Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=C)[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:53].[Na+].CC(=O)OCC>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=[O:53])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1c(ccc(F)c1F)O[C@@H](C)CCCCOC1(C)CCN2CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-16,17-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (0.15 g, 0.214 mmol, 1.0 equiv) was dissolved in dioxane (6.41 mL) and water (2.14 mL). To this solution was added sodium periodate (0.16 g, 0.748 mmol, 3.5 equiv) and 4% osmium tetroxide (0.136 g, 0.021 mmol, 0.1 equiv). The mixture was stirred at r.t. for 2 hours. Then it was diluted by EA, washed by water, dried over MgSO4, concentrated to load onto 12 g ISCO column and purified with 0-100% EtOAc[2% TEA]/Hexane to afford the product (0.14 g, 93%). 1H NMR (400 MHz, CDCl3) δ 11.23 (s, 1H), 8.28 (d, J=7.8 Hz, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.10 (d, J=9.3 Hz, 1H), 6.72-6.65 (m, 1H), 6.19-5.95 (m, 1H), 4.53-4.43 (m, 1H), 4.05-3.93 (m, 1H), 3.80-3.74 (m, 1H), 3.71 (s, 3H), 3.50 (d, J=16.1 Hz, 2H), 3.21-3.13 (m, 1H), 2.77 (s, 3H), 2.74-2.66 (m, 1H), 1.96 (d, J=13.6 Hz, 2H), 1.86-1.69 (m, 8H), 1.29 (s, 3H), 1.25 (s, 9H), 1.13 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 704.25.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=3)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>ClCCl>[C:29]1([C:16]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:10][CH:11]=3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=3)[N:17]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(N)cc3)nc2c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(NS(=O)(=O)C(C)C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Propane-2-sulfonyl chloride (300 mg, 2.10 mmol, 5.00 equiv) was added to a solution of methyl 3-(4-aminophenyl)-2-phenylquinoxaline-6-carboxylate (150 mg, 0.42 mmol, 1.00 equiv) and DIEA (545 mg, 4.22 mmol, 10.00 equiv) in dichloromethane (30 mL) at 0° C., and the resulting solution was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate/petroleum ether (1:10)), affording 170 mg (87%) of methyl 2-phenyl-3-(4-(propan-2-ylsulfonamido)phenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=1>CN(C=O)C>[CH2:1]([N:24]1[CH2:23][CH2:22][CH:21]([N:19]2[CH:20]=[C:16]([Br:15])[CH:17]=[N:18]2)[CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnn(C2CCNCC2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Benzyl bromide (0.42 mL, 3.56 mmol) and potassium carbonate (670 mg, 4.85 mmol) were added to a solution of 4-(4-bromo-1H-pyrazol-1-yl)piperidine (743.7 mg, 3.23 mmol) in DMF (10 mL), and the reaction stirred at room temperature overnight. The reaction was quenched with the addition of water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were combined and washed with water (2×50 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified directly via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford 1-benzyl-4-(4-bromo-1H-pyrazol-1-yl)piperidine (673 mg, 65%) as a light yellow oil. MS (ESI, pos. ion) m/z 321 [M+H]+.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][CH:4]=1.Cl>CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=C(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
Magnesium metal (1.23 g, 51.0 mmol) was added in three portions over approximately 0.3 h to a stirred solution of the product of step D (1.85 g, 5.1 mmol) in methanol (40 mL) at ambient temperature. After stirring overnight, the reaction mixture was poured into 1 N hydrochloric acid (100 mL) and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–25% ethyl acetate/hexanes as eluent) provided the title compound (mixture of cis/trans diastereoisomers) as a colorless oil (1.5 g).
Reaction SMILES: [C:1]([S:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:18][CH:17]=1.[Cl-].[Na+]>COCCOC.C(O)(=O)C.O>[C:1]([S:5][C:6](=[O:11])[CH:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:20][CH:21]=1)[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)SC(C)(C)C
Temperature: 15 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
A solution of 3-oxothiobutyric acid S-tert-butyl ester (3.7 g) in 1,2-dimethoxyethane (5.0 mL) was added to a stirred suspension of sodium hydride (60% in oil, 0.92 g) in 1,2-dimethoxyethane (25 mL) at −10° C., and the resulting mixture was warmed to 15° C. over 15 minutes, cooled to −10° C. and then treated dropwise with a mixture of 1-(4-bromomethylphenyl)-1H-pyrazole (5.0 g) in 1,2-dimethoxyethane (20 mL) over a period of 30 minutes. The resulting mixture was warmed to room temperature and then stirred at this temperature for overnight. The mixture was diluted water, pH adjusted to 5 by the addition of glacial acetic acid and then saturated with sodium chloride. The mixture was extracted ethyl acetate and the combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue purified by column chromatography on silica gel, eluting with a mixture of pentane, dichloromethane and ethyl acetate (1:3:0, 0:1:0 to 0:10:1 by volume) gave title compound as a colourless gum (0.6 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Br)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH3:10]
Reactant: Oc1ccccc1I
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1I
Yield: 63.7 %

