium carbonate (41.7 mg, 0.128 mmol), and methyl iodide (4.7 μL, 0.075 mmol) was suspended in anhydrous N,N-dimethylformamide (0.5 ml) and stirred for 3 hours at room temperature. The mixture was diluted with ethyl acetate (10 mL). The mixture was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (4.6 mg) as a yellow amorphous product. (Yield 32%)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.CON(C)[C:15](=[O:17])[CH3:16]>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: Clc1ccsc1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1sccc1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
To a solution of 3-chlorothiophene (4.80 g, 40.48 mmol) in THF (50 mL) was added BuLi (2.5N in hexane, 17.9 mL) at −30° C. After addition, the mixture was stirred for 30 min at −10° C., and then cooled to −45° C. N-methoxy-N-methyl acetamide (55.0 g, 48.8 mmol) was added and allowed to warm to room temperature during 40 min and maintained for an additional 20 min. Brine (80 mL) was added to quench the reaction, extracted with EA (60 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to afford 24-1 (˜80% pure) as a yellow oil (6.80 g) which used for the next step directly.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C@:6]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:41])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.[O:48](C(OC(C)(C)C)=O)[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:52]([O:51][C:49]([N:4]([CH2:5][C@:6]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:41])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH2:3][CH2:2][OH:1])=[O:48])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCO)C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (600 mg, 0.932 mmol) was dissolved in CH2Cl2 (10 mL), BOC2O (0.260 mL, 1.118 mmol) was added followed by Hunig's Base (0.163 mL, 0.932 mmol) to form a colorless solution that was stirred at 0° C. for 6 hrs. LCMS indicated formation of desired product (M+23=767). The solvent was removed in vacuo and the resultant white solid was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Cl:1])[CH:9]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)NCc2ccccc2)cc1-c1c(Cl)cnn1C
Yield: 46.1 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (59 mg, 0.25 mmol) was treated with benzyl isocyanate (34 μL, 0.28 mmol) in a similar manner to Example 1.53, providing 42.7 mg (46.1%) of Compound 105: LCMS m/z (%)=371 (M+H35Cl, 100), 373 (M+H37Cl, 40). 1H NMR (400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 7.58 (s, 1H), 7.50 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.33 (m, 5H), 7.30 (d, J=4 Hz, 1H), 7.10 (d, J=12 Hz, 1H), 6.58 (s, 1H), 4.28 (s, 2H), 3.73 (s, 3H), 3.58 (s, 3H).
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[C:6]1([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][C:16]=2[CH:23]=[O:24])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2csc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1sc2ccccc2c1-c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (62.5 ml of 1.6M solution in hexane, 0.1 mole) was added dropwise to a stirred solution of 3-phenylbenzo[b]thiophene (21.0 g, 0.1 mole) in tetrahydrofuran (150 ml) at -70° C. The solution was stirred at -70° C. for 30 minutes and dimethylformamide (10 ml, 0.13 mole) was added. The resulting mixture was stirred at -70° C. for 30 minutes and then allowed to warm to ambient temperature. After a further hour the reaction was quenched by the addition of dilute hydrochloric acid (100 ml, 2M) and the tetrahydrofuran removed under reduced pressure. The resulting oil was extracted into diethyl ether, the ethereal extract washed with water, dried over potassium carbonate and concentrated.
Reaction SMILES: Cl.[CH2:2]([C:4]1([CH2:36][CH3:37])[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][C:13]([NH:16][CH2:17][C@@H:18]([C:20]2[CH:21]=[CH:22][C:23]([OH:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=2)[OH:19])([CH3:15])[CH3:14])[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]1=2)[CH3:3].CC(C)=O>CO>[CH2:36]([C:4]1([CH2:2][CH3:3])[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][C:13]([NH:16][CH2:17][CH:18]([C:20]2[CH:21]=[CH:22][C:23]([OH:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=2)[OH:19])([CH3:14])[CH3:15])[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]1=2)[CH3:37]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NC[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(O)c(NS(C)(=O)=O)c2)c2ccccc21

Procedure:
The (R)- and (S)-enantiomers of this embodiment may be obtained by common methods known in the art. Particular importance attaches to the (R)-enantiomer of this embodiment according to the invention. The angle of rotation of (R)- N-(5-{2-[3-(4,4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide hydrochloride (cocrystallised with a molecule of acetone) is −28.8° (c=1%, in methanol at 20° C.).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[C:25]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[N:26]1([C:25]2[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)=[N:21][CH:22]=[CH:23][N:24]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1nccnc1N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: c1cnc(N2CCCC2)c(-c2cnc3[nH]ccc3c2)n1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.2048 mmol, 1 eq) and 2-chloro-3-(pyrrolidin-1-yl)pyrazine (72) (33 mg, 0.184 mmol, 1 eq) in DME (8 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.409 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(3-(pyrrolidin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 128 in 10 mg quantity. The compound 128 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.50 (s, 1H), 8.58 (d, J=1.95, 1H), 8.15 (d, J=1.58, 1H), 8.04 (m, J=2.56, 2H), 7.38 (m, J=3.45, 1H), 6.56 (m, J=1.58, 1H), 3.18 (m, J=6.70, 1H), 1.81 (m, J=2.92, 4H; MS m/z 265.9 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC=C)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O[C:19]1[CH:24]=CC(C(C)C([O-])=O)=C[CH:20]=1.C(OC1C=CC(CCC(OCC)=O)=CC=1)C=C.C(C1C=C(CCC(OCC)=O)C=CC=1O)C=C>>[CH3:1][CH:2]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([CH2:24][CH:19]=[CH2:20])[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC(C(=O)[O-])c1ccc(O)cc1
Reactant: C=CCOc1ccc(CC(C)C(=O)OC)cc1
Agent: C=CCOc1ccc(CCC(=O)OCC)cc1
Agent: C=CCc1cc(CCC(=O)OCC)ccc1O
Product: C=CCc1cc(CC(C)C(=O)OC)ccc1O