Procedure:
Under the conditions of example 2A, 25 g of 2-iodophenol and 22.16 g of 4-bromobutyric acid ethyl ester are reacted in 100 ml of dimethylformamide in the presence of 74 g of cesium carbonate, worked up, and 24.2 g of 4-(2-iodophenoxy)butyric acid ethyl ester with a boiling point of 200° C./0.02 mbar is obtained as a colorless oil.
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2[N:17]=[C:18]([C:26]3[CH:27]=[C:28]([CH2:32][OH:33])[CH:29]=[CH:30][CH:31]=3)[N:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[C:20]=23)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>N.CC(O)C>[NH2:1][C:21]1[C:20]2[N:19]([C:18]([C:26]3[CH:27]=[C:28]([CH2:32][OH:33])[CH:29]=[CH:30][CH:31]=3)=[N:17][C:16]=2[C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:11]=2)[CH:24]=[CH:23][N:22]=1
Reactant: N
Reactant: OCc1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)c1
Solvent: CC(C)O
Product: Nc1nccn2c(-c3cccc(CO)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 110 °C
Yield: 89 %

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of {3-[1-(3-benzyloxyphenyl)-8-chloroimidazo[1,5-a]pyrazin-3-yl]-phenyl}-methanol (366 mg, 0.829 mmol) in NH3/i-PrOH (2M, 5 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 19 h. After excess NH3/i-PrOH was removed in vacuo, the residue was suspended between CH2Cl2 and water, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous MgSO4, and filtered. The crude material was purified by filtration through a plug of silica gel, eluting with 5% MeOH:CH2Cl2 (400 mL), concentrated in vacuo, giving 311.5 mg (89%, 0.737 mmol) of the title compound, as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 4.80 (s, 2H), 5.09 (s, —NH2), 5.16 (s, 2H), 7.05-7.09 (m, 1H), 7.11 (d, J=4.8 Hz, 1H), 7.29-7.37 (m, 3H), 7.37-7.48 (m, 5H), 7.47-7.51 (m, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.73-7.78 (m, 1H), 7.86 (s, 1H); MS (ES+): m/z 423.0 (100) [MH+].
Reaction SMILES: ClC(OC1C=CC=CC=1)=O.[F:11][C:12]([F:22])([F:21])[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.N1(CCC2C=CC(N3CCC(N[C:43]([N:45]4[CH2:50][CH2:49][C:48](=[CH:51][C:52]5[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=5[F:59])[CH2:47][CH2:46]4)=[O:44])CC3)=CC=2)C=CN=N1.CCN(CC)CC>C(#N)C.CC(N(C)C)=O.O>[F:59][C:53]1[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:52]=1[CH:51]=[C:48]1[CH2:49][CH2:50][N:45]([C:43]([NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:12]([F:11])([F:21])[F:22])[CH2:15][CH2:16]2)=[O:44])[CH2:46][CH2:47]1
Reactant: O=C(NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1)N1CCC(=Cc2cc(F)ccc2F)CC1
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: O=C(NC1CCN(CC(F)(F)F)CC1)N1CCC(=Cc2cc(F)ccc2F)CC1
Reaction time: 1 h
Yield: 16.8 %

Procedure:
Phenyl chloroformate (200 μL, 1.57 mmol) was added dropwise to 1-(2,2,2-trifluoroethyl)piperidin-4-amine (400 mg, 1.57 mmol) dissolved in a mixed solvent of acetonitrile (3 mL) and dimethylacetamide (1 mL) at 0° C., followed by stirring at the same temperature for 1 hour, and 4-(2,5-difluorobenzylidene)piperidine hydrochloride (580 mg, 2.36 mmol) obtained in Example 34 (1) and Et3N (430 μL) were added thereto, followed by stirring at 60° C. overnight. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:50), thereby giving the title compound (110 mg, 17%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:38][CH2:39][CH3:40])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:33]([O:35]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:42][NH2:43]>CO>[CH2:1]([O:3][CH:4]([O:38][CH2:39][CH3:40])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:42][NH:43][C:33](=[O:35])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:28]([CH3:30])[CH3:29])=[O:31])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(=O)N(C)C)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Ethyl 2-(4-(diethoxymethyl)phenyl)-3-(4-(dimethylcarbamoyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, 0.46 mmol) and hydrazine monohydrate (85%, 5 mL) were added in MeOH (15 mL) and the mixture was stirred room temperature for 5 h. The resulting mixture was concentrated under reduced pressure to a volume of 15 mL and then filtered; the filtrate was evaporated to give the title compound as a white solid (180 mg, yield 76%). LC-MS (ESI) m/z: 513 (M+1)+.
Reaction SMILES: [OH-].[Li+].[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][C:12]=2[C:24]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1.O>[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][C:12]=2[C:24]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 8 h

Procedure:
Lithium hydroxide (9.24 mg, 0.39 mmol) was added to a solution of ethyl 3-{4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}propanoate (may be prepared as described in Example 87; 52 mg, 0.13 mmol) in tetrahydrofuran (2 ml) and water (0.5 ml) and the mixture was stirred overnight. The reaction mixture was purified by MDAP to yield the title compound as a golden solid. 62 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(C)cc1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)Oc1ccc(CBr)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
17 gm (0.08 mol) of ethyl 2-(4-methyl-phenoxy) -propionate and 0.2 gm of 2,2'-azo-bis-(2-methyl-propionitrile) were dissolved in 100 ml of chloroform, and the solution was heated to its boiling point. One-half of a solution of 5.4 ml of bromine in 20 ml of chloroform was then added to the boiling solution over a period of 45 minutes. The reaction mixture was now cooled to about 40° C., an additional 0.2 gm of the catalyst was added, the mixture was again heated to its boiling point, and the other half of the chloroformic bromine solution was added. The mixture was kept boiling for two hours more and was then cooled to room temperature. The resulting reddish-brown solution was extracted three times with 100 ml each of a saturated aqueous sodium bicarbonate solution, the combined aqueous extracts were extracted twice with 50 ml each of methylene chloride, and the combined organic extracts were dried over sodium sulfate. The methylene chloride was now distilled off in a water aspirator vacuum, and the liquid evaporation residue was fractionally distilled in an oil pump vacuum, yielding 70% of theory of ethyl 2-(4-bromomethyl-phenoxy)-propionate, b.p. 128°-134° C. at 0.2 mm Hg.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[O:19]1[C:20]2[C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([OH:5])([C:7]([F:8])([F:10])[F:9])[CH2:6][NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[N:25][N:26]4[C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: CCOC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Product: CCOC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cccc5c4OCC5)C(F)(F)F)cccc32)c1