Procedure:
Methyl 2-methyl-3-(4-allyloxyphenyl)propionate m/z 235(M+H) was prepared from methyl 2-methyl-3-(4-hydroxyphenylpropionate using the method described in Example 1 for the preparation of ethyl 3-(4-allyloxyphenyl)propionate. Methyl 2-methyl-3-(3-allyl-4-hydroxyphenyl)propionate was prepared from methyl 2-methyl-3-(4-allyloxyphenyl)propionate using the method described in Example 1 for the preparation of ethyl 3-(3-allyl-4-hydroxyphenyl)propionate. The product was isolated as an orange oil; NMR(CDCl3): 1.13(3H,d), 2.40-2.73(2H,m), 2.92(1H,q), 3.37(2H,d), 3.63(3H,s), 4.91(1H,s), 5.03-5.18(2H,m), 5.89-6.10(1H,m), 6.70(1H,m) and 6.91(2H,m); m/z 235(M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[C:9]([O:13][C:14]([N:16]([CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH3:17])=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:20]1[CH2:21][CH2:22][CH:18]([N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH3:17])[CH2:19]1
Reactant: Brc1ccccc1Br
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccccc2Br)C1

Procedure:
The title compound was prepared from dibromobenzene and 3-(N-t-butyloxycarbonyl-N-methylamino)pyrrolidine as for Example 110 (a).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([O:17][C:7](=[O:8])[C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 23.19 g (0.15 mol) of m-toluoyl chloride in 70 mL of methylene chloride was added dropwise to a solution containing 14.12 g (0.15 mol) of phenol and 16.7 g (0.165 mol) of triethylamine in 70 mL of methylene chloride at ice bath temperature. A precipitate formed upon addition. The reaction mixture was stirred overnight at room temperature and was then filtered. The filtrate was washed successively by water (100 mL) and then by brine (75 mL) The organic layer was removed and dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. The clear liquid product amounted to 29.91 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=[O:14])=[CH:4][C:3]=1[F:18].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][OH:14])=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of ethyl 5-(4-chloro-3-fluorophenyl)isoxazole-4-carboxylate (12.00 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 100 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-chloro-3-fluorophenyl)-4-isoxazolylmethanol (9.73 g, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 87–88° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][CH:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@@H:11]([CH2:19][OH:20])[O:10]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[CH3:7][O:8][CH:9]1[C@@H:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]2[C@H:11]([CH:19]=[O:20])[O:10]1
Reactant: COC1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Agent: [Cr+3]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1O[C@@H](C=O)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
By using the literature known procedure (Barrett, A. G. M.; Lebold, S. A., J. Org. Chem., 1990, 55, 3853), to a solution of dry pyridine (48.5 ml) in anhydrous methylene chloride (700 ml) was added chromium oxide (30 g, 0.3 mole) portionwise under nitrogen. During this procedure the reaction mixture was kept at room temperature by occasional cooling with an ice-water bath. To this dark red solution was added a solution of [(3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (5 g, 24.48 mmole, obtained from Reference Example 35) in methylene chloride (100 ml) under nitrogen. The resulting mixture was stirred at room temperature for 30 min, and poured into a cold aqueous solution of saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined extracts were washed well with saturated sodium chloride solution until the color of the organic layer turned yellow, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in benzene, and the solvent was removed in vacuo. This procedure was repeated several more times, to give [(3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde (2.8 g, 56.6%) as a yellow amorphous solid. The aldehyde was dissolved in benzene and stored in the freezer under argon.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1.C(OC(=O)N[C@H](C)C(N(OC)C)=O)(C)(C)C.COC1C=CC(Br)=CC=1>>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[C:9]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Fc1cc(F)cc(Br)c1
Agent: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: COc1ccc(Br)cc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1cc(F)cc(F)c1

Procedure:
With the exception that (S)-t-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate and 1-bromo-3,5-difluorobenzene were used instead of (R)-t-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate and 4-methoxybromobenzene, respectively, the same procedure as in Preparation Example 5-5 was repeated to afford the title compound. 1.3 g (46%).
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C([C:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[CH:23][CH:22]=1)(=O)N.C[N:31](C)[CH:32]=[O:33]>>[C:26]12[C:21](=[CH:22][CH:23]=[N:24][CH:25]=1)[NH:31][C:32](=[O:33])[O:29][C:27]2=[O:28]
Reactant: NC(=O)c1ccncc1C(=O)O
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=c1[nH]c2ccncc2c(=O)o1
Reaction time: 0.17 h