Procedure:
Prepared similarly to Example 1 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and ethyl 3-(4-amino-1H-indazol-1-yl)benzoate (Intermediate 6).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=3[O-:9])[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13]
Reactant: CCOc1ccc(-c2nc(-c3ccccn3)cs2)cc1OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(-c2nc(-c3cccc[n+]3[O-])cs2)cc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of 38.5 g of metachloroperbenzoic acid (80%) dissolved in 400 ml of methylene chloride was dropwise added, with ice cooling, to a solution of 49.6 g of 2-(3,4-diethoxyphenyl)-4-(2-pyridyl)thiazole dissolved in 250 ml of methylene chloride. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution, followed by separation of layers. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was recrystallized from ethyl acetate to obtain 45.2 g of 2-[2-(3,4-diethoxyphenyl)-4-thiazolyl]pyridine-1-oxide.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[NH2:15][C:14]1[N:1]([C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=2)[N:2]=[C:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[CH:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1cc[nH]c(=O)c1
Product: CC(C)(C)c1cc(N)n(-c2cc[nH]c(=O)c2)n1
Yield: 33 %

Procedure:
Following the procedure for Example 282A Step 1, 4-hydrazinylpyridin-2(1H)-one was heated at 80° C. overnight with 4,4-dimethyl-3-oxopentanenitrile. The reaction mixture was concentrated, triturated with DCM, and purified using silica gel chromatography eluting with a MeOH/DCM gradient (2-10%) to afford 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (307 mg, 33% yield). 1H NMR (300 MHz, DMSO d6) δ 1.18 (s, 9H), 5.43 (s, 1H), 5.47 (s, 2H), 6.55 (s, 1H), 6.66 (m, 1H), 7.37 (d, 1H), 11.40 (s, 1H); LC-MS (ESI) m/z 233 (M+H)+
Reaction SMILES: [O:1]([C:8]1[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[O:1]([C:8]1[S:12][C:11]([CH2:13][NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Oc2ccccc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 89.9 %

Procedure:
To a solution of 5-phenoxythiophene-2-carbonitrile described in Preparation Example 25 (1.4 g, 7.0 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (1.1 g, 28 mmol), and the solution was stirred at room temperature for 25 minutes. Water and ethyl acetate were added to the reaction solution, this mixed solution was filtered through Celite pad, furthermore, the organic layer was partitioned. The solvent was evaporated in vacuo, and the title compound (1.29 g, 6.3 mmol, 89.9%) was obtained as a brown oil.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][CH2:4][CH3:5].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: CCC=CCBr
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC=CCn1ccnc1

Procedure:
Pent-2-enyl bromide (18.5 g) was added dropwise to a stirred refluxing mixture of imidazole (10 g) and sodium bicarbonate (12.4 g) in methanol (50 ml). After addition was complete, the mixture was stirred under reflux for a further 24 hours. The mixture was filtered to remove unsoluble material and the filtrate evaporated to remove solvent. Residue taken in 2N-HCl (150 ml) and washed with ether (50 ml). The aqueous layer was basified with 10N NaOH and extracted with chloroform (3×50 ml). Combined extracts dried over anhydrous MgSO4 and chloroform removed under vacuum to leave crude product which was purified on silica gel column (EtOAc/MeOH 9:1 was used as eluent). Product fractions were collected; total weight 4.9 g. 1.0 g was distilled under vacuum; yield 1.08 g. B.p. 134° C./15 mmHg. Micro analysis: C8H12N2 requires C,70.59; H,8.82; N,20.59. Found: C,69.72, H,8.88; N,20.43.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:28]2[CH2:30][CH2:29]2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH:28]1([C:27]2[CH:26]=[C:25]3[C:16]([N:17]4[C:22]([CH2:23][O:24]3)=[N:21][NH:20][C:19](=[O:31])[CH:18]4[CH3:32])=[CH:15][C:14]=2[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:29][CH2:30]1
Reactant: CC1C(=O)NN=C2COc3cc(C4CC4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(C4CCNCC4)cc3N21
Yield: 87 %

Procedure:
A solution of 4-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.030 g, 0.068 mmol) in DCM (6 mL) and trifluoroacetic acid (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 7-cyclopropyl-4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (0.0275 g, 87%). LC/MS (Table 1, Method 5) Rt=2.041 min.; MS m/z: 341 [M+H]+.