Procedure:
A 50 ml. flask was charged with 2.6 g. lead tetra-acetate suspended in 10 ml. dimethylformamide and stirred while a solution of 0.96 g. of 4-carbamylnicotinic acid in 5 ml. dimethylformamide was added dropwise during 10 minutes. The mixture was stirred for 10 minutes after completion of the addition, then poured onto 40 g. crushed ice. A precipitate of cream solids was collected by filtration, washed with water and dried in vacuo. The yield of 5-azaisatoic anhydride amounted to 0.68 g., melting point 180° with decomposition, and represented 72 percent of theory. On attempted purification by crystallization from organic solvents, extensive decomposition occurred. The structure was confirmed by elemental analysis, infra-red spectroscopy and mass spectrometry.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:17])[CH2:7][C:8]([CH3:16])([CH2:13][CH2:14][CH3:15])[O:9]2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:17])[CH2:7][C:8]([CH3:16])([CH2:13][CH2:14][CH3:15])[O:9]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC1(C)CC(=O)c2ccc(O)c(C)c2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC1(C)CC(=O)c2ccc(OCc3ccccc3)c(C)c2O1
Yield: 91 %

Procedure:
The mixture of 11.7 g. of the compound obtained in (1), 11.1 g. of benzyl bromide, 10.2 g. of potassium carbonate, and 100 ml of acetone was refluxed for 2 hours, followed by filtration. The filtrate was concentrated. Ether was added to the concentrate. The ether solution was washed successively with water, 1 N aqueous solution of sodium hydroxide, and again with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to column chromatography filled with silica gel, to obtain 11.5 g. (yield: 91.0%) of the subject compound. Melting point: 45° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[C:17]1[NH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:21]=1.[Br:26]Br.CC(C)=O.CCCCCC>O.C(Cl)(Cl)Cl>[Br:26][C:20]1[N:21]=[C:17]([C:8]2[C:9]([F:16])=[C:10]([F:15])[C:11]([F:14])=[C:12]([F:13])[C:7]=2[F:6])[NH:18][C:19]=1[C:22]([F:25])([F:24])[F:23]
Reactant: Fc1c(F)c(F)c(-c2ncc(C(F)(F)F)[nH]2)c(F)c1F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1c(F)c(F)c(-c2nc(Br)c(C(F)(F)F)[nH]2)c(F)c1F

Procedure:
Sodium bicarbonate is made into a paste by adding a few drops of water to 1.5 g (9.4 mol). The 2-(2,3,4,5,6-pentafluorophenyl)-5-trifluoromethylimidazole is dissolved in 100 ml chloroform and added to the flask containing the paste. 1.5 g of bromine is added and stirred. TLC on alumina using 50:50 acetone-hexane clearly differentiates starting material from product. Additional bromine is added until starting material is no longer present (0.1 g). Water is added and the organic phase removed. The layer is washed with sodium bisulfite, brine and dried over sodium sulfate. The organic phase is stripped and the residue taken up in 1:1 ether hexane and filtered through silica gel.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH:21][C@@H](C3C=CC=CC=3)C)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1>[OH-].[Pd+2].[OH-].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@@H:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[NH2:21])=[O:14])[CH2:8]2)=[CH:30][CH:31]=1
Reactant: C[C@@H](N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H]1COCC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Reaction time: 20 h
Yield: 96.4 %

Procedure:
[(S)-3-(4-Fluoro-benzyl)-piperidin-1-yl]-[(3S,4R)-3-((R)-1-phenyl-ethylamino)-tetrahydro-pyran-4-yl]-methanone (1.10 g, 2.6 mmol), palladium hydroxide (20 weight % on carbon, dry basis; 440 mg) and ethanol (40 mL) were combined in a pressure bottle and shaken under a hydrogen atmosphere (55-60 psig) for 20 h . The mixture was filtered through Celite, and the solids were washed thoroughly with ethanol. The filtrate was concentrated to give the product as a glassy foam (803 mg, 96%), used without further purification. 1H NMR (300 mHz, CD3OD) δ7.22 (m, 2H), 7.04 (m, 2H), 4.50 and 4.30 (2m, 1H), 4.1-3.6 (3H), 3.5-3.4 (2H), 3.3-2.9 (2H), 2.8-2.4 (4H), 2.0-1.2 (7H), ESI MS: (M+H)+=321.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC=CC=1>[F:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:6]2[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=[C:2]([NH:1][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])[N:7]=2)=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Solvent: c1ccccc1
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(NC(=O)Nc2ccccc2)n1
Yield: 12.3 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (288.3 mg) was dissolved in benzene (50 mL) and phenyl isocyanate (119.1 mg) was added. The reaction mixture was heated to reflux for 48 hours, and the solvent was removed under vacuum. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate, to yield 1-[4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidin-2-yl]-3-phenylurea (49.1 mg), m.p. 117-178° C